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Critical Reviews in Food Science and Nutrition
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Beneficial effects of fish and fish peptides on
main metabolic syndrome associated risk factors:
Diabetes, obesity and lipemia
Soheila Abachi, Geneviève Pilon, André Marette, Laurent Bazinet & Lucie
Beaulieu
To cite this article: Soheila Abachi, Geneviève Pilon, André Marette, Laurent Bazinet & Lucie
Beaulieu (2022): Beneficial effects of fish and fish peptides on main metabolic syndrome associated
risk factors: Diabetes, obesity and lipemia, Critical Reviews in Food Science and Nutrition, DOI:
10.1080/10408398.2022.2052261
To link to this article: https://doi.org/10.1080/10408398.2022.2052261
Published online: 17 Mar 2022.
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REVIEW
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
Beneficial effects of fish and fish peptides on main metabolic syndrome
associated risk factors: Diabetes, obesity and lipemia
Soheila Abachia,b, Geneviève Pilona,c, André Marettea,c, Laurent Bazineta,b,d and Lucie Beaulieua,b
aInstitute of Nutrition and Functional Foods (INAF), Université Laval, Quebec, Quebec, Canada; bDepartment of Food Science, Faculty of
Agricultural and Food Sciences, Université Laval, Quebec, Quebec, Canada; cDepartment of Medicine, Faculty of Medicine, Cardiology Axis of
the Quebec Heart and Lung Institute, Quebec, Quebec, Canada; dLaboratory of Food Processing and ElectroMembrane Processes (LTAPEM),
Université Laval, Quebec, Quebec, Canada
ABSTRACT
The definition of metabolic syndrome (MetS) fairly varies from one to another guideline and health
organization. Per description of world health organization, occurrence of hyperinsulinemia or
hyperglycemia in addition to two or more factors of dyslipidemia, hypoalphalipoproteinemia,
hypertension and or large waist circumference factors would be defined as MetS. Conventional
therapies and drugs, commonly with adverse effects, are used to treat these conditions and
diseases. Nonetheless, in the recent decades scientific community has focused on the discovery
of natural compounds to diminish the side effects of these medications. Among many available
bioactives, biologically active peptides have notable beneficial effects on the management of
diabetes, obesity, hypercholesterolemia, and hypertension. Marine inclusive of fish peptides have
exerted significant bioactivities in different experimental in-vitro, in-vivo and clinical settings. This
review exclusively focuses on studies from the recent decade investigating hypoglycemic,
hypolipidemic, hypercholesterolemic and anti-obesogenic fish and fish peptides. Related extraction,
isolation, and purification methodologies of anti-MetS fish biopeptides are reviewed herein for
comparison purposes only. Moreover, performance of biopeptides in simulated gastrointestinal
environment and structure-activity relationship along with absorption, distribution, metabolism,
and excretion properties of selected oligopeptides have been discussed, in brief, to broaden the
knowledge of readers on the design and discovery trends of anti-MetS compounds.
Introduction
Metabolic syndrome (MetS) instigated physiological, bio-
chemical, clinical, and metabolic abnormalities could seri-
ously debilitate the affected individual and contribute to
an upsurge of global mortality rates. MetS, as a cluster of
cardiometabolic risk factors, is strongly associated with
increasing predominance of various chronic conditions like
arthritis, schizophrenia including atherosclerotic cardiovas-
cular disease and cancer. According to a survey, prevalence
of MetS took a sharp leap from 1988 to 2012 among adults,
≥ 18 years of age, totaling one in three of the entire US
population. Two-thirds of US population are overweight
and or obese thus obesity, according to Yang et al., is at
epidemic proportions which should directly be confronted
to prevent MetS outbreak (Moore, Chaudhary, and
Akinyemiju 2017). Obesity, also heritable, is strongly asso-
ciated with increased morbidity and mortality. Cardiac
fatality is 40-times more likely to occur in the obese rather
than the non-obese population (Messerli et al. 1987).
Widely applied criteria, set by different organizations, for
the diagnosis of a syndrome has been detailed out in
supplementary Table 1 (Parikh and Mohan 2012). High fat
high sugar hypercaloric diets (cholesterol and animal fat
plus naturally occurring sugars sucrose and/or fructose)
over time lead to the development of chronic pathologies
like hyperlipidemia, hypercholesterolemia, hyperinsulin-
emia, hyperglycemia, and excess weight causing diabetes,
obesity, hypertension and atherosclerosis in humans and
experimental animal models (Khaled et al. 2012; Nasri
et al. 2018). These diseases are conventionally treated by
various classes of drugs however often adverse and side
effects as well as patient noncompliance and cost issues
impede the treatment.
Evidently, nutrition and natural bioactives may be more
than just food thus offering beneficial health effects upon
intake to the consumer in addition to daily essential nutri-
ents. Once turned down by drug developers, therapeutic
peptides now are ideal candidates for new drug discoveries
(Uhlig et al. 2014). Throughout decades reports have been
compiled about the bioactivities of marine-extracted chem-
icals specifically biopeptides on communicable and
non-communicable diseases. Additionally, in recent years
more attention has been given to anti-MetS phytochemicals,
© 2022 Taylor & Francis Group, LLC
CONTACT Lucie Beaulieu lucie.beaulieu@fsaa.ulaval.ca
Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2022.2052261.
https://doi.org/10.1080/10408398.2022.2052261
KEYWORDS
cardiovascular diseases;
diabetes; sh peptides; metabolic
syndrome; obesity
2 S. ABACHI ETAL.
Table 1. Bioactivities of free amino acids on MetS and associated risk factors.
Amino acid supplement (single or
mixture) Major eect(s) Aected disease (reference)
Diabetes, its risk factors, and associated complications
Aspartate and asparagine ↑ insulin sensitivity,
↓ in-vitro glucose uptake by muscle at maximal insulin
concentrations, glucose transport at higher glycogen levels in
rat muscle
(Lancha, Poortmans, and Pereira 2009)
L-alanine and or L-arginine ↓ perigonadal and retroperitoneal fat pads,
↑ fed-state glycemia, IRβ, pAS160, glucose tolerance and insulin
secretion in monosodium glutamate-induced obese rats
Diet-induced obesity (Araujo et al. 2017)
BCAA ↑HbA1c of peripheral (primarily muscle) tissue in insulin
resistance chronic hepatitis C patients
Chronic liver diseases (Takeshita etal. 2012)
BCAA ↓ glycated albumin and chronic liver disease-HbA1c
post-exercise (enhanced glycemic control) in patients
Liver cirrhosis (Nishida et al. 2017)
BCAA ↓ HbA1c and glycoalbumin, fasting plasma glucose, insulin, and
C-peptide (enhanced glycemic control) in nonalcoholic
steatohepatitis-related liver cirrhosis patients
Alternative treatment in absence of eective
conventional therapy for NASH-related
liver cirrhosis (Miyake et al. 2012)
BCAA, arginine, lysine and threonine ↑ early postprandial serum insulin response, GLP-1 response,
↓ postprandial glycemia in healthy subjects
(Gunnerud et al. 2012)
Cysteine ↓ blood glucose, glycated Hb, CRP, MCP-1, insulin resistance,
plasma protein oxidation, pAkt, and pNF-κB in hypercaloric
fed Zucker diabetic fatty rats
Adjuvant therapy for reduction of vascular
inammation and CVD in diabetics (Jain
et al. 2009) (Jain 2012)
Glutamine ↓ FBG, waist circumference,
↑ fat-free mass in T2D patients
(Mansour et al. 2015)
Glutamine dipeptide (Dipeptiven®) ↓ hyperglycemic episodes (mean daily insulin dose) in
polytrauma patients
(Grintescu et al. 2015)
Glutamine with or without sitagliptin ↑ GLP-1 and insulin secretions,
↓ postprandial glycemia, HbA1c and fructosamine in
well-controlled T2D patients
(Samocha-Bonet et al. 2014) (Greeneld
et al. 2009) (Samocha-Bonet etal. 2011)
Glycine ↓ hyperglycemia, cholesterol and glycated hemoglobin, opacity
in lens and microaneurysms in eyes, expression of O-acetyl
sialic acid in brain vessels, intensity of corporal weight loss in
STZ-induced diabetic rat
Diabetic complications: retinopathy, brain
micro-infarcts and renal damage
(Alvarado-Vásquez etal. 2006)
(Alvarado-Vásquez etal. 2003)
Histidine ↓ HOMA-IR, BMI, waist circumference, fat mass, serum NEFA and
inammatory cytokines, oxidative stress, GPX,
↑ adiponectin in obese subjects
Metabolic syndrome (Feng et al. 2013)
Hydroxyproline, proline, lysine, glycine,
and alanine
↑ TG accumulation and expression of adiponectin in bovine
retinal pericytes
Protection against proliferative diabetic
retinopathy (Vidhya et al. 2018)
Leucine ↑ energy expenditure, fatty acid oxidation and locomotor
activity, expression of UCP-3 in BAT, insulin sensitivity,
intestinal gluconeogenesis,
↓ body weight and fat mass, islets of Langerhans damage,
hepatic lipid in high fat fed rats
Prevention of T2D development (Binder
et al. 2013)
Leucine ↑ glucose tolerance, leptin sensitivity during weight
maintenance in obese rats
Adjuvant benecial nutritional therapy
during weight loss and maintenance in
previously diet-induced obesity (Binder
et al. 2014)
Leucine ↑ insulin secretion (down-regulation of surface expression of
adrenergic α2A receptor via mTOR) in diabetic Goto-Kakizaki
rats
Clinical management of renal transplant
patients (Yang etal. 2012)
L-leucine, L-lysine, L-isoleucine, L-valine,
L-threonine, L-cysteine, L-histidine,
L-phenylalanine, L-methionine,
L-tyrosine, and L-tryptophan
↓ fasting and postprandial blood glucose and HbA1c, fasting
insulin and insulin resistance,
↑ HDL-c in poorly controlled T2D (HbA1c > 7%) of elderly
subjects
Nutritional supplement for treatment of
elderly T2D diabetes (Solerte et al. 2004)
L-tryptophan and tryptamine ↑ in-vitro insulin-stimulated glucose incorporation into
dierentiated adipocyte, in-vivo glucose-associated energy,
↓ serum glucose and insulin, glucose absorption from intestine,
expenditure in T2D rats
Delaying progression of hereditary T2D
(Inubushi et al. 2012)
Lysine ↓ blood sugar (maintaining glycosylated hemoglobin and
glycated lens proteins levels), cataract development
Anticataractous in diabetes (Sulochana,
Punitham, and Ramakrishnan 1998)
Methionine ↑ blood glucose,
↓ hepatic glycogen in arsenic-induced hypoglycemic rats
Arsenic-induced hypoglycemia and
hypoglycolytic activity management (Pal
and Chatterjee 2004)
Phenylalanine and leucine ↑ insulin response following carbohydrate intake in T2D patients Nutritional interventions to improve
postprandial glucose disposal in diabetes
(van Loon et al. 2003)
Serine ↓ diabetes incidence and insulitis score, HOMA-IR and blood
glucose, body weight, food, and water intake in non-obese
diabetic rats
Treatment of autoimmune (T1D) diabetes
(Holm et al. 2018)
(Continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 3
Taurine ↓ cytosolic [Ca2+]i oscillations in response to stimulatory glucose
concentrations,
↑ insulin secretion at stimulatory glucose concentrations,
glucose metabolism, cytosolic insulin, sulfonylurea receptor-1,
glucokinase, GLUT2, PDX-1 gene expression, nucleus PDX-1
expression, basal and insulin stimulated tyrosine
phosphorylation of insulin receptor in skeletal muscle and
liver tissues, peripheral insulin sensitivity in pancreatic islet
cells of rats
(Carneiro et al. 2009)
Taurine ↓ serum glucose and immunoreactive insulin,
↑ glucose clearance, deoxyglucose accumulation in skeletal
muscle and liver, hepatic glycogen synthesis in rats
(Ito, Schaer, and Azuma 2012; Kulakowski
and Maturo 1984)
Taurine ↓ hyperglycemia in alloxan-induced T1D rabbits (Tenner, Zhang, and Lombardini 2003)
Taurine ↓ lectin-type oxidized LDL receptor 1 and ICAM-1 expression on
aortas (improving vascular endothelial dysfunction) in
streptozotocin-induced T1D rats
(L.-j. Wang et al. 2008)
Hypercholesterolemia, its risk factors, and associated complications
Arginine with simvastatin ↓ serum TG in hypertriglyceridemic patients Lipid metabolism (Schulze et al. 2009)
Arginine, alanine, glycine ↓ serum cholesterol and extent of aortic sudanophilia in
casein-induced hypercholesterolemic and atherosclerotic
rabbits and rats
(Katan, Vroomen, and Hermus 1982)
L-aspartate and l-glutamate ↑ serum HDL-c, maintaining ApoA-1 in hypercholesterolemic
diet fed rabbits
Antiatherogenic (Yanni, Perrea, and Yatzidis
2005)
BCAA ↓ HOMA-IR, insulin, hsCRP, waist/height ratio and SBP in twin
subjects
Eects on cardiometabolic health (Jennings
et al. 2016)
Histidine ↓ food intake, retroperitoneal fat pad weight, fat accumulation,
↑ brown adipose tissue UCP-1 mRNA in rats
(Kasaoka et al. 2004)
Histidine, isoleucine, leucine, lysine,
methionine, phenylalanine,
threonine, valine, and arginine
↓ plasma TG, TC, and VLDL-c, hepatic fat in impaired glucose
tolerant elderly patients
Treatment of hypertriglyceridemia or hepatic
steatosis (Børsheim et al. 2009)
(Abete et al. 2010)
Isoleucine ↓ body weight gain, eWAT mass, hepatic and skeletal muscle
TG, hyperinsulinemia, WAT leptin,
↑ WAT adiponectin, hepatic levels of protein CD36/fatty acid
translocase, PPARα, and UCP-2, skeletal muscle levels of
UCP-3 in high fat fed obese rats
(Nishimura et al. 2010)
Leucine ↑ appendicular muscle mass during intentional weight loss in
obese older adults
Reducing sarcopenia risk in obesity
(Verreijen et al. 2015)
Leucine ↓ hepatic steatosis, adipose tissue inammation, subcutaneous
fat pad and liver weight, insulin resistance, glucose
intolerance, expression of lipogenic genes, hepatic lipid
deposition,
↑ insulin-stimulated phosphorylation of p70S6 kinase, activation
of mTOR in high fat fed obese rats
Adjunct therapy in management of
obesity-related insulin resistance
(Macotela et al. 2011)
Methionine ↑ plasma homocysteine, cholesterol in plasma and liver, hepatic
expression of HMG-CoA reductase and CYP7A1,
phosphatidylcholine: phosphatidylethanolamine ratio in liver
of rats
Methionine-induced hypercholesterolemia
via enhanced hepatic cholesterol
synthesis (Hirche et al. 2006)
Phenylalanine, arginine, and alanine ↑ serum glycerol, FFA and acetoacetic acid in healthy subjects Stimulating fat metabolism during exercise
(Ueda et al. 2016)
Taurine ↓ liver weight and liver weight/body weight ratio, plasma TC,
glucose and LDL-c, hepatic cholesterol, and TG,
↑ HDL-c in hypercholesterolemic diet fed rats
Hypercholesterolemia (M.-J. Choi, Kim, and
Chang 2006)
Taurine and n-3 FA ↓ TC, LDL-c, ApoB, TG, thromboxane B (2), TNF-α, and MCP-1,
↑ HDL-c in healthy subjects
Hypolipidemic and antiatherogenic eects
of seafood diet (Elvevoll et al. 2008)
Threonine ↓ hepatic TL, TG, TC, and lipid deposition in Pekin ducks (Jiang et al. 2017)
Valine and leucine ↓ serum SOD and GPx in hypercholesterolemic rats Improving atherosclerosis-associated
endothelial dysfunction (Cojocaru et al.
2014)
Weight management, obesity, and its related complications
Alanine and or leucine ↓ body fat accumulation, hepatic TG, expression of lipogenic
enzymes and plasma cholesterol in high fat diet induced
obese rats
Metabolic syndrome (Freudenberg, Petzke,
and Klaus 2013; K. Petzke, Freudenberg,
and Klaus 2014)
Arginine ↓ serum TG, fat mass,
↑ serum glucagon, body weight gain and skeletal-muscle mass
in growing-nishing pigs
Obesity therapeutic development (Tan etal.
2009)
Arginine ↓ weight of abdominal and epididymal adipose tissues, serum
glucose, TG, FFA,
↑ lipolysis and glucose oxidation in abdominal and epididymal
adipose tissues of diabetic obese Zucker rats
Obesity (Fu et al. 2005)
BCAA ↓ BMI and waist circumference, prevalence of overweight/
obesity, abdominal obesity, postprandial glucose tolerance
and status of inammation in young subjects
Prevention of obesity (Li et al. 2015)
BCAA ↓ food intake and weight gain,
↑ insulin resistance in high fat fed rats
Obesity-associated BCAA-induced insulin
resistance (Newgard et al. 2009)
Table 1. (Continued).
Amino acid supplement (single or
mixture) Major eect(s) Aected disease (reference)
(Continued)
4 S. ABACHI ETAL.
BCAA ↓ body weight and eWAT mass, hepatic, and skeletal muscle TG,
↑ hepatic expression of PPARα and UCP-2, skeletal muscle
expression of PPARα and UCP-3 in high fat fed obese rats
(Arakawa et al. 2011)
BCAA ↓ prevalence of overweight/obesity in healthy East Asian and
Western middle-aged subjects
(Qin et al. 2011)
EAA ↑ lean body mass, basal muscle protein synthesis, and IGF-1
expression in elderly subjects
(Dillon et al. 2009)
Glutamine ↓ body weight, waist circumference, insulinemia and HOMA-IR
in obese subjects
Enhancing glucose metabolism and weight
loss (Laviano et al. 2014)
Glutamine ↓ body weight, plasma glucose and insulin in high fat fed
hyperglycemic and hyperinsulinemic overweight rats
Obesity and diabetes amelioration in
pre-diabetic and diabetic state (Opara
et al. 1996)
Glycine ↑ weight loss and mRNA expression of metabolic involved
genes,
↓ whole-body and epididymal fat mass, glucose intolerance,
mRNA expression of pro-inammatory involved genes, S6
protein phosphorylation in high fat induced obese rats
Accelerating loss of adipose tissue and
protecting muscle mass in obesity
treatment (Caldow etal. 2016)
Histidine ↓ energy intake,
↑ FFA, lipolysis in moderately obese subjects
Weight loss in moderate obesity (Konomi
et al. 2004)
L-arginine ↓ maternal lipid and adiposity and circulating leptin,
↑ fetal brown adipose tissue development in diet-induced obese
sheep
Maternal obesity (Sattereld et al. 2012)
L-arginine ↓ adiposity, WAT, and fat mass,
↑ mitochondrial biogenesis and brown adipose tissue
development, muscle mass, expression of glucose and FA
oxidation involved genes in obese rats, nishing pigs and
T2D patients
Reducing obesity (McKnight et al. 2010)
Leucine ↓ weight gain and adiposity, hyperglycemia, plasma glucagon
and glucogenic AA, hepatic glucose-6-phosphatase, plasma
TC and LDL-c
↑ resting energy expenditure, expression of UCP-3 in brown and
white adipose tissues and in skeletal muscle, insulin
sensitivity in high fat fed obese rats
(Yao et al. 2016; Y. Zhang et al. 2007)
Leucine ↑ peripheral fat oxidation and glucose transport (independent
of appetite and weight regulation) in ospring from high fat
fed obese mother rats
Management of metabolic disorders and
maternal obesity and (Chen et al. 2012)
Leucine ↑ glycemic control, insulin response to food challenge and
insulin, energy expenditure, skeletal muscle expression of
genes involved in regulating energy metabolism (UCP-3,
carnitine acetyltransferase, PPARα, and NRF-1),
↓ HbA1c, adipose tissue inammation in obese and T2D rats
Dietary intervention in prevention and
management of obesity and T2D (Guo
et al. 2010)
L-phenylalanine ↑ insulin, GLP-1, and peptide tyrosine tyrosine (PYY) release
↓ food intake (via blockade of calcium-sensing receptor), plasma
ghrelin, glucose intolerance in rats
Treatment of obesity and diabetes
(Alamshah et al. 2017)
Lysine, proline, alanine, and arginine
with or without conjugated linoleic
acid
↓ body weight and fat, BMI, waist, and hip circumferences
after a period of daily exercise in healthy overweight subjects
Reducing visceral fat and enhancing
fat-burn during exercise, prevention of
metabolic syndrome (Michishita et al.
2010)
Taurine ↓ glucose intolerance, glucagon-induced hepatic glucose output,
insulin hypersecretion and hyperinsulinemia, pancreatic islet
hypertrophy,
↑ glucose homeostasis, pancreatic islet-cell morphology, and
function in leptin-decient genetically obese rats
Management of insulin hypersecretion and
hyperinsulinemia in obesity and T2D
(Santos-Silva et al. 2015)
Tryptophan ↑ weight loss in moderately obese patients (Heraief et al. 1985)
Tryptophan and lysine ↓ food intake and body weight in rats (Ayaso etal. 2014)
Tyrosine ↑ food intake of nocturnal period, fasting plasma insulin,
↓ food intake of diurnal period, fasting plasma glucose in rats
(Bassil, Hwalla, and Obeid 2007)
IRβ: Insulin receptor β, pAS160: Phosphorylated Akt substrate of 160 kDa, pAkt: Phosphorylated Akt, pNF-κB: Phosphorylated NF-κB, PDX-1: Proconvertase and
pancreas duodenum homeobox-1, BMI: Body mass index, HDL-c: High-density lipoprotein-cholesterol, TG: Triglyceride.
food-derived lipids, fibers as well as peptides including
amino acids and their regulatory effects on the syndrome’s
main risk factors (Table 1) (Cicero and Colletti 2016;
Delzenne and Cani 2005; Iwaniak, Darewicz, and Minkiewicz
2018; Nagao and Yanagita 2008; Power et al. 2014;
Ricci-Cabello, Olalla Herrera, and Artacho 2012; Xia etal.
2017). As discussed in this review, anti-obesity, anti-diabetes
and anti-MetS fish biopeptides could be extracted by dif-
ferent methods and techniques. Peptides with anti-MetS
attributes have been successfully extracted from fish, fish
products and byproducts by mainly enzymatic hydrolysis.
Nevertheless, atypical extraction methods such as subcritical
water extraction, isoelectric precipitation and or microwave
pretreatment have as well been practiced. All sorts of fil-
tration procedures, micro-, nano- and ultra-filtration, are
typically exercised before chromatographic peptide purifi-
cation techniques (Table 2). For characterization purposes
of fish anti-MetS peptides, chromatography, spectrophotom-
etry, and electrophoresis techniques are frequently in use
(Table 2).
Table 1. (Continued).
Amino acid supplement (single or
mixture) Major eect(s) Aected disease (reference)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 5
Table 2. Techniques used for extraction, isolation, purication, and characterization of anti-MetS biopeptides from sh and sh-derived products.
Fish name (common,
scientic) and part used
Hydrolysis, fractionation,
and purication Condition and resin/material Characterization References
Alaska pollack (Theragra
chalcogramma) llet
1- enzymatic hydrolysis,
2- RP-HPLC
1- trypsin,
2- octadecyl silica (ODS) Cosmosil
5 C18 column
MS, protein sequencer, UPLC
(Acquity BEH-C18 RP
column) coupled to Xevo
Q-TOF–MS equipped with
electrospray ionization
(ESI) source
(Ayabe etal. 2015)
Alaska pollack (Theragra
chalcogramma) llet
1- enzymatic hydrolysis 1- pepsin (Mizushige et al.
2017)
Alaska pollock (Theragra
chalcogramma) llet
1- dehydration 1- N2 gas (Hosomi et al.
2013) (Hosomi
et al. 2011)
Alaska pollock (Theragra
chalcogramma) llets
1- our preparation 1- lyophilization HPLC, SDS-PAGE (Maeda etal. 2015)
Allaska pollock (Theragra
chalcogramma)) llet
1- enzymatic hydrolysis 1- papain SDS-PAGE, HPLC, gel
permeation HPLC (TSK
gel column)
(Hosomi et al.
2010; Hosomi
et al. 2012)
Atlantic cod (Gadus
morhua),
commercial preparation by
Firmenich Bjørge
Biomarin AS, Norway
1- enzymatic hydrolysis 1- protamex (Dale et al. 2018)
Atlantic herring (Clupea
harengus) byproducts
(heads, guts, and
backbones), Atlantic
salmon (Salmo salar)
byproducts (backbones)
1- enzymatic hydrolysis 1- papain and bromelain (Drotningsvik,
Pampanin, et al.
2018)
Atlantic herring (Clupea
harengus) head, gut,
backbone byproducts,
Atlantic salmon, (Salmo
salar) backbone
byproduct, Atlantic cod
(Gadus morhua) muscle,
commercial tablet
preparation by Faun
Pharma AS, Vestby,
Norway
1- enzymatic hydrolysis,
2- cod our preparation
(cooking, drying and
micro-milling),
3- dosage preparation
1- herring and salmon (mixture of
papain and bromelain),
2- −
3- tableting
HPLC (Hovland etal.
2019)
Atlantic salmon (Salmo
salar) fresh skin
byproducts (recovered
from skin-o llets)
1- aqueous gelatin
extraction,
2- enzymatic hydrolysis,
3- UF,
4- HPLC
1- distilled, deionized water (ddH2O),
2- alcalase (DH: 35 − 41%), bromelain
(DH: 28 − 38%), avourzyme (DH:
42%),
3- MWCO 2.5 − 1 kDa,
4- Zorbax Eclipse Plus C18 column
Amino acid analyzer,
Q-TOF-MS-ESI
(Li-Chan et al.
2012)
Atlantic salmon (Salmo
salar) fresh skin
byproducts (recovered
from skin-o llets)
1- aqueous gelatin
extraction,
2- enzymatic hydrolysis
1- distilled, deionized water (ddH2O),
2- avourzyme
(Hsieh et al. 2015)
Atlantic salmon (Salmo
salar) frozen frames
1- alkaline solubilization,
2- enzymatic hydrolysis,
3- UF,
4- RP-HPLC
1- NaOH
2- pepsin, tr ypsin + chymotrypsin,
3- MWCO 1 kDa,
4- C12 column
(Chevrier et al.
2015)
Atlantic salmon (Salmo
salar) skin and
trimmings byproduct
1- aqueous gelation
extraction,
2- enzymatic hydrolysis
1- 1:5 H2O (w/v) (skin only)
2- alcalase (DH: skin and trimming,
DH: 11% and 27%,
alcalase + avourzyme (DH: 17%
and 34%), promod (DH: 6% and
27%)
Gel permeation (GP)-HPLC,
RP-UPLC, UPLC-ESI-MS/
MS coupled to impact
HD ultra-high resolution
(UHR) Q-TOF
(Harnedy et al.
2018a)
Barbel (Barbus callensis)
fresh muscle
1- enzymatic hydrolysis,
2- SEC, RP-HPLC, HPLC
1- alcalase (DH: 16.4%),
2- gel ltration Superdex peptide
10/30 column, TRACER-Excel 1200
DS-A column, HALO Peptide
ES-C18 column
ESI-MS, and ESI-MS/MS (Assaad Sila et al.
2016)
Barbel (Barbus callensis)
fresh skin
1- enzymatic hydrolysis 1- barbel crude acid protease
(limited gelatin hydrolysis),
esperase (DH: 9.3%), savinase (DH:
9.2%), alcalase (DH: 14.2%),
trypsin (DH: 8.5%), izyme G (DH:
5.8%), protamex (DH: 10.4%),
neutrase (DH: 9.4%), peptidase
(DH: 7.4%)
Amino acid analyzer,
SDS–PAGE
(Assaâd Sila et al.
2015)
(Continued)
6 S. ABACHI ETAL.
Bester sturgeons (Huso
huso × Acipenser
ruthenus) skin, n, and
bone
1- collagen extraction,
2- collagen enzymatic
hydrolysis,
3- atelocollagen extraction
4- atelocollagen enzymatic
hydrolysis,
5- gel ltration
chromatography, RP-HPLC
1- salt (1% NaCl), acid (0.2 M HCl),
alkali (0.2 M NaOH),
2- papain,
3- 5% H2O2, salt (1% NaCl), acid
(0.2 M HCl), alkali (0.2 M NaOH),
99.5% ethanol,
4- pepsin,
5- Sephadex G50 and Sephadex
G25, Mightysil RP18 GP Aqua
column
RP-HPLC (protein sequencer
Procise 493), SDSPAGE
(Sasaoka et al.
2018)
Bighead carp
(Hypophthalmichthys
nobilis) muscle
1- enzymatic hydrolysis,
2- UF,
3- gel ltration
chromatography,
semi-preparative RP-HPLC
1- papain (DH: 6 − 8%), alcalase (DH:
6 − 10%), tr ypsin (DH: 11 − 13%),
pepsin (DH: 14 − 16%),
2- MWCO 5 − 3 kDa,
3- Sephadex G-15, Kromasil 100-5-C18
semi-preparation column
Size exclusion (SE)-HPLC
(TSK gel G2000 SWXL
column), LC-MS/MS (RP
capillary column)
(C. Zhang et al.
2017)
Blacktip shark (Carcharhinus
limbatus) skin byproduct
1- aqueous gelatin
extraction,
2- enzymatic hydrolysis
1- H2O,
2- crude enzyme from papaya
(Carica papaya) latex (DH: 10, 20,
30 and 40%)
(Kittiphattanabawon
et al. 2013)
Blue whiting
(M. poutassou), fresh frozen
muscle, commercial food
supplement preparation
containing Slimpro® by
Compagnie des Pêches
Saint Malo Santé, France
1- enzymatic hydrolysis 1- − (Nobile et al. 2016;
Zaïr et al. 2014)
Blue whiting
(Micromesistius
poutassou) fresh frozen
muscle
1- enzymatic hydrolysis
(pH-stat method)
1- alcalase (DH: 18.8%) (Cudennec et al.
2012)
Blue whiting
(Micromesistius
poutassou) muscle
1- enzymatic hydrolysis 1- alcalase + avourzyme (DH: 29%) HPLC, amino acid analyzer,
UPLC-ESI-MS/MS coupled
to impact HD UHR Q-TOF
(Harnedy et al.
2018b)
Blue whiting fresh frozen 1- aqueous soluble protein
extraction (cooking,
dewatering, sieving,
centrifugation and
drying)
1- H2O(Drotningsvik,
Vikøren, et al.
2018)
Boarsh (Capros aper)
muscle
1- enzymatic hydrolysis 1- alcalase + avourz yme RPUPLC (Acquity BEH
300 C18 RP column),
GPHPLC (TSK G2000 SW
separating and guard
columns)
(Parthsarathy et al.
2019)
Bogue (Boops boops) llet 1- enzymatic hydrolysis 1- crude alkaline proteases from
smooth hound viscera (DH: 20%)
HPLC (AccQ.Tag amino acid
analyzing column
(Nova-Pak C18 column)
(Lassoued et al.
2014)
Cod (Theragra
chalcogramma) and
tuna (Thunnus orientalis)
light muscle
1- dehydration 1- − HPLC, SDS-PAGE (Hosomi etal.
2017)
Cod llet 1- freeze drying and milling 1- − (Myrmel et al.
2019)
Crucian carp (Carassius
carassius) muscle (head
and viscera excluded)
1- enzymatic hydrolysis 1- neutral protease (DH: ∼20%),
alkaline protease (DH ∼25%),
papain (DH: ∼20%), and protamex
(DH: ∼20%)
(L. Liu et al. 2013)
Fish (lean-sh cod, pollock
and haddock skin),
commercial preparation
of high MW food/
pharmaceutical-grade sh
gelatin by Norland
Products Incorporated,
United States
1- enzymatic hydrolysis
(collagen extraction)
1- − (Picard-Deland
et al. 2012)
Fish scales, commercial
collagen preparation by
Nippi Co. Ltd., Japan
1- enzymatic hydrolysis 1- Streptomyces collagenase, DPP-IV
from Pichia pastoris
Gel ltration
chromatography
(Superdex peptide
column), HPLC
(Hypercarb column)
coupled with evaporative
light scattering detector
(ELSD)
(Hatanaka,
Kawakami, and
Uraji 2014)
Table 2. (Continued).
Fish name (common,
scientic) and part used
Hydrolysis, fractionation,
and purication Condition and resin/material Characterization References
(Continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 7
Fresh Norwegian Atlantic
salmon o-cut
byproducts (spine),
commercial 91% pure
protein preparation by
Marine Bioproducts AS,
Norway
1- enzymatic hydrolysis,
2- ltration (micro- and
ultra-)
1- alkaline and neutral proteases
2- −
(Bjørndal et al.
2013; Parolini
et al. 2014)
Goby sh (Zosterisessor
ophiocephalus) fresh
muscle
1- enzymatic hydrolysis 1- Bacillus mojavensis A21 (DH:
13.4%), gray triggersh digestive
crude proteases (DH: 23.4%)
HPLC (AccQ·Tag amino acid
analyzing Nova-Pak C18
column)
(Nasri et al. 2018;
Nasri et al.
2015)
Gray triggersh (Balistes
capriscus) muscle
1- enzymatic hydrolysis 1- crude enzyme preparations from
Bacillus mojavensis A21,
sardinelle (Sardinella aurita)
viscera, Zebra blenny (Slaria
basilisca) viscera
(Siala et al. 2016)
Herring milt hydrolysate
commercial preparation
1- enzymatic hydrolysis,
2- UF,
3- electro-separation
1- −
2- −
3- EDUF 50, 20 kDa
(Durand et al.
2019)
Mixture of wild caught cod
llet and Canadian
scallop muscles (cod/
scallop, 1 : 1 on amino
acid content)
1- freeze drying and milling 1- − (I.-J. Jensen et al.
2016; Tastesen
et al. 2014)
Nile tilapia (Oreochromis
niloticus) fresh
skin
1- alkaline and aqueous
collagen extraction,
2- enzymatic hydrolysis
1- 0.05 M NaOH, H2O, 1% Ca(OH)2,
2- alcalase
Automatic amino acid
analyzer, HPLC (TSK gel
column)
(R. Zhang, Chen,
Chen, et al.
2016)
Norwegian spring spawning
herring and salmon
(backbones) fresh
byproducts
1- enzymatic hydrolysis 1- papain and bromelain (Drotningsvik et al.
2016)
Pacic hake (Merluccius
productus), halibut
(Hippoglossus
stenolepis), tilapia
(Oreochromis niloticus),
milksh (Chanos chanos)
fresh byproduct skins
recovered from skin-o
llets
1- aqueous gelatin
extraction,
2- enzymatic hydrolysis,
3- UF
1- −
2- avourzyme,
3- MWCO 2.5 − 1.5 kDa
(T.-Y. Wang et al.
2015)
Pollock (Theragra
chalcogramma) esh
and frame byproduct
1- enzymatic hydrolysis,
2- UF
1- alcalase and avourzyme,
2- MWCO 1 kDa
SEC (TSK G2000 column) (Cai et al. 2015; Xu
et al. 2016;
Zheng et al.
2014)
Rainbow trout
(Oncorhynchus mykiss)
fresh frames
1- microwave assisted
extraction,
2- enzymatic hydrolysis,
3- electrodialysis with
ultraltration membrane
(EDUF)
1- microwave pretreatment (90 °C,
10 min, 800 W ),
2- alcalase,
3- anionic and cationic
exchange membranes, MWCO
20 kDa
MALDIMS (Ketnawa et al.
2019)
Salmon (Salmo salar) and
cod (Gadus morhua)
frozen byproduct frames
1- alkaline solubilization,
2- aqueous dispersion,
3- enzymatic hydrolysis,
4- UF
1- 0.1 and 1 M NaOH,
2- dH2O,
3- pepsin, pancreatin, trypsin and
chymotrypsin (alone or in
combination), 4- MWCO 1 kDa
(Jin 2013)
Salmon (Salmo salar)
trimmings
1- enzymatic hydrolysis,
2- semi-preparative RP-HPLC
1- dierent preparations and 1-,
2- and 4-h durations (alcalase
(DH: 14.0 − 18.3%),
alcalase + avourzyme (DH:
15.1 − 16.0%), corolase (DH:
21.8 − 24.3%), PROMOD (DH:
20.3 − 22.1%),
2- C18 semi-preparative column
SDS-PAGE, RP-HPLC, gel
permeation HPLC,
UPLC-MS/MS (Peptide
XB-C18 column)
(Neves et al. 2017)
Salmon frame byproducts 1- alkaline solubilization,
2- isoelectric precipitation,
3- enzymatic hydrolysis,
4- UF,
5- EDUF,
1- NaOH (1 N),
2- pH of 4.5,
3- pepsin, trypsin/chymotrypsin,
4- MWCO 1 kDa,
5- MWCO 50, 20, 5 kDa
RP-UPLC-MS/MS (C18
column)
(Henaux et al.
2019)
Table 2. (Continued).
Fish name (common,
scientic) and part used
Hydrolysis, fractionation,
and purication Condition and resin/material Characterization References
(Continued)
8 S. ABACHI ETAL.
Salmon frames 1- alkaline solubilization,
2- isoelectric precipitation,
3- enzymatic hydrolysis,
4- UF, EDFM
1- 1 M NaOH,
2- pepsin at pH 4.5,
3- trypsin and chymotrypsin,
4- prep/scale tangential ow
ltration (TFF) cartridge MWCO
1 kDa, Neosepta CMX-SB cationic
and AMX-SB anionic membranes,
UF polyether sulfone (PES) MWCO
of 20 kDa
RP-HPLC and HPLC/MS (BEH
C18 column), HPLC
(AccQTag amino acid
analysis column (silica
base bonded with C18))
(Roblet et al. 2016)
Salmon fresh backbones 1- enzymatic hydrolysis 1- corolase PP (DH: 18 − 22%) and
corolase 7089 (DH: 14 − 18%),
protamex (DH: 15 − 21%),
papain + bromelain (DH: 13 − 17%),
trypsin (DH: 14 − 18%), protex 6 L
(DH: 14 − 18%), seabzyme L200
(DH: 13 − 17%)
Gel ltration on FPLC
(Superdex™ Peptide
10/300 GL column), HPLC
(Slizyte et al. 2016)
Salmon spine and or
backbones including
heads, commercial
preparation by Marine
Bioproducts AS, Norway
1- enzymatic hydrolysis,
2- ltration (micro- and
ultra-)
1- salmon spine: alkaline and neutral
protease with sequential
hydrolysis (acid protease A and or
umamizyme of Aspergillus
oryzae), salmon backbones
including heads: alcalase
2- −
(Vik et al. 2015)
Sardine (S. pilchardus) and
sardinelle (S. aurita)
fresh muscle
1- enzymatic hydrolysis 1- alcalase (DH: 8%) (Athmani et al.
2015)
Sardine (Sardina pilchardus)
and bogue (Boops
boops) fresh muscle
1- enzymatic hydrolysis 1- alcalase (DH: 8%) HPLC (Benomar et al.
2015)
Sardine (Sardina pilchardus)
fresh byproducts (viscera,
heads, skins and edges)
and llets
1- our preparation,
2- isoelectric precipitation
1- cooking, oven drying and hexane
dilapidation
2- 98% H2SO4
(Aane et al. 2018)
Sardine (Sardina
pilchardus), horse
mackerel (Trachurus
mediterraneus), axillary
seabream (Pagellus
acarne), bogue (Boops
boops), small-spotted
catshark (Scyliorhinus
canicula), blue whiting
(Micromesistius
poutassou) west
Mediterranean Sea sh
discards
1- enzymatic hydrolysis
(sequential 2-stage and
1-stage)
1- sequential 2-stage (1st: subtilisin,
2nd: trypsin (DH: 14.9 − 19.7%) and
(1st: trypsin, 2nd: subtilisin (DH:
13.2 − 18.3%)), 1-stage
(combination of subtilisin + tr ypsin
(DH: 13.7 − 21.0%))
(Pérez-Gálvez et al.
2015)
Sardine llet
muscle tissue
1- alkaline solubilization 1- NaOH (Madani et al.
2015)
Sardine llet (head, internal
organs and bones
excluded)
1- acid and alkaline
solubilization
1- 2 N HCl, 2 N NaOH (Madani et al.
2012)
Sardinelle (Sardinella
aurita) fresh muscle
1- meat our preparation,
2- fermentation
1- cooked and oven dehydrated,
2- Bacillus subtilis A26 (DH: 21%)
and B. amyloliquefaciens An6
(DH: 24%)
RP-HPLC (Symmetry C18
column, Pico Tag
column), MALDI-TOF-MS
(Jemil, Abdelhedi,
et al. 2017;
Jemil, Nasri,
et al. 2017)
Sardinelle (Sardinella
aurita) fresh muscle
1- enzymatic hydrolysis Bacillus pumilus A1 (DH: 14%),
Bacillus mojavensis A21 (DH:
7.5%), sardinelle viscera (DH:
8.5%) crude proteases extract
(Khaled et al. 2012)
Shark (Squalus mitsukurii
and Chiloscyllium
plagiosum) fresh healthy
liver
1- cooking,
2- UF,
3- IEC, gel chromatography,
FPLC, RP-HPLC
1- −
2- MWCO 30 kDa,
3- DEAESepharose column, BioGel
P10 column, monoQ column, C18
column
SDSPAGE, MALDIMS,
automatic amino acid
analyzer
(F. J. Huang & Wu,
2010)
Siki (Centroscymnus
coelolepis) cooked head
and saithe (Pollachius
virens) cooked muscle
1- enzymatic hydrolysis,
2- UF,
3- deodorization,
4- SEC, RP-HPLC
1- siki: alcalase, saithe: commercial
proteases,
2- MWCO 10 kDa,
3- active carbon,
4- HW-40 Toyopearl column,
Prosphere 300 C18 column
Protein sequencer, SEC
(Superdex peptide PC
3.2/30 column),
LC-ESI-IT-MS/MS (RP trap
column (PepMap C18
-precolumn) and ACE
3 m C18 RP analytical
column)
(Martínez-Alvarez
et al. 2012)
Table 2. (Continued).
Fish name (common,
scientic) and part used
Hydrolysis, fractionation,
and purication Condition and resin/material Characterization References
(Continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 9
Silver Carp
(Hypophthalmichthys
molitrix Val.) fresh
muscle
1- enzymatic hydrolysis,
2- UF,
3- thin layer
chromatography, RP-HPLC
1- alcalase (DH: 29%), papain (DH:
∼25%), neutrase ∼20%),
avourzyme, trypsin and pepsin
(DH: ∼11 − 12%),
2- MWCO 10, 5, and 3 kDa,
3- ready-use silica gel 60 plate,
analytical C18 column
LC-ESI-MS/MS (Ying Zhang, Chen,
Chen, et al.
2016)
Skate (Raja Kenojei) skin,
collagenous preparation
to capsule form by
Serom Co., Ltd.
(Jeonnam, South Korea)
1- enzymatic hydrolysis,
2- dosage preparation
1- −
2- capsuling
(Tak et al. 2019)
Skate skin 1- collagen extraction 1- − (H. Lee et al. 2018)
Skipjack Tuna (Katsuwonus
Pelamis) heart
1- ethanolic extraction 1- 70% ethanol (Ali et al. 2016)
Smooth hound (M.
mustelus) muscle
1- enzymatic hydrolysis 1- crude smooth hound intestinal
proteases (DH: 20.3%)
ESI-MS, GC/MS (CPSil5 CB
Low bleed/MS capillary
column)
(Bougatef et al.
2010)
Smooth hound viscera 1- enzymatic hydrolysis,
2- successive UF
1- Purafect® (DH: 14.5%),
2- MWCO 1 kDa
RP-HPLC (PicoTag® column) (Abdelhedi et al.
2019)
Steelhead (Oncorhynchus
mykiss) fresh skin gelatin
1- enzymatic hydrolysis,
2- UF
1- alcalase, bromelain, papain,
protease P “Amano” 6SD, protease
M “Amano” SD, sequentially
hydrolyzed with corolaseN and or
pepsin,
2- MWCO 3 kDa
(Cheung and
Li-Chan 2017)
Thornback ray (Raja
clavata) fresh muscle
1- enzymatic hydrolysis 1- mixture of neutrase, alcalase,
crude proteases of B. subtilis A26
and R. clavata
(Lassoued et al.
2018)
Tilapia (Oreochromis sp.)
scale, commercial food
grade collagen (Wellnex®
Type D) preparation by
Nitta Gelatin, Inc., Japan
1- enzymatic hydrolysis (Iba et al. 2016)
Tuna (Thunnus tonggol)
cooking juice (5.44%
protein)
1- enzymatic hydrolysis,
2- gel ltration
chromatography, RP-HPLC
1- protease XXIII (PR) (DH: 19.4%)
and orientase (OR) (DH: 23.6%),
2- Sephadex G-25 column, Zorbax
Eclipse Plus C18 column
MALDI-TOF/TOF MS/MS (S.-L. Huang et al.
2012)
Tuna extract 1- desalination and boiling,
2- ltration,
3- precipitation (soluble and
insoluble proteins),
4- HPLC
1- −
2- MWCO 200 Da,
3- methanol, chloroform, and water,
4- C18 column
SDS-PAGE, Q-TOF MS/MS (Y. M. Kim etal.
2015)
Tuna extract 1- desalination and boiling,
2- ltration,
3- sterilization
1- −
2- MWCO 200 Da
3- −
(Y. Kim etal. 2016)
Tuna skin byproduct 1- subcritical water
extraction
1- 190 °C and pressure chamber of
1100 kPa
(E. J. Lee et al.
2017)
Unicorn leatherjacket sh
(Aluterus monoceros)
skin byproduct
1- enzymatic hydrolysis,
2- UF, tangential ow
ltration
1- crude collagenase enzyme from
sh ns (DH: 7.6%) (at 5, 25,
50 °C temperatures),
2- MWCO 30 kDa, MWCO 10, 3 kDa
(Kumar, Shakila,
and Jeyasekaran
2019)
Warm sea sh skin,
commercial type I and III
collagen preparation
(Naticol®) by Weishardt,
France
1- enzymatic hydrolysis 1- − (Astre et al. 2018)
Wild marine deep-sea sh
fresh meat, commercial
preparation
1- enzymatic hydrolysis 1- mixed proteases (C.-F. Zhu, Li, Peng,
Li, et al. 2010)
Wild marine sh 1- enzymatic hydrolysis
(collagen extraction)
1- mixed proteases (25% pepsin +
35% trypsin + 35% chymotrypsin
+ 5% pancreatic lipase)
HPLC, MALDI-TOF-MS,
H835-50 automatic
amino acid analyzer
(C.-F. Zhu, Li, Peng,
Zhang, et al.
2010)
Wild marine fresh sh 1- enzymatic hydrolysis,
2- UF,
3- desalination,
4- cryoconcentration,
5- decolorization and
lyophilization
1- mixed proteases,
2- −
3- −
4- 70 °C under vacuum,
5- −
HPLC, MALDI-TOF-MS,
automatic amino acid
analyzer
(Cui-Feng etal.
2010)
Table 2. (Continued).
Fish name (common,
scientic) and part used
Hydrolysis, fractionation,
and purication Condition and resin/material Characterization References
(Continued)
10 S. ABACHI ETAL.
Wild marine fresh sh scales 1- demineralization,
2- collagen extraction,
3- salting out precipitation,
4- dialysis,
5- enzymatic hydrolysis,
6- ltration
1- 0.4 M HClO4,
2- 0.5 M acetic acid (+ 0.005 M EDTA),
3- 0.9 M NaCl concentration,
4- against distilled water,
5- pepsin,
6- ceramic membrane (200 m ∼ ≤
26 kDa)
(Raksha et al. 2018)
Wild-caught chum salmon
skin
1- collagen extraction,
2- enzymatic hydrolysis,
3- UF,
4- HPLC,
5- desalination,
6- decolorization
1- −
2- mixed proteases,
3- MWCO 10 kDa,
4- C18 column,
5- −
6- medicinal charcoal
MALDI-TOF-MS, automatic
amino acid analyzer,
HPLC
(C. Zhu, Zhang, Mu,
et al. 2017)
Wild-caught chum salmon
skin
1- collagen extraction,
2- enzymatic hydrolysis,
3- spray drying
1- −
2- alcalase, protamex
3- −
HPLC, MALDI-TOF-MS,
automatic amino acid
analyzer
(C. Zhu, Zhang, Liu,
et al. 2017)
Wild-caught chum salmon
skin
1- collagen extraction 1- − (J. Wang et al.
2010)
Yellown tuna (Thunnus
albacares) fresh bone
1- alkaline, acid, and
aqueous solubilization
(collagen extraction),
2- enzymatic hydrolysis
1- 0.1 M NaOH, 1.5% acetic acid and
aquadest,
2- collagenase from Bacillus sp. 6-2
(Natsir, Dali, and
Arif 2019)
Zebra blenny (Salaria
basilisca) fresh and or
fresh frozen muscle
1- enzymatic hydrolysis 1- crude proteases from viscera of
zebra blenny (DH: 10%), smooth
hound (Mustelus mustelus) (DH:
9.1%), sardinelle (S. aurita) (DH:
6.65%)
HPLC (AccQ·Tag amino acid
analyzing Nova-Pak C18
column), SEC (Sephadex
G-25 column)
(Ktari et al. 2015;
Ktari et al. 2013)
Zebra blenny (Salaria
basilisca) fresh muscle
1- enzymatic hydrolysis 1- crude alkaline proteases from
homogenized viscera of zebra
blenny, sardinella and smooth
hound
HPLC-SEC (PL aquagel-OH
MIXED-H
preparative-column)
(Ktari et al. 2017)
Table 2. (Continued).
Fish name (common,
scientic) and part used
Hydrolysis, fractionation,
and purication Condition and resin/material Characterization References
Amino acids, mixture or single, or peptides as mono-
and or combination therapies with clinical drugs, have
shown promising health effects on MetS throughout many
studies in animals, humans and in cell analysis (Table 1).
Dietary amino acid supplementation had glucoregulatory
and hypocholesterolemic effects among human subjects with
spinal cord injury (glucoregulatory activity of all amino
acids, in particular lysine, exclusive of cysteine, glutamic
acid, threonine, leucine and histidine on fasting plasma
glucose as well as hypocholesterolemic activity of threonine
and leucine on TG and total cholesterol (TC)) (Javidan
et al. 2017). Fermented mackerel extract and its fractions,
free amino acid deficient NH4OH-HCl fraction (3.2%) and
free amino acid rich acetonitrile (ACN) fraction (94.5%),
with various peptide concentration, 94.2% and 5.8% respec-
tively, exhibited hypocholesterolemic activity at varying
degrees in Wistar rats (Itou and Akahane 2009). In contrary,
effects of free amino acid mixtures and undigested blue
whiting protein tended to be negligible on cholecystokinin
(CCK) secretion from secretin tumor cell line (STC-1)
where its digested sarcoplasmic proteins significantly
increased the hormone level (+45% greater than the egg
albumin hydrolysate) (Cudennec et al. 2012). Interestingly,
among fractions peptide rich/free amino acid deficient
NH4OH-HCl fraction presented better hypocholesterolemic
activity on plasma lipid levels of rats than the peptide defi-
cient/free amino acid rich ACN fraction (Itou and Akahane
2009). Nonetheless, fecal lipids (bile acid (BA) and total
lipid (TL)) excretion was more affected by heshiko extract
(M/G 1.33) and its ACN fraction (M/G 1.16) compared to
NH4OH-HCl fraction (Itou and Akahane 2009). These
observations may point to the contribution of both free AA
and peptides to the anti-hypercholesterolemic activity of
the heshiko extract (Itou and Akahane 2009). The ACN
free amino acid rich fraction, with comparatively lower M/G
ratio of 1.16 compared to heshiko extract (M/G ratio 1.33),
was more modulatory, up to +29-times, on hepatic lipid
levels (TC: +13% (13 vs. 26%), LDL-c: +13% (13 vs. 26%),
TG: +29% (0 vs. 29%)) (Itou and Akahane 2009).
Marine biopeptides have exerted significant hypoglycemic,
insulinotropic, hypolipidemic, hypocholesterolemic, hypoten-
sive, pro-and anti-inflammatory and anti-obesogenic effects
in many studies thus being potential therapy candidates in
prevention and treatment risk factors (Ko and Jeon 2013;
Tørris, Småstuen, and Molin 2018). The topics of fish anti-
hypertensive and immunomodulatory biopeptides have been
carefully reviewed by the authors (Soheila Abachi, Bazinet,
and Beaulieu 2019; Soheila Abachi et al. 2021). Yet, herein
beneficial effects of similar bioactives on additional risk factors
of MetS are further comprehensively discussed. Many types
of fish and fish byproducts have cardio-protecting, anti-diabetes,
and anti-obesity potency yet interestingly fish diet itself has
also demonstrated health effects in many human intervention
studies (Tables 3–5). Nonetheless, marine, and fish-based
material or hydrolysates can be used as unprocessed diet,
dietary supplements and or as therapeutically active ingredi-
ents in food, nutraceutical, and pharmaceutical preparations
(Table 6). Fish biopeptides have proven to be safe and
non-cytotoxic thus being suitable alternatives to classic and
conventional drugs (Cudennec et al. 2008; Y. M. Kim etal.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 11
Table 3. Fish peptides with bioactivities on MetS associated risk factors (in-vitro and cell studies).
Fish name and part used
Observed eect(s) including percentage of
eect and IC50
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
Atlantic salmon (S. salar)
fresh skin byproducts
(recovered from skin-o
llets)
↓ DPP-IV activity (5 mg non-hydrolyzed gelatin
and its hydrolysates mL-1 ≤ 45%, 2 mg mL-1
of UF fractions ≤ 61%,
100 g mL-1 of HPLC F1-F5 fractions ≤ 68%,
IC50: F1 57.3 g mL-1, GPAE 49.6 M, GPGA
41.9 M)
HAA 61 > C AA 24 > imino acids (Hyp + Pro)
18 > BCAA 4 mol 100-1 mol AA, L/A 0.47,
M/G 0.04, GPAE 372 Da, GPGA 300 Da
(Li-Chan et al. 2012)
Atlantic salmon (S. salar) skin
and trimmings byproduct
↓ DPP-IV activity (IC50: skin lysates
0.90 − 2.13 mg mL-1, trimming lysates
0.84 − 1.27 mg mL-1),
High in Gly-Pro motif,
Skin: HAA 50 > CAA 27 > Gly 23 > Pro
11 > BCAA 5, L/A 0.38, M/G 0.11,
Trimming: CAA 34 > HAA 33 > BCAA 12 > Gly
7 > Pro 4, L/A 1.27, M/G 0.38
alcalase: <1 kDa (60 − 61%), 1 − 5 kDa
(35 − 38%),
alcalase + avourzyme: <1 kDa (67 − 69%),
1 − 5 kDa (28 − 32%),
promod: <1 kDa (33 − 59%), 1 − 5 kDa
(39 − 53%),
skin and trimming lysates digestion
susceptible and resistant respectively
(Harnedy et al. 2018a)
2.5 mg mL-1
↑ intracellular cAMP concentration in
BRIN-BD11 cells (except skin lysates),
membrane potential (depolarization),
intracellular calcium ([Ca2+]i) concentration,
insulin secretion (insulinotropic response) from
BRIN-BD11 cells (except promod lysates),
GLP-1 secretion from enteroendocrine GLUTag
cells (except alcalase and promod lysate)
Barbel (B. callensis) fresh
muscle
↓ DPP-IV activity (IC50: hydrolysate 1.94 mg
mL-1, SEC fraction 1.23 mg mL-1, RP-HPLC
fraction 0.21 mg mL-1, HPLC fraction 96 µg
mL-1)
WSG 330 Da, FSD 349 Da (Assaad Sila etal. 2016)
Barbel (B. callensis) fresh skin ↓ DPP-IV activity (IC50: lysates of esperase
2.2 mg mL-1, savinase 2.7 mg mL-1, alcalase
2.6 mg mL-1, trypsin 2.5 mg mL-1, izyme G
3.7 mg mL-1, protamex 2.4 mg mL-1,
neutrase 2.7 mg mL-1, peptidase 2.7 mg
mL-1)
HAA (HAA) 629 > Gly 354 > CAA 189 > imino
AA 184 > BCAA 45 residues/1000, L/A
0.52, M/G 0.04,
Lysate of esperase 2,935 Da, savinase
2,322 Da, alcalase 1,995 Da, trypsin
3,925 Da, izyme G 5,797 Da, protamex
2,325 Da, neutrase 7,878 Da, peptidase
15,053 Da
(Assaâd Sila et al. 2015)
Bighead carp (H. nobilis)
muscle
↓ DPP-IV activity (lysates, fractions, and
sub-fractions (IC50 YNLKERYAAW 12.46 mM,
MKAVCFSL 1.37 mM, LGQNPAAML 0.96 mM,
INEFTTGIPVL 0.73 mM, IADHFL 0.61 mM),
and IC50 IPI (diprotin A) 0.005 mM
0.5 − 2 kDa (lysate of papain: 54%, alcalase:
76%, trypsin: 69%, pepsin: 82%),
MKAVCFSL 898 Da, YNLKERYAAW
1,314 Da, INEFTTGIPVL 1,203 Da, IADHFL
715 Da, LGQNPAAML 914 Da
(C. Zhang et al. 2017)
Blacktip shark (C. limbatus)
skin byproduct
↓ LDL-c oxidation (≤ 39%), hydroxyl and
peroxyl radical-induced DNA scission
(Kittiphattanabawon
et al. 2013)
Blue whiting (M. poutassou)
fresh frozen muscle
0.5 − 1% (w/v)
↑ CCK and GLP-1 in STC-1 cell
(dose-dependent)
(Cudennec et al. 2012)
Blue whiting (M. poutassou)
muscle
↓ DPP-IV activity (IC50 1.28 mg mL-1), 1 − 5 kDa (21%), 0.5 − 1 kDa (29%), <0.5 kDa
(49%), C AA 26 > HAA 23 > BCAA 10 g
100 g-1, L/A 1.32, M/G 0.65
(Harnedy et al. 2018b)
2.5 mg mL-1
↑ insulin secretion from BRIN-BD11 cells,
GLP-1 secretion from GLUTag cells,
insulin-stimulated glucose uptake in 3T3-L1
adipocytes
Boarsh (C. aper) muscle ↓ DPP-IV activity (IC50 1.18 mg mL-1), 2 − 1 kDa (18%), <1 kDa (74%) (Parthsarathy et al. 2019)
2.5 mg mL-1
↑ insulin secretion from BRIN-BD11 cells,
GLP-1 secretion from GLUTag cells, glucose
uptake in 3T3L1 adipocytes (30%), [Ca2+]i,
membrane depolarization
Cod, commercial preparation
by DP&S®, Netherlands
↑ GLP1 and CCK release (trypsin and or
DPPIV digested and or non-digested) in
STC1 cell
(Geraedts et al. 2011)
Fish scales, commercial
collagen preparation by
Nippi Co. Ltd., Japan
↓ DPP-IV activity (IC50 3.5 mg mL-1, GA(HP) >
20 mM, GPA 5.03 mM, GP(HP) 2.51 Mm) and
IC50 IPI (diprotin A) 0.03 mM
GA(HP), GPA, GP(HP) (Hatanaka, Kawakami,
and Uraji 2014)
Herring milt hydrolysate
commercial preparation
1 ng mL-1
↑ glucose uptake (27%) in insulin stimulated
L6 cells (except charged peptides and
non-electrodialyzed)
Neutral >50 kDa fraction: CAA 32 > EAA
15 > BCAA 7 > proline 3, L/A 0.13, M/G
0.37
(Durand et al. 2019)
Pacic hake (M. productus),
halibut (H. stenolepis),
tilapia (O. niloticus),
milksh (C. chanos) fresh
skins, byproducts
recovered from skin-o
llet
↓ DPP-IV activity (3 mg hydrolysate mL-1: ≤
48%, and 1 mg UF fraction mL-1: ≤ 52%)
High in Gly, Pro and Hyp (tilapia and
milksh: 1.95 − 2.03 µmole imino acids
mg-1 sample, halibut and hake:
1.77–1.79 µmole imino acids mg-1
sample), halibut: SPGSSGPQGFTG 862 Da,
GPVGPAGNPGANGLN 1,021 Da,
PPGPTGPRGQPGNIGF 1261 Da,
tilapia: IPGDPGPPGPPGP 920 Da,
LPGERGRPGAPGP 1,027 Da,
GPKGDRGLPGPPGRDGM 1,359 Da
(T.-Y. Wang et al. 2015)
(Continued)
12 S. ABACHI ETAL.
Rainbow trout (O. mykiss)
fresh frames
↓ DPP-IV activity (IC50: hydrolysate 4.8 mg
mL-1,
EDUF fraction (without cationic peptides)
2.1 mg mL-1, EDUF cationic peptides 1.2 mg
mL-1)
hydrolysate: HAA 47 > CAA 27 > BCAA 12%
mole, L/A 2.08, M/G 0.18, 0.5 − 1 kDa (∼
35%),
EDUF fraction (without cationic peptides):
HAA 41 > CAA 38 > BCAA 10% mole, L/A
1.96, M/G 0.17, 0.5 − 1 kDa (∼ 25%),
EDUF cationic peptides: CAA 33 > HAA
24 > BCAA 7% mole, L/A 2.23, M/G 0.21,
0.5 − 1 kDa (∼ 50%)
(Ketnawa et al. 2019)
Salmon (S. salar) and cod (G.
morhua) frozen byproduct
frames
1 mg mL-1
water-dispersed and or alkaline-solubilized
enzymatic lysates
↑ insulin-induced glucose uptake in L6
myocytes,
↓ glucose production in FAO rat hepatocytes
(except cod lysates)
(Jin 2013)
Salmon (S. salar) trimmings ↓ DPP-IV (IC50: hydrolysate 0.30 − 2.41 mg mL-1
and IC50: corolase hydrolysate-separated
peptides (GPAV 246 M, VP 758 M, VC
5413 M, YP 7564 M, FF 547 M, PP
4343 M, W 438 M, F 295 M, Y 75 M)
GI digestion stable corolase hydrolysate:
GPAV, VP, VC, YP, FF, PP, DP, I/LD, I/LH, W,
L/I, F, Y
(Neves et al. 2017)
Salmon frames 1 ng mL-1
↑ glucose uptake ≤ 40% in insulin stimulated
and non-stimulated L6 skeletal muscle cells
CAA, <800 Da (90 − 92%) (Roblet et al. 2016)
Salmon fresh backbones 8 mg (papain + bromelain) mL-1
↓ uptake of radiolabeled glucose (39%) into
CaCo-2 cells (cellular GLUT/SGLT ) activity)
papain + bromelain hydrolysate 250 − 300 Da (Slizyte et al. 2016)
Sardine (S. pilchardus), horse
mackerel (T.
mediterraneus), axillary
seabream (P. acarne),
bogue (B. boops),
small-spotted catshark (S.
canicula), blue whiting (M.
poutassou) west
Mediterranean Sea sh
discards
100 mg protein
↑ BA (cholic and chenodeoxycholic acid)
binding capacity (sardine 13.1 − 25.0%,
horse mackerel 13.4 − 30.8%, axillary
seabream 17.7 − 20.9%, bogue 17.7 − 28.4%,
small-spotted catshark 14.1 − 17.9%, blue
whiting 24.3 − 28.2% relative to
cholestyramine)
(Pérez-Gálvez et al. 2015)
Siki (C. coelolepis) cooked
heads and saithe (P.
virens) cooked muscle
↓ CGRP binding to receptors in rat liver
membrane (ED50: 1.68 mg protein (siki
lysate), 0.017 mg protein (siki lysate
puried fraction), 1.38 mg protein (saithe
lysate))
Siki hydrolysate: 800 − 1,500 Da (74%),
≤340 Da (26%), GFP(HP)GPEGL
(Martínez-Alvarez et al.
2012)
Silver carp (H. molitrix Val.)
fresh muscle
1.25 mg mL-1
↓ DPPIV activity ≤ 57% (neutrase lysate and
fractions ≤ 56%) (IC50: APGPAGP
229.14 M, LPIIDI 105.44 M) and IC50 IPI
(diprotin A) 6.36 M
APGPAGP 566 Da, LPIIDI 683 Da (Ying Zhang, Chen, Chen,
et al. 2016)
Skipjack Tuna (K. Pelamis)
heart
↓ PTP1B (IC50 416 g mL-1), αglucosidase
activity (IC50 1136 g mL-1), HRAR activity
(IC50 984 g mL-1)
(Ali et al. 2016)
Steelhead (O. mykiss) fresh
skin gelatin
0.5 mg mL-1
↓ DPPIV activity ≤ 44%
(Cheung and Li-Chan
2017)
Tilapia (Oreochromis sp.)
scale, commercial food
grade collagen (Wellnex®
Type D) preparation by
Nitta Gelatin, Inc., Japan
↓ DPP-IV activity (IC50 0.77 mg mL-1), (Iba etal. 2016)
1% protein
↑ GLP-1 secretion (258%) in NCI-H716 cells
Tuna (T. tonggol) cooking
juice (5.44% protein)
↓ DPP-IV activity (10 mg non-hydrolyzed
gelatin and its hydrolysates mL-1 ≤ 45%,
5 mg gel ltered fractions mL-1 ≤ 40%,
2 mg RP-HPLC fractions mL-1 ≤ 63%), IC50:
PGVGGPLGPIGPCYE 116.1 M, CAYQWQRPVDRIR
78.0 M, PACGGFWISGRPG 96.4 M
Protease XXIII lysate high in
PGVGGPLGPIGPCYE 1,413 Da,
CAYQWQRPVDRIR 1,691 Da,
and orientase lysate high in
PACGGFWISGRPG 1,305 Da
(S.-L. Huang et al. 2012)
Tuna extract 500 − 1000 ng mL-1 of DIVDKIEI (TP-D)
↓ glucose uptake (preadipocytes
dierentiation), TG, adipocyte formation
(expression of C/EBP-α/-β/-δ and PPAR-γ),
expression levels of ACC, FAS, LPL, FABP,
SREBP-1, SOCS3, CD36, expression level of
mitochondrial UCP-2, GLUT4, and GSK-3β,
high-MW- and total adiponectin,
↑ expression level of UCP-1, CCND1 and
β-catenin/TCF/LEF levels (Wnt-10b/LRP6/
Frizzled activated) in 3T3-L1 cells during
dierentiation
DIVDKIEI 944 Da (Y. M. Kim etal. 2015)
Table 3. (Continued).
Fish name and part used
Observed eect(s) including percentage of
eect and IC50
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
(Continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 13
Tuna skin byproduct 1 mg mL-1, 8-d
↓ intracellular TG, lipid accumulation and lipid
droplets (adipogenic dierentiation of
preadipocytes), expression of adipogenic
genes (C/EBP-α and PPAR-γ) and target
genes (aP2) in 3T3-L1 preadipocytes,
(E. J. Lee et al. 2017)
1 mg mL-1, 24-h
↓ palmitate-induced lipogenesis in HepG2
cells
Unicorn leatherjacket sh (A.
monoceros) byproduct
skin
↓ α-amylase activity (IC50 hydrolysate (various
process temperatures) 5 °C 1.17 mg mL-1,
25 °C 1.92 mg mL-1, 50 °C 2.65 mg mL-1
(Kumar, Shakila, and
Jeyasekaran 2019)
Yellown tuna (T. albacares)
fresh bone
↓ α-glucosidase activity ≤ 24% (Natsir, Dali, and Arif
2019)
Zebra blenny (S. basilisca)
muscle
↓ α-amylase activity (IC50: 90 − 93 g mL−1)CAA 35% > BCAA 31% > sulfur containing
AA 3%, L/A ∼ 0.51
(Ktari et al. 2013)
Increased, improved, stimulated and or upregulated expressions are denoted as “↑”, and decreased, inhibited and or downregulated expression denoted as “↓”.
HAA: hydrophobic amino acids (glycine, alanine, valine, isoleucine, leucine, phenylalanine, proline, methionine, and tryptophan), AAA: aromatic amino acids
(phenylalanine, tryptophan, and tyrosine), PCAA: positively charged amino acids (arginine, histidine, lysine); NCAA: negatively charged amino acids (aspartic
acid, glutamic acid), EEA: essential amino acids (phenylalanine, valine, threonine, isoleucine, methionine, histidine, leucine, lysine and tryptophan), BCAAs:
branched chain amino acids (isoleucine, leucine and valine), TCF/LEF: T-cell factor/lymphoid enhancer factor, UCP-1 and UCP-2: Uncoupling protein a and 2,
GSK-3β: Glycogen synthase kinase 3 beta, SOCS3: Suppressor of cytokine signaling 3, ACC: AcetylCoA carboxylase, FAS: Fatty acid synthase, LPL: Lipoprotein
lipase, FABP: Fatty acid binding protein, SREBP-1: Sterol regulatory element binding protein-1c, SOCS-3: Suppressor of cytokine signaling-3, CD36: Cluster of
dierentiation 36, GLUT4: Glucose transporter type 4, GSK-3β: Glycogen synthase kinase-3β, CCND1: Cyclin D1, TCF/LEF: T-cell factor/lymphoid enhancer factor,
LRP6: Low-density lipoprotein receptor-related protein 6, Wnt-10b: Wingless-type MMTV integration site family, GLUT: Glucose transporter, SGLT: Sodium
glucose cotransporter.
Table 3. (Continued).
Fish name and part used
Observed eect(s) including percentage of
eect and IC50
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
2015; E. J. Lee et al. 2017; Nasri et al. 2015). Anti-diabetic
fish biopeptides exert their effect through different mecha-
nisms nevertheless they commonly lower blood glucose and
activities of α-amylase, α-glucosidase, and DPP-IV, increase
intracellular calcium concentration, insulin, CCK and GLP-1
secretion, glucose uptake and clearance improving glucose
tolerance and preventing insulin resistance. Like glucoregula-
tory fish biopeptides, hypolipidemic, anti-obesogenic and
anti-MetS peptides act via various modes too but generally
by modulating plasma and hepatic lipid parameters, lipid
peroxidation, bile acid binding and excretion, food intake and
body weight gain (lean and fat), expression of adipogenic
genes, appetite related proteins and their expression, athero-
genic index (AI) and coronary risk index (CRI). Not only
that fish anti-MetS peptides have been fairly stable in the
gastrointestinal (GI) environment but also proteolytic activity
of the digestive tract in many examples have shown to improve
the bioactivity of these compounds. Moreover, many of the
fish anti-hyperglycemic and or anti-hyperlipidemic peptides,
based on their absorption, distribution, metabolism, and excre-
tion (ADME) properties, are druglike compounds which could
further be used on as pharmaceutical biomolecules. In the
following text, authors will discuss the topics of production
of anti-MetS fish biopeptides, effects of these products on
metabolic impairments, their multi-functional properties and
structure-activity relationship including their susceptibility to
GI proteases.
Extraction, isolation, and purication techniques
A broad range of enzymes are in use for the preparation
of anti-MetS biopeptides from fish and fish products or
byproducts. Enzyme choices range from pure or mixed
commercial enzymes to alkaline, neutral, acid proteases and
or in-house prepared crude plant-, fish- and or
bacterial-proteases. Fish enzymes were derived from the
digestive tract of many types of fish such as zebra blenny,
smooth hound, etc. Typically, bacterial crude enzymes were
derived from Bacillus species, yet handful studies have made
use of Aspergillus and or Streptomyces species. Plant-originated
enzyme was prepared from papaya latex for hydrolysis of
shark skin (Kittiphattanabawon etal. 2013). Among the so
commonly used enzymes some peculiar ones e.g., seabzyme,
izyme, etc. are also found in literature. It is of note that
enzymatic hydrolysis has not always been the best course
for preparation of glucoregulatory fish biopeptides since it
could under certain experimental conditions diminish and
or interrupt the bioactivity (Li-Chan etal. 2012; T.-Y. Wang
et al. 2015). For efficient isolation, filtration methods were
applied to the material in the majority of the studies.
Furthermore, except in a few studies for selective separation
and purification, as routine for fish hypotensive and immu-
noregulatory peptides, chromatographic procedures were
commonly practiced (Ktari et al. 2013; Nasri et al. 2018;
Nasri et al. 2015; Siala et al. 2016).
Antidiabetic fish peptides were generally prepared by enzy-
matic hydrolysates however to optimize the digestion various
studies employed pretreatments of some sort like microwave
and alkaline/acidic solubilization particularly those attempting
to isolate gelatinous and or collagenous material out of fish
byproducts. Handful studies effectively proceeded without
hydrolyzing the material (e.g., preparation of soluble and
insoluble proteinous fractions) (Kato etal. 2011; Y. M. Kim
et al. 2015; Madani et al. 2012). Among many enzyme
choices, flavourzyme has been superior over alcalase,
14 S. ABACHI ETAL.
Table 4. Fish peptides with bioactivities on MetS associated risk factors (in-vivo studies with mono- and or multi-functionalities).
Fish name and part used Observed eect(s)
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
In-vivo studies (mono-functional)
Alaska pollack (T.
chalcogramma) llet
100 mg kg−1 (intraperitoneal)
↓ blood glucose in T2D KK-Ay rats,
ANGEVAQWR 1,029 Da, IWHHTFYNELR
1,515 Da
(Ayabe etal.
2015)
3 mg kg−1 ANGEVAQWR (intraperitoneal)
↓ blood glucose in T2D KK-Ay rats,
1 mg kg−1 of QWR (intraperitoneal)
↓ blood glucose in T2D NSY and KK-Ay rats
Alaska pollack (T.
chalcogramma) llet
300 mg kg−1 BW, 2-times daily, 2- and 3-d
(intraperitoneal)
↓ total food intake and total BW gain, perirenal and
epididymal adipose tissue weight, sum of perirenal
and epididymal adipose tissue weights, appetite
related mRNA expression in hypothalamus
(neuropeptide Y), agouti-related protein,
↑ soleus skeletal muscle weight in rats
(Mizushige et al.
2017)
Alaska pollack (T.
chalcogramma) meat,
commercial
water-insoluble
dehydrated protein
preparation
197 g kg-1 diet (methionine supplemented (low- (2.5 g
kg-1 diet) and high-Met (5 g kg-1 diet)), ad libitum,
28-d
↓ plasma cholesterol,
↑ mRNA levels of IBAT, ApoB, SREBP-1a, cholesterol
12α-hydroxylase and fecal BA (except high-Met
diet), BA in small-intestinal contents, mRNA levels of
SREBP-1c in OVX rats
CAA 84 > HAA 57 > BCAA 31 g kg-1 diet, L/A
2.0, M/G 0.38
(Kato et al. 2011)
Alaska pollock (T.
chalcogramma) llet
10% sh protein or 2% pure tuna oil (FO) or sh
protein + FO, 4-wks
↓ serum TG (≤ 17%), cholesterol (≤ 18% except FO),
and LDL-c (≤ 8%), hepatic TG (≤ 50% except sh
protein), and cholesterol (≤ 32% except FO),
↑ HDL-c (≤ 9% except FO), fecal cholesterol (≤ 32%
except FO), and BA (≤ 74%) in rats
CAA 50 > HAA 42 > BCAA 19 > AAA 9 g 100 g-1
protein, L/A 1.56, M/G 0.92
(Hosomi et al.
2013)
Alaska pollock (T.
chalcogramma) llet
4-wks diet
↓ serum cholesterol (15%), TG (15%), and LDL-c (26%),
hepatic cholesterol (27%),
↑ serum HDL-c (11%), fecal cholesterol and BA (102%)
compared to casein in hypercholesterolemic diet fed
rats
HAA 430 > C AA 420 > BCAA 187 g kg-1
protein, L/A 1.82, M/G 0.45
(Hosomi et al.
2012)
Alaska pollock (T.
chalcogramma) llet
10% casein + 10% sh (100 g kg-1 diet) protein (w/w),
4-wks
↓ serum cholesterol and LDLc, hepatic cholesterol,
↑ fecal cholesterol, BA acid, and nitrogen excretion
compared to 20% casein diet in
hypercholesterolemic fed rats
CAA 47 > HAA 39 > BCAA 18 g 100 g-1 protein,
L/A 1.56, M/G 0.92
(Hosomi et al.
2011)
Alaska pollock (T.
chalcogramma) llet
113.8 g kg-1 diet, 4-wks
↓ serum TG (42%), NEFA (29%), AST (18%), and ALT
(20%), hepatic TL (43%), and TG (29%), relative
mRNA SCD-1 expression level (59%), hepatic FA and
FA desaturase indices
↑ fecal FA (37%) compared to casein in obese T2D
KK-Ay rats
High in myobril proteins (myosin heavy
chain ∼120 kDa and actin ∼45 kDa), CAA
471 > BCAA 184 > AAA 87 > Gly 36 > Pro
33 g kg-1 total AA, L/A 1.56, M/G 0.92
(Maeda et al.
2015)
Allaska pollock (T.
chalcogramma) llet
4-wks diet
↓ serum cholesterol (≤ 18%), serum LDL-c (≤ 17%),
liver cholesterol (≤ 32%),
↑ serum HDL-c (7%) compared to casein in
hypercholesterolemic diet fed rats
(Hosomi et al.
2010)
Bester sturgeons (Huso
huso × Acipenser
ruthenus) skin, n, and
bone
1.5 g kg-1 BW, single oral injection
↓ blood glucose levels in rats
Atelocollagen (type I collagen): βchain
220 kDa, collagen fraction: A(HP)
GPAGPTGK 868 Da, A(HP)GPVGPAGP
835 Da, E(HP)GPAGP(HP)GP 907 Da,
TGGIGG(HP)GGS 775 Da, AVGPVGPIGP
863 Da, AAGPHPG 485 Da, A(HP)GPAG
485 Da, GPGGPA 455 Da, L(HP)GPTG
557 Da, GPLGPA 511 Da, APAG 314 Da,
GYGPGPA 618 Da, GGYE 424 Da, GEYGP
522 Da, F(HP)GG(HP)GAKG 819 Da, FVA
335 Da, APNPFRHY 1,001 Da
(Sasaoka et al.
2018)
Blue whiting (M.
poutassou) muscle
100 mg kg-1 BW
↓ blood glucose,
↑ insulin release in normal rats
1 − 5 kDa (21%), 0.5 − 1 kDa (29%), <0.5 kDa
(49%),
CAA 26 > HAA 23 > BCAA 10 g 100 g-1, L/A
1.32, M/G 0.65
(Harnedy et al.
2018b)
Boarsh (C. aper) muscle 50 mg kg-1 BW
↑ insulinotropic response, glucose tolerance in oral
glucose challenged normal rats
2 − 1 kDa (18%), <1 kDa (74%) (Parthsarathy
et al. 2019)
(Continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 15
Chum salmon (O. keta)
and rainbow trout (O.
mykiss) skin,
commercial > 90%
purity collagen
preparation)
0.4 g single dose (oral)
↓ plasma TG in fat fed rats,
3 − 10 kDa
HAA 63% > Gly 37% > CAA 23% > imino
acid 15% > BCAA 45%
(Saito et al. 2009)
0.17% sh collagen, 14-d
↓ plasma TL, TG and VLDL-TG in fat fed rats
Cod llet powder (93%
protein)
21 g d-1 (19.61% protein) diet, 21-d
↑ BW gain pre-injury (6%), sham muscle mass at 3-d
post-injury, sham (13%) and injured muscle (12%)
mass at 14-d post-injury, myober cross-sectional
area in sham muscle at 14-d post-injury compared
to casein in rats
EAA 43 > C AA 47 > BCAA 19 g 100 g-1 AA, L/A
1.83, M/G 0.82
(Dort et al. 2012)
Pacic hake (M.
productus), halibut (H.
stenolepis), tilapia (O.
niloticus), milksh (C.
chanos) fresh skins,
byproducts recovered
from skin-o llet
750 mg kg-1 d-1 28-d
↓ blood glucose (except pacic hake and milksh),
DPP-IV activity (except pacic hake, halibut, and
milksh) 28%,
↑ total GLP-1 and secretion (except pacic hake and
milksh) in streptozotocin-induced diabetic rats
High in Gly, Pro and Hyp (tilapia and
milksh: 1.95 − 2.03 µmole imino acids
mg-1 sample, halibut and hake;
1.77 − 1.79 µmole imino acids mg-1
sample), halibut: SPGSSGPQGFTG 862 Da,
GPVGPAGNPGANGLN 1,021 Da,
PPGPTGPRGQPGNIGF 1261 Da, tilapia:
IPGDPGPPGPPGP 920 Da, LPGERGRPGAPGP
1,027 Da, GPKGDRGLPGPPGRDGM 1,359 Da
(T.-Y. Wang et al.
2015)
Salmon (S. salar) and cod
(G. morhua) frozen
byproduct frames
10% salmon (<1 kDa) protein, 3-mos
↓ fasting hyperinsulinemia and glucose intolerance,
hepatic glucose production from gluconeogenesis in
HFHS fed LDLR-/-/ApoB100/100 rats
(Jin 2013)
Sardine (S. pilchardus) and
bogue (B. boops) fresh
muscle
1 g kg-1 BW d-1, 30-d
↓ serum lipids (TC 66%, TG ≤ 41%, PL ≤ 53%,
unesteried cholesterol ≤ 36%, cholesteryl ester ≤
68%), liver lipids (TC ≤ 22%, cholesteryl esters ≤
29%, unesteried cholesterol ≤ 15%),
↑ serum apolipoprotein A-IV ≤ 33%, fecal cholesterol
excretion in hypercholesterolemic diet fed rats
CAA 34 − 36% > BCAA 9 − 20% > sulfur
containing AA 7 − 14%
(Benomar et al.
2015)
Sardine (S. pilchardus) and
sardinelle (S. aurita)
fresh muscle
300 mg sh diet, 14-d (oral gavage)
↓ serum lipid parameters (TC ≤ 42%, TG ≤ 46%,
unesteried cholesterol ≤ 35%, cholesteryl ester ≤
51%), serum LDL-HDL1 ≤ 57%, AI ≤ 17%,
↑ HDL2 ≤ 22%, HDL3 ≤ 40% in hypercholesterolemic
diet fed rats
(Athmani et al.
2015)
Siki (C. coelolepis) cooked
heads and saithe (P.
virens) cooked muscle
50 mg d-1 per rat, 21-d
↑ plasma CGRP levels (70%) (except saithe lysate)
Siki hydrolysate: 800 − 1,500 Da (74%),
≤340 Da (26%), GFP(HP)GPEGL
(Martínez-Alvarez
et al. 2012)
Smooth hound (M.
mustelus) muscle
5 mg d-1 per rat, 3-wks (oral)
↓ BW gain, food intake in rats
CAA 30% > BCAA 21% > Gly 12% > Ala
10%, L/A 1.46
(Bougatef et al.
2010)
Tilapia (Oreochromis sp.)
scale, commercial food
grade collagen
(Wellnex® Type D)
preparation by Nitta
Gelatin, Inc., Japan
3 g kg-1
↓ glycemic response during OGTT (28%) and IPGTT
(18%), intestinal glucose uptake
↑ glucose-stimulated active GLP-1 and insulin secretion
in normal rats
(Iba et al. 2016)
Tuna skin byproduct 300 mg kg BW d-1, 8-wks (oral)
↓ BW gain, expression of adipogenic genes and
transcription factors, epididymal adipocyte size,
plasma TC (11%), TG (6%), and LDL-c (14%),
↑ HDL-c (19%) in HFD-fed obese rats
(E. J. Lee et al.
2017)
Zebra blenny (Salaria
basilisca) fresh muscle
400 mg kg-1 BW d-1, 8-wks (gastric gavage)
↓ serum AST and LDH activities, lipid peroxidation,
protein oxidation and ROS production, TBARS, AOPP
and H2O2 in heart tissues, GPx, SOD, and CAT,
↑ ATPase activities and GSH in heart tissues back to
normal levels in hypercholesterolemic diet (1%
cholesterol + 0.1% cholic acid) fed rats
Zebra blenny, smooth hound, and sardinelle
proteases: 5 − 20 kDa (46, 49, 49%),
<5 kDa (43, 42, 27%)
(Ktari et al. 2017)
In-vivo studies (bi- and or multi-functional)
Atlantic herring (C.
harengus) byproducts
(heads, guts, and
backbones), Atlantic
salmon (Salmo salar)
byproducts (backbones)
5% sh hydrolysate + 15% casein/whey, 4-wks
↑ daily dietary intake of sodium, chloride, and
potassium,
↓ urine concentrations (relative to creatinine
concentration) of total protein, glucose and cystatin
C, urine concentrations of potassium
(Drotningsvik,
Pampanin,
et al. 2018)
Atlantic salmon (S. salar)
fresh skin byproducts
(recovered from skin-o
llets)
300 mg d-1, 5-wks
↓ blood glucose levels, plasma DPP-IV activity, food,
and water intake,
↑ active GLP-1 secretion, insulin, insulin-to-glucagon
ratio, body weight in STZ-induced diabetic rats
(Hsieh et al.
2015)
Table 4. (Continued).
Fish name and part used Observed eect(s)
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
(Continued)
16 S. ABACHI ETAL.
Atlantic salmon (S. salar)
frozen frames
10.75 g peptides kg-1 diet, 12-wks
↓ body and liver weight, feed eciency, plasma TG
and glycerol, glucose intolerance in LDLR−/−/
ApoB100/100 rats
EAAs 46 > HAA 43 > CAA 40 > BCAA 19 g
100 g −1 protein
(Chevrier et al.
2015)
Blue whiting (M.
poutassou) fresh frozen
muscle
100 − 250 mg, 12- d (oral)
↓ food consumption, weight gain (except 250 mg),
↑ active GLP-1 (≤ 55%), plasma CCK (≤ 66%) (dose
dependent) in rats
(Cudennec et al.
2012)
Blue whiting fresh frozen
whole
33% sh (108 g kg-1 diet) + 67% casein, 5-wks
↓ serum TC, cholesteryl ester, LDL-c and HDL-c, hepatic
cholesterol, HMG-CoA reductase, and LDL receptors
compared to casein obese Zucker fa/fa rats
HAA 59 > BC AA 34 > PCAA 27 > Tau 0.2 g kg-1
diet, L/A 2.08, M/G 0.65, >20 kDa 37%,
10 − 20 kDa 13%, 0.2 − 10 kDa 13%,
<0.2 Da 37%, GGV
(Drotningsvik,
Vikøren, et al.
2018)
Bogue (B. boops) llet 0.1, 0.5 and 2 g kg-1 BW d-1 (digested and
non-digested)
↓ TC (≤ 35%), TG (≤ 43%), LDL-c (≤ 72%), ALT, AST,
atherosclerotic plaques (including formation of foam
cells),
↑ HDL-c (≤ 22%) in hypercholesterolemic diet fed rats
HAA 45 − 48%, CAA 28 − 29%, BCAA
14 − 14%, AAA 8 − 9%, L/A 0.23 − 0.33,
M/G 0.22 − 0.26
(Lassoued et al.
2014)
Bonito, herring, mackerel,
salmon, commercial
preparations by Ocean
Nutrition (Nova Scotia,
Canada), Aquatic
Products Technology
Center (Quebec,
Canada), Marine Harvest
Ingredients (Hjelmeland,
Norway)
20% protein (w/w), 28-d
↓ BW gain (gross weight gain eciency ratio), dietary
fat mediated accretion of eWAT (visceral adiposity)
(except bonito, herring, mackerel),
↑ energy expenditure, glucose infusion rate, circulating
sCT (except bonito, herring, mackerel) in HFHS (20%
lard + 22% sucrose + 0.2% choline bitartrate) diet
fed rats
(Pilon et al. 2011)
Chub mackerel (fermented),
commercial preparation
(51.1% crude protein)
10 − 20 g kg-1 diet
↓ ACC, FAS, serum TG, AI,
↑ feed intake, body weight gain, CYP7A1, HDL-c in
diabetic rats
(Santoso,
Ishikawa, and
Tanaka 2010)
Cod (T. chalcogramma)
and tuna (T. orientalis)
light muscle
23% protein diets, 4-wks
↑ weight gain, nal weight, food intake, fecal acidic
sterols, and nitrogen (except cod), fecal neutral
sterols and HMGCR mRNA expression (except tuna),
SHP-1 mRNA expression,
↓ serum cholesterol, HDL-c, non-HDL-c, PL, NEFA,
relative liver weight, and hepatic cholesterol (except
tuna), CYP7A1 mRNA expression compared to casein
in hypercholesterolemic diet fed rats
myosin ∼116 kDa and actin ∼45 kDa,
Cod: CAA 47% > HAA 39% > BCAA 16%,
L/A 1.17, M/G 0.71,
Tuna: CAA 47% > HAA 38% > BCAA 16%,
L/A 0.99, M/G 0.79
(Hosomi et al.
2017)
Cod llet 200 g protein kg-1 diet for low fat and or 400 g protein
kg-1 diet for high-fat/high-protein, 6- and 12-wks
(ad libitum)
↓ further weight and fat mass gain, feed eciency,
↑ lean mass, insulin sensitivity in hyper- and
normo-caloric diet fed C57BL/6J (obese or lean) rats
(Myrmel et al.
2019)
Cod powder, commercial
non-hydrolyzed
preparation by
Seagarden AS, Norway
5% cod + 15% casein/whey + (w/w), 4-wks (ad
libitum)
↑ BW and growth percentage, liver weight, cholesterol
level in liver,
↓ postprandial blood glucose in obese Zucker fa/fa rats
(Drotningsvik
et al. 2015)
Fish collagen, commercial
preparation by Nippi
Inc., Japan and Oriental
Yeast Co. Ltd., Japan
6% casein + 4% sh collagen, 10-wks
↑ food intake, hepatic expressions of lipid metabolism
involved genes and their targets,
↓ adiponectin, TC, free cholesterol, esteried
cholesterol, expression of unfolded protein response
involved genes compared to casein in rats
MW 4 − 6 kDa (Tometsuka et al.
2017)
Fresh Norwegian Atlantic
salmon o-cut spine
byproducts, commercial
91% pure protein
preparation by Marine
Bioproducts AS, Norway
5% (w/w), 12-wks
↑ plasma non-esteried FA, C18:2n-6 (linoleic acid) and
C20:4n-6 (arachidonic acid)
↓ plaque area in sinus and aortic arch, hepatic mRNA
level of ACACA, SCD1 compared to casein diet in
ApoE-/- rats
<1,200 Da (<200 Da 25%) (Parolini et al.
2014)
Fresh Norwegian Atlantic
salmon o-cut spine
byproducts, commercial
91% pure protein
preparation by Marine
Bioproducts AS, Norway
165 g kg-1 diet (15% (w/w)), 2-wks
↓ hepatic activity of FA synthase,
↑ weight gain, feed intake, hepatic activities of
peroxisomal ACOX1 and mitochondrial carnitine
palmitoyltransferase-II in hTNF-α mice
(Bjørndal et al.
2013)
Table 4. (Continued).
Fish name and part used Observed eect(s)
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
(Continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 17
Goby sh (Z.
ophiocephalus) fresh
muscle
400 mg kg-1 BW d-1, 10-wks (gastric gavage)
↓ plasma glucose 25 − 34%, α–amylase activity ≤ 62%,
hepatic glycogen, hepatic and renal MDA levels,
creatinine, renal damage (improvement of kidney
architecture)
↑ hepatic and renal GPx, CAT, SOD and GSH activities,
uric acid in hypercaloric (high fat high fructose: 10%
animal fat + 5% fructose + 0.1% cholic acid) diet
fed rats
HAA 44 − 47% > EAA 39 − 42% > CAA
27 − 30% > Gly 15 − 16% > BCAA
13 − 15%, L/A 0.46 − 0.58, M/G 0.13 − 0.19
(Nasri et al. 2015)
Goby sh (Z.
ophiocephalus) fresh
muscle
400 mg kg-1 BW d-1, 10-wks (gastric gavage)
↓ weight gain, food intake ≤ 38%, TC, TG, LDL-c and
VLDL-c levels, AI, AIP and CRI, hepatic TG ≤ 43%
and TC ≤ 47%, pancreatic lipase activity ≤ 45%,
liver structure damage, lipid accumulation
↑ HDL-c in high fat/ fructose diet rats
EAA ∼ 42% > HAA ∼ 40% > CAA 27% >
BCAA ∼14% > AAA ∼ 8%, sulfur
containing AA ∼5%,
(Nasri et al. 2018)
Gray triggersh (B.
capriscus) muscle
↓ TG, TC, LDL-c, serum α -amylase activity, blood
glucose, hepatic, and serum GHbA1c, serum
bilirubin, lipid accumulation in hepatocytes
(pancreatic β-cells degeneration), ALT, ALP, and GGT
activities in hepatic and pancreatic tissues
↑ HDL-c in alloxan-induced diabetic rats
High Lys and Arg (Siala et al. 2016)
Mixture of wild caught cod
lets and Canadian
scallop muscles (cod/
scallop, 1 : 1 on amino
acid content)
13-wks diet (ad-libitum)
↓ weight gain, atherosclerotic plaque burden, leptin,
hepatic fat and fatty acid concentration, serum
LDL-c and glucose levels, hepatic gene expression of
antioxidative PON2 and VCAM1 in ApoE−/− rat
CAA 62 > HAA 58 > EAA 56 > BCAA 23 mg g-1
diet, L/A 1.48, M/G 0.62
(I.-J. Jensen et al.
2016)
Mixture of wild caught cod
llet and Canadian
scallop muscles (cod/
scallop, 1 : 1 on amino
acid content)
200 g protein kg-1 diet, 7-wks (pair-feeding design)
↓ body mass gain, adipose tissue masse, hepatic TG,
↑ glucose clearance, energy expenditure and activity in
obesity prone C57BL/6J mice
CAA 550 > EAA 512 > BCAA 237 > Gly
192 > sulfur containing AA 137 > Tau
61 mmol/kg, L/A 1.59, M/G 0.18
(Tastesen et al.
2014)
Nile tilapia (O. niloticus)
fresh
skin
1.7 g kg−1 BW, 25-d
↓ typical symptoms of T2D (hunger and thirst), weight
gain, blood glucose levels (≤ 32%) in alloxan
induced diabetic rats
CAA 23 > imino acids 21 > Gly 19 g 100-1 g,
<1,000 Da 77% (short peptides < 9 AAs),
L/A 0.05, M/G 0.07
(R. Zhang, Chen,
Chen, et al.
2016)
Norwegian spring
spawning herring and
salmon (backbones)
fresh byproducts
114 g kg-1 diet (25% sh lysate + 75% casein/whey),
4-wks
↓ serum LDL-c, HDL-c, TC, cholesteryl ester levels, total
serum n-6 PUFA (except salmon), postprandial
glucose, WAT 16:0 and total SFA (except herring),
20:4n-6,
↑ mean growth %, serum 18:2n-6, WAT 18:3n-3 and
total n-3 PUFA (except herring), serum TG, -9
desaturated MUFA (16:1n-7 and 18:1n-9), total
MUFA, 22:5n-3, n-3:n-6 PUFA ratio (except salmon),
18:3n-3 compared to casein/whey in obese Zucker
fa/fa rats
<4 kDa (93 − 98%), 200 − 500 Da (14%),
200 − 1,000 Da (31 − 32%), <200 Da
(herring: 34%, salmon: 20%),
Herring: GPL, IPI, VW, GPAE, LGPG, IIAEK,
PGPL, HAA 66 > BCAA 41 > PCAA 35 > Tau
1 g kg-1 diet, L/A 1.6, M/G 1.0,
Salmon: GPL, IPI, VW, PGPL, HAA 68 > BCAA
42 > PCAA 32 > Tau 0.4 g kg-1 diet, L/A 2.0,
M/G 0.9
(Drotningsvik
et al. 2016)
Pollack (T. chalcogramma)
frame byproduct
11, 16, 21 and 26% of 310 g kg−1 sh meal (w/w) +
690 g kg−1 plant protein), hand-fed to apparent
satiation 2-times daily, 2-wks
↓ Liver IGFI mRNA level
↑ nal BW and SGR, feeding rate in high plant protein
fed Japanese ounder (Paralichthys olivaceus)
< 1,000 Da (93%), non-EAA 176 > CAA
166 > EAA 151 > BCAA 54 g kg−1 dry diet,
L/A 0.97, M/G 0.32
(Zheng et al.
2014)
Pollack (T. chalcogramma)
frame byproduct
6.2 − 12.4% of sh meal (w/w) (10 − 20% of diet’s total
protein + plant protein) 12-wks (hand-fed to
apparent satiation 2-times daily)
↓ SGR, FER, PER, PR, VSI, serum TG, TC and LDL-c,
↑ food intake in high plant protein fed Juvenile turbot
(Scophthalmus maximus)
>2 kDa (1%), 0.5 − 2 kDa (27%), 0.2 − 0.5 kDa
(57%), <0.2 Da (15%), non-EAA ∼20% >
EAA ∼18%, CAA ∼18% > BCAA ∼7%, Tau
∼0.15% dry matter, L/A 1.19, M/G 0.50
(Xu et al. 2016)
Pollock (T. chalcogramma)
esh
Hydrolysate and UF fractions 40% of sh meal diet,
30-d (hand-fed to apparent satiation 5-times daily)
↓ mRNA expression of peptide transporter 1 (PepT1)
and CCK,
↑ AST and ALT activities (except hydrolysate) in large
yellow croaker (Larimichthys crocea) larvae
Hydrolysate: (2 − 0.5 kDa 59%, < 0.5 kDa
41%), UF retentate: (2 − 0.5 kDa 76%,
<0.5 kDa 24%), UF permeate: (2 − 0.5 kDa
25%, <0.5 kDa 74%), EAA 35, non-EAA
35 > CAA 33 > BCAA 13 g 100 g-1 dry
matter, L/A 1.47, M/G 0.64
(Cai et al. 2015)
Table 4. (Continued).
Fish name and part used Observed eect(s)
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
(Continued)
18 S. ABACHI ETAL.
Salmon spine and or
backbones including
heads, commercial
preparation by Marine
Bioproducts AS, Norway
(15% casein + 5% salmon peptide), 6-wks
↓ BW gain, total weight gain, plasma and hepatic TG,
FAS activity, hepatic MUFA, FADS1 and HMGCR
expression (except umamizyme spine lysate), liver
index (% liver weight/BW) and hepatic TC (except
spine lysates), hepatic ACACA and FADS2 expression
(except umamizyme spine and alcalase backbone
lysates), n-3 and n-6 PUFAs (except acid protease A
spine and alcalase backbone lysates),
↑ feed intake, FAS activity, hepatic n-6 PUFAs (except
umamizyme spine and alcalase backbone lysates),
plasma TG, TC, PL, HDL-c and hepatic 9 desaturase
mRNA level, 9 desaturase index and MUFA (except
acid protease A spine and alcalase backbone
lysates), hepatic n-3 PUFAs, NEFA, β-oxidation, 5
and 6 desaturase (n-3) index (except spine lysates),
hepatic ACOT1 expression (except acid protease A
spine lysate), hepatic 5 desaturase (n-6) index, and
PL (except umamizyme spine lysate) compared to
20% casein in high fat fed rats
Spine hydrolysates: 200 − 1,200 Da (>50%),
<200 Da (25%), backbone and head
hydrolysate: <1,200 Da (∼60%), HAA
42 − 48% > CAA 38 − 44% > BCAA
17 − 23% > imino AA 10 − 13%
(Vik et al. 2015)
Sardine (C. pilchardus)20% protein (w/w), 28-d
↑ serum albumin, relative liver weight, RBC MDA and
SOD activity, epididymal fat and heart CAT activity
compared to casein in hypercholesterolemic diet
(1.5% cholesterol + 0.75% cholic acid) fed rats
(HamzaReguig
et al. 2013)
Sardine (S. pilchardus)
fresh byproducts
(viscera, heads, skins,
and edges) and llets
20% (200 g kg-1 diet) llet and/or byproducts protein,
4-wks
↓ BW gain 41 − 84%, food intake 19 − 36%, food
eciency rate 27 − 75%, nal BW ≤ 6%, liver
relative weight ≤ 11%, adipose tissue relative
weight ≤ 18%, lipid intake 19 − 36%, serum leptin
14 − 29% and LDL-HDL1-c 43 − 56%, serum TC
27 − 31%, VLDL-c 55 − 62%, VLDL-TG 31 − 41%, liver
TG 29 − 37%, HDL3-PL 43 − 48%, HDL3-UC 26 − 35%,
serum and lipoproteins TBARS ≤ 64%,
↑ fecal lipid 21 − 35%, and cholesterol 27 − 47%,
plasma HDL2-c 50 − 62%, and HDL3-c 25 − 35%, LCAT
activity 35 − 57%, HDL3-apo 19 − 49%, HDL2-CE
88 − 108%, serum and lipoproteins PON-1 ≤ 119%
compared to casein in high fat fed obese rats
Byproduct protein diet: CAA 43% > HAA
38% > BCAA 18% > Gly 6% > Tau 5%,
L/A 1.33, M/G 0.51
(Aane et al.
2018)
Sardine llet (head,
internal organs and
bones excluded)
200 g kg-1 diet (with or without fructose), 8-wks
↓ food intake, perirenal and epididymal adipose tissue
wet weight, body composition index, plasma
glucose, insulin, TG, FFA, brinogen, HOMA-IR index
and HbA1c, perirenal and brown adipose tissues
hydroperoxide,
↑ plasma α-tocopherol, taurine and calcium, brown
adipose tissue GSH-Px activity, epididymal and
perirenal WAT SOD activity, perirenal, epididymal
and BAT CAT activity compared to casein in high
fructose diet fed rats
(Madani et al.
2012)
Sardine muscle 1 g kg-1 BW d-1, 4-wks (oral)
↓ plasma glucose (13%), heart weight and ratio of
heart weight to BW, urinary albumin excretion
(73%) in stroke prone SHR at 4 weeks
(Otani et al.
2009)
Sardine muscle tissue 20% sh diet, 8-wks
↓ plasma glucose, insulin, creatinine, uric acid, and
homeostasis model assessment-insulin resistance
index levels, weight gain, food, and energy intakes
↑ GLP-1 secretion in high fructose fed rats
CAA 45 > HAA 41 g 100 g-1 protein (Madani et al.
2015)
Sardinelle (S. aurita) fresh
muscle
400 mg kg−1 BW, 10-wks (gastric gavage)
↓ fat accumulation and epididymal fats ≤ 31%, serum
TC ≤ 40%, TG ≤ 23.5%, LDL-c ≤ 43% and
VLDL-c ≤ 40%, atherogenic index, atherogenic index
of plasma ≤ 60% and coronary risk index ≤ 45%,
hepatic TG ≤ 38% and TC ≤ 53% concentrations,
lipase activity, liver fatty inltration and formation
of lipid vacuoles, hypertrophy of cells in infarction
of heart tissue, lipid deposition within intima of
aorta and lesion development in aortic wall,
↑ HDL-c in hypercaloric diet fed rats
High HAA, MW 150 − 900 Da (B. subtilis A26
(150 − 600 Da) > B. amyloliquefaciens
An6)
(Jemil, Abdelhedi,
et al. 2017)
Table 4. (Continued).
Fish name and part used Observed eect(s)
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
(Continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 19
Sardinelle (S. aurita) fresh
muscle
400 g kg − 1 BW d-1, 10-wks (gastric gavage)
↓ plasma glucose ≤ 22%, α-amylase activity ≤ 45%,
hepatic glycogenesis ≤ 71%, hepatic and renal MDA
levels, hepatic ALP ≤ 25%, renal creatinine 45%,
renal glomerular atrophia, hepatic tissue damage
↑ hepatic and renal SOD activity (≤ 52% and ≤ 42%),
hepatic and renal GPx activity (≤ 32% and ≤ 84%),
hepatic and renal CAT activity (≤ 41% and ≤ 62%),
hepatic and renal GSH activity (≤ 30% and ≤ 41%)
in hypercaloric diet (10% sheep fat, 5% fructose,
0.1% cholic acid) induced hyperglycemic and
oxidative stressed rats
B. subtilis A26 product: EAA 45 > CAA 27,
HAA 27 > imino acids 5, BCAA 5 > Tau 0.4
residue 100-1 AA residues, L/A 2.71, M/G
0.55,
B. amyloliquefaciens An6 product: EAA
40 > CAA 36, HAA 21 > imino acids
5 > BCAA 2 > Tau 1.8 residue 100-1 AA
residues, L/A 2.37, M/G 0.38,
undigested product: EAA 36, CAA 35 > HAA
33 > imino acids 11 > BCAA 3 > Tau 1.0
residue 100-1 AA residues, L/A 2.30, M/G
0.15
(Jemil, Nasri,
et al. 2017)
Sardinelle (S. aurita) fresh
muscle
5% sh diet (w/w), 7-wks
↓ serum TC ≤ 22%, serum TG ≤ 46%, AI ≤ 47%,
LDL-c ≤ 41%, hepatic damage (AST ≤ 41%, ALT ≤
30%, PAL ≤ 21%, LDH ≤ 44%),
↑ HDL-c ≤ 29% in hypercholesterolemic diet fed rats
(Khaled et al.
2012)
Shark (S. mitsukurii and C.
plagiosum) fresh
healthy liver
50 µg S8300 peptide mL-1
↓ degree of injury in STZinduced mouse insulinoma
βcells (NIT1β),
8,201 and 8,300 Da, NH2terminal sequence
(NH2 MLVGPIGAAKVVYEQ)
(F. J. Huang &
Wu, 2010)
3 − 10 mg S8300 kg-1 BW d-1, 4-wks (intraperitoneal)
↑ hepatic (≤ 24%) and renal (≤ 35%) SOD,
↓ body weight loss, blood glucose 28 − 49% and
HbA1c levels, plasma lipid levels (cholesterol ≤ 24%,
TG ≤ 61% and FFA ≤ 67%), hepatic (≤ 23%) and
renal (≤ 29%) MDA, FAS and FAS/GAPDH mRNA
expression in pancreas, FAS protein expression,
apoptosis of pancreatic tissue (degree of βcells
injury) dose dependently in alloxaninduced diabetic
rats
Skate (R. kenojei) skin,
commercial collagen
perperation
200 − 300 mg kg-1 BW d-1, 8-wks (oral)
↓ liver, visceral and subcutaneous adipose tissue
weight (but not epididymis adipose tissue), lipid
droplet size, plasma TG (≤30%), NEFA (≤ 31%), and
LDL-c (≤ 42%), hepatic TG (≤ 25%), liver lipid
accumulation, hepatic expression of SREBP-1 (≤
18%), FAS (≤ 29%), ACC (≤ 39%), SREBP-2 (≤ 13%),
HMGCR (≤ 32%), and CYP7A1 (≤ 176%), leptin (≤
23%),
↑ plasma HDL-c (≤ 320%), hepatic expression of
PPAR-α (≤ 159%), CPT-1 (≤ 163%), and p-AMPK
(156%), adiponectin (≤ 131%) in HFD fed obese rats
1,050 Da, CAA 31% > Gly 22% > imino AA
16% > BCAA 9%, L/A 0.45, M/G 0.01
(Woo et al. 2018)
Skate skin 200 mg kg-1 BW d-1, 8-wks (oral)
↓ plasma and hepatic TG and TC, hepatic expression of
SREBP-1, FAS, ACC, and SREBP-2,
↑ hepatic expression of MAPK, PPAR-α, ACOX1, and
CYP7A1 in obese rats
(H. Lee et al.
2018)
Smooth hound viscera ↓ food intake (except for undigested and hydrolysate),
plasma glucose levels (≤ 28%), uric acid (except <
1 kDa fraction) (≤ 27%), plasma TC (≤ 17%), TG (≤
23%), atherogenic index of plasma (AIP) (≤ 68%),
↑ plasma HDL-c (≤ 61%), creatinine (≤ 16%) in
high-salt (18% NaCl) and -fructose (10%) diet
(HSFD)-induced hypertensive rats
CAA 38 − 41 > HAA 29 − 40 > EAA
33 − 34 > BCAA 11 − 12 > imino AA 7 − 9 g
100 g-1 AA, L/A 1.36 − 1.54, M/G
0.13 − 0.19
(Abdelhedi et al.
2019)
Thornback ray (R. clavata)
fresh muscle
700 mg kg-1 BW d-1, 1-mo
↓ hepatic damage (AST ≤ 21%, ALT ≤ 27% and ALP ≤
15%), renal dysfunction (urea ≤ 20%, creatinine ≤
37%, uric acid ≤ 16%), plasma lipid prole (TG ≤
35%, TC ≤ 26%, LDL-c ≤ 49%, VLDL-c ≤ 45%), AI ≤
61%, blood glucose ≤ 25%, α–amylase ≤ 22%,
↑ HDL-c ≤ 30% in hypercholesterolemic diet fed rats
(Lassoued et al.
2018)
Tuna extract 200 − 400 mg kg-1 BW d-1, 10-wks
↓ BW, epididymal and abdominal adipose tissue
weight, liver weight, serum glucose (≤ 24%), TG (≤
28%), TC (≤ 23%), LDL-c (≤ 24%), insulin (≤ 28%),
leptin (≤ 35%), ALT and AST, hepatic expression of
lipogenesis and adipogenesis related genes (C/
EBP-α/-β/-δ, PPAR-γ, CD36, SREBP-1, LPL and FAS),
expression of GLUT4,
↑ serum HDL-c (≤27%), hepatic expression of AMPKα,
and AMPKβ in HFD-fed obese rats
(Y. Kim etal.
2016)
Table 4. (Continued).
Fish name and part used Observed eect(s)
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
(Continued)
20 S. ABACHI ETAL.
Warm sea sh skin,
commercial type I and
III collagen preparation
(Naticol®) by Weishardt,
France
4 g kg-1 BW d-1 20-wks
↓ BW gain (fat- but not lean-mass), basal plasma
glucose, plasma cholesterol, plasma insulin
(non-signicant),
↑ plasma TG in HFD fed obese rats
2 kDa, CAA 30% > Gly 30% > imino AA 23%
> BCAA 6%
L/A 0.39, M/G 0.04
(Astre et al. 2018)
Wild marine fresh sh
scales
1 g kg-1 BW every other day, 6-wks (intragastrical)
↓ weight gain (8%), food intake, blood fasting glucose
(29%), relative level of insulin (34%) and GHbA1c
(36%) in obese hypercaloric diet fed rats
(Raksha et al.
2018)
Wild-caught chum salmon
skin
9 g kg−1 BW d-1, 28-d (intragastrical)
↓ weight loss, leptin and resitin,
↑ blood lipid and glucose metabolism, insulin
resistance, adiponectin levels, GLUT4 expression in
skeletal muscle, liver steatosis, PPAR-α expression in
live in hypercaloric (high-cholesterol/fat) diet
induced diabetic rats
130 − 3,000 Da (> 95%), GLPGPLGPAGPK (C. Zhu, Zhang,
Mu, et al.
2017)
Wild-caught chum salmon
skin
9 g kg-1 BW d-1, 4-wks
↓ FBG, endothelial thinning and inammatory
exudation in carotid-artery vascular endothelial cells
in high-cholesterol, high-fat diet (31% beef tallow +
0.2% choline bitartrate)-induced diabetic rats
(C. Zhu, Zhang,
Liu, et al.
2017)
Wild-caught chum salmon
skin, collagenic
preparation
1.35 g kg−1 BW, 8-wks (intragastrical)
↓ fasting insulin and glucose, TC and TG, serum
malondialdehyde, ultrastructural impairment of islet
in high fat diet induced hyperinsulinemic rats
(J. Wang et al.
2010)
Zebra blenny (S. basilisca)
fresh frozen muscle
400 mg kg-1 BW, 8-wks (gastric gavage)
↓ serum and hepatic TG (≤ 38%), TC (≤ 70%), and
LDL-c (≤ 81%), hepatic damage (ALAT and ALP) (≤
38%), kidney damage (urea (≤ 24%), creatinine (≤
8%))
↑ serum and hepatic HDL-c (≤ 54%) in
hypercholesterolemic diet fed rats
Lysates of crude proteases of zebra blenny
(3 − 7 kDa (34%), >10 kDa (29%)), smooth
hound (>10 kDa (54%), 3 − 7 kDa (12%),
and sardinelle (>10 kDa (41%), 7 − 10 kDa
(26%))
(Ktari et al. 2015)
Zebra blenny (S. basilisca)
muscle
400 mg kg-1 BW d-1, 21-d (gastric gavage)
↓ serum and intestine α-amylase activity, blood
glucose ≤ 60%, HbA1c, serum lipid prole (TC ≤
38%, TG ≤ 62%, LDL-c ≤ 51%), hepatic lipid prole
(TC ≤ 65%, TG ≤ 38%, LDL-c ≤ 83%), myocardial
enzymes (CPK ≤ 32.9%, AST ≤ 44.6%, LDH ≤
32.7%), serum enzymes (ALT ≤ 46%, ALP ≤ 44%,
GGT ≤ 45%), serum bilirubin (T-Bili ≤ 46%, D-Bili ≤
63%), hyperglycemic hepatotoxicity, apoptosis of
pancreatic β-cells,
↑ serum and hepatic HDL-c (23 − 38%) in
alloxan-induced diabetic rats
CAA 35% > BCAA 31% > sulfur containing
AA 3%, L/A ∼ 0.51
(Ktari et al. 2013)
Increased, improved, stimulated and or upregulated expressions are denoted as “↑”, and decreased, inhibited and or downregulated expression denoted as “↓”.
HAA: Hydrophobic amino acids (glycine, alanine, valine, isoleucine, leucine, phenylalanine, proline, methionine, and tryptophan), AAA: Aromatic amino acids
(phenylalanine, tryptophan, and tyrosine), PCAA: Positively charged amino acids (arginine, histidine, lysine); NCAA: Negatively charged amino acids (aspartic
acid, glutamic acid), EEA: Essential amino acids (phenylalanine, valine, threonine, isoleucine, methionine, histidine, leucine, lysine and tryptophan), BCAA:
Branched chain amino acids (isoleucine, leucine and valine), LDH: Lactate dehydrogenase, AOPP: Advanced oxidation protein product, ACACA: Acetyl-CoA
carboxylase A, SCD1: Stearoyl-CoA desaturase 1, ALT: Alanine aminotransferase, ALP: Alkaline phosphatase, GGT: Gamma-glutamyl transpeptidase, PON2:
Protein paraoxonase 2, VCAM1: Vascular cell adhesion protein 1, p-AMPK: Phosphorylated 5’ AMP-activated protein kinase, SGR: Specic growth rate, FER:
Feed eciency ratio, PER: Protein eciency ratio, PR: Protein retention, VSI: Viscerosomatic index, ACOT1: Acyl-CoA thioesterase, MUFA: Monounsaturated
fatty acids, FADS1: Fatty acid desaturase 1, sCT: Salmon calcitonin.
Table 4. (Continued).
Fish name and part used Observed eect(s)
Characteristics of material and or peptide
(AA, sequence, and MW) Reference
bromelain, pepsin, trypsin and pancreatin in producing
DPP-IV inhibitor peptides from Pacific hake, halibut, tilapia,
milkfish and salmon skin, irrespective of degree of hydrolysis
and process efficiency in terms of enzyme/substrate (E/S)
ratio (Li-Chan etal. 2012; T.-Y. Wang etal. 2015). Accordingly,
potent antidiabetic and anti-obesity biopeptides were pro-
duced from fish by the proteolytic activity of various Bacillus
species (Jemil, Nasri, et al. 2017; Nasri et al. 2018; Nasri
etal. 2015). Plasma glucose and hepatic glycogen levels were
rather more affected by B. mojavensis A21 digested goby fish
fillet protein than gray triggerfish digestive crude proteases
digested and non-digested proteins (Nasri et al. 2015).
Hypoglycemic goby fish derived proteins rather contained
similar amounts of amino acids, yet their L/A and M/G
ratios differed to significant extent (non-digested: 0.49, 0.13,
gray triggerfish digestive crude proteases digested lysate: 0.46,
0.15, B. mojavensis A21 digested lysate: 0.58, 0.19 respec-
tively) (Nasri etal. 2015). Corolase followed by alcalase and
combination of alcalase + flavorzyme were the most appro-
priate enzymes for production of hypoglycemic peptides from
salmon trimmings (Neves et al. 2017). In line with Neves
et al. study, among a wide variety of enzymes, pepsin,
CorolaseN or papain digested steelhead skin gelatinous prepa-
ration exhibited markedly strong anti-ACE and anti-DPP-IV
activity over others (Cheung and Li-Chan 2017; Neves etal.
2017). Nonetheless, gray triggerfish digestive crude proteases
digested peptides of goby fish were more potent antioxidants
enhancing superoxide dismutase (SOD), catalase (CAT), and
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 21
Table 5. Fish peptides with bioactivities on MetS associated risk factors (preclinical and clinical studies).
Fish/product name and
or protein source Experimental design
Subjects and inclusion
criteria Observation
Characteristics of
material and or
peptide (AA,
sequence, and MW)
Study parameter
(reference)
Atlantic cod (Gadus
morhua),
commercial preparation
by Firmenich Bjørge
Biomarin AS, Norway
20 mg sh kg-1 BW or
casein control, before
standardized breakfast
meal, double-blind
cross-over trial, 2-study
days with 4 − 7 d
wash-out in between
41 healthy and active
subjects, aged
41 − 64 y, BMI
20 − 30 kg/m2, no
food allergies or
intolerance to sh,
no anti-diabetes,
hypertension, chronic
diseases, and acute
infection medications
↓ postprandial insulin
concentration
compared with casein
in subjects
<1 kDa (66%), HAA
348 > CAA
335 > BCAA
169 > Tau 7 mg g-1
protein, L/A 1.40,
M/G 0.43
(Dale et al. 2018)
Atlantic cod (Gadus
morhua),
commercial preparation
by Firmenich Bjørge
Biomarin AS, Norway
40 mg sh kg-1 BW d-1,
double-blind cross-over
trial, 1 week with
1-week washout periods
in between
31 healthy subjects,
aged 60 − 80 y, BMI
20 − 30 kg/m2, no
food allergies or
intolerance to sh,
no anti-diabetes,
hypertension, chronic
diseases, and acute
infection medications
↓ serum glucose and
insulin levels in
subjects
CAA 335 > HAA
307 > BCAA
127 > Tau 7 mg g-1
of protein, L/A
1.40, M/G 0.43
(C. Jensen et al.
2019)
Atlantic herring (Clupea
harengus) head, gut,
backbone byproducts,
Atlantic salmon,
(Salmo salar)
backbone byproduct,
Atlantic cod (Gadus
morhua) muscle,
commercial tablet
preparation by Faun
Pharma AS, Vestby,
Norway
2.5 g protein d-1 8-wk
double-blind, randomized,
intervention study with
parallel group design
and four intervention
arms
93 overweight/ obese
adult subjects, aged
18 − 69 y, BMI >27 kg/
m2, FBG <
7.0 mmol/L, no
anti-inammatory or
glucose/lipid
metabolism
inuencing
medications
↓ fasting and
postprandial serum
glucose, fructosamine/
albumin ratio (except
herring and salmon),
serum
α-hydroxybutyrate,
acetoacetate, total n-3
PUFA and n-3/n-6
PUFA ratio (except
salmon and cod),
serum
β-hydroxybutyrate
(except salmon)
↑ fasting adiponectin
(except herring and
salmon), total SFA
(except cod)
compared to casein/
whey in overweight
subjects
Cod: CAA 1156 > EAA
1106 > HAA
1051 > BCAA
473 > imino acids
110 mg d-1, L/A
1.56, M/G 0.65,
Salmon: <4 kDa
(93%),
0.2 − 0.5 kDa
(14%),
HAA 1096 > C AA
928 > EAA
818 > BCAA
332 > imino acids
226 mg d-1, L/A
1.12, M/G 0.23,
Herring <4 kDa
(97%),
0.2 − 0.5 kDa
(14%), CAA
982 > EAA
782 > HAA
955 > BCAA
311 > imino acids
178 mg d-1, L/A
0.66, M/G 0.24
(Hovland et al.
2019)
Blue whiting
(M. poutassou), fresh
frozen muscle,
commercial food
supplement
preparation
containing Slimpro®
by Compagnie des
Pêches Saint Malo
Santé, France
one- or two-dose (1.4 g
Slimpro® dose-1) before
main meal (if one-dose),
before lunch and dinner
(if two-dose) sh and or
placebo (Slimpro®
replacement by whey
protein isolate)
treatment, monocentric,
randomized study, 90-d
120 (25% males, 75%
females) slightly
overweight Caucasian
subjects, aged
18 − 55 y, BMI:
25 − 30 kg/m2, mild
hypocaloric
(-300 kcal/day)
↓ weight, fat mass, BMI,
extracellular water,
waist, hip, and thighs
circumference,
↑ serum GLP-1 and CCK
levels in slightly
overweight subjects
Body weight control
(Nobile et al.
2016)
Cod protein, commercial
tablet preparation by
Science in Nutrition
Ltd., Bergen, Norway
6 cod or placebo tablets
d-1 (500 mg of cod
protein + 350 mg
stabilization and lling
agents (maltodextrin,
microcrystalline
cellulose, ascorbic acid,
and α-tocopherol) and
sweeteners (fructose
and vanilla) for 1st 4-wk
and 12 tablets d-1 for
2nd
4-wk, double-blind,
randomized, controlled
intervention study, 8-wk
40 subjects (20 males,
20 females (20 for
each intervention)
aged 20 − 70 y, BMI ≥
27 kg/m2, FBG
<7 mmol/l, no
allergies conicting
with sh intake, no
medications aecting
blood pressure,
blood lipids or blood
sugar
↓ 2-h insulin C-peptide
level relative to
baseline, fasting and
2-h glucose level (at
end of study), serum
LDL-c
↑ GHbA1c, palsma
HDL:LDL ratio
compared to placebo in
overweight adults
CAA 414 > BCAA
171 > imino AA
34.5 > Tau 7 g kg
sh protein,
L/A 1.47, M/G 0.50
(Vikøren et al.
2013)
(Continued)
22 S. ABACHI ETAL.
Fatty- (salmon, rainbow
trout, Baltic herring,
whitesh, vendace, or
tuna) or lean- (pike,
pike-perch, perch,
saithe, or cod) sh
≥ 4 sh portin wk-1 or
control (lean beef, pork,
or poultry and < 1 sh
portion wk-1) diet in
parallel with routine
clinic drugs as part of
regular coronary heart
disease treatment
including statins and
betablockers, controlled
randomized dietary
intervention study, 8-wk
35 coronary heart
disease subjects
(myocardial infarction
or unstable ischemic
attack diagnosed
patients in past ≤
3 y), aged 55 − 67 y,
BMI 24 − 30 kg/m2
↑ size of HDL particles,
serum cholesterol,
cholesterol esters, TL
in very large HDL
particles, serum
n-3 FA, DHA, and ratio
of n-3 FA/ total FA
(except lean sh),
↓ serum cholesterol,
cholesterol esters, TL
in very large HDL
particles (except fatty
sh) in coronary heart
disease subjects
Benecial eect of
sh intake on
lipoprotein
particles in
patients with
coronary heart
disease (Erkkilä
et al. 2014)
Fish (lean-sh cod,
pollock and haddock
skin), commercial
preparation of high
MW food/
pharmaceutical-grade
sh gelatin by
Norland Products,
United States
25% of total daily protein
from sh gelatin + n-3
PUFA and or n-3 PUFA
alone, crossover
randomized study,
2 × 8-wk experimental
periods, a 4-wk run-in
period and a 12-wk
washout period
21 subjects (10 males,
11 females), aged
35 − 70 y, 75 g oral
glucose tolerance
test, BMI > 25 kg/m2,
overweight/ obese,
insulin-resistant with
high fasting plasma
insulin, impaired
fasting plasma
glucose
(5.6 − 6.9 mM), and or
with had impaired
glucose tolerance
following 2-h post
75 g oral glucose
tolerance test with
plasma glucose
corresponding to
7.8 − 11.0 mM, no
food allergies or
intolerance to sh,
no lipid and glucose
metabolism
interfering
medications, no
current diabetes
hyperlipidemia,
hypertension, hepatic
or metabolic diseases
↑ protein intake, hsCRP
in females (20%)
(except n-3 PUFA),
hsCRP males (13%)
(except gelatin + n-3
PUFA)
↓ carbohydrate intake,
hsCRP in males (40%)
(except n-3 PUFA),
hsCRP in females (6%)
(except gelatin + n-3
PUFA), plasma TG in
females 8 − 23%
(gelatin + n-3 PUFA
more eective),
plasma TG in males
11 − 25% (n-3 PUFA
more eective)
in free-living
insulin-resistant
subjects
Reducing CVD risk
by lipid lowering
and
anti-inammatory
eects of sh
gelatin and n-3
PUFA
supplementation
in
insulin-resistant
subjects
(Picard-Deland
et al. 2012)
Fish and tuna Mean energy-adjusted
14.4 g d-1 sh intake,
cross-sectional study,
dish-based
semiquantitative food
frequency questionnaire
420 (female) subjects,
aged > 30 y
↓ MetS (96%),
hypertriglyceridemia
(89%), low HDL-c
(43%) and blood
pressure (77%),
↑ intake of total energy,
carbohydrates, and
rened grains in
female subjects
Alleviation of
metabolic
syndrome
(Zaribaf et al.
2014)
Lean seafood (cod,
pollock, saithe, and
scallops)
Lean-seafood (e.g., 150 g
pollock for lunch, 115 g
cod for dinner) or
no-seafood lunch and
dinner meals,
randomized controlled
trial with crossover
design, 2 × 4-wk
separated by a 5-wk
washout period with
3-wk run-in period
20 healthy Caucasian
subjects, aged
18 − 65 y, BMI
24.9 − 26.3 kg/m2
↓ serum fasting and
postprandial TG
(fasting TG in
chylomicrons and
VLDLs, fasting VLDL
particle size,
postprandial
medium-sized VLDL
particles), TC/HDL-c
ratio in fasted and
postprandial serum,
fasting TG/
HDL-cholesterol ratio
(13%), fasting serum
transferrin receptors,
postprandial serum
C-peptide and lactate
concentrations in
subjects
Lean seafood: CAA
46 > HAA
41 > BCAA 18 > Tau
0.3%, L/A 1.25,
M/G 0.45
Benecial health
eects of
lean-seafood diet
on cardiovascular
lipid risk factors
and long-term
development of
insulin
resistance, T2D,
and CVD in
healthy subjects
(Eli Kristin Aadland
et al. 2015) (Eli
K Aadland et al.
2016)
Table 5. (Continued).
Fish/product name and
or protein source Experimental design
Subjects and inclusion
criteria Observation
Characteristics of
material and or
peptide (AA,
sequence, and MW)
Study parameter
(reference)
(Continued)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 23
Salmon, Atlantic salmon,
sardine, trout, tuna
(skin on/ o,
marinated, avored,
canned, slices in
spring water, or
lightly seasoned
frozen sh llets)
4-servings wk-1 (∼800 mg
d-1 EPA + DHA), parallel
randomized controlled
study stratied by CRP
(< 3 and ≥ 3 mg/L) on
entry to study, 8-wk
80 healthy elderly
subjects, aged ≥
64 y, BMI ≥ 18.5 kg/
m2
↓ total n-6 FA in plasma
PL,
↑ very long chain (VLC)
n-3 PUFA in
erythrocytes, plasma
PL compared to red
meat in healthy
subjects
Benecial eect of
sh diet on
cardiovascular
biomarkers
(Grieger, Miller,
and Cobiac
2014)
Skate (Raja Kenojei)
skin, collagenous
preparation to
capsule form by
Serom Co., Ltd.
(Jeonnam, South
Korea)
2 g d-1 (4 × 0.5 g sh or
placebo capsule, twice
daily in morning and
evening), randomized,
placebo-controlled, and
double-blinded study,
12-wks
90 (17 males, 73
females) healthy
volunteer subjects,
aged 40 − 52 y, BMI
24 − 27 kg/m2
↓ body fat (-1.2 kg, no
toxicity, and adverse
eects) in overweight
subjects
Treatment for
obesity and
related disorders
(reduction of
body fat) (Tak
et al. 2019)
Tuna (canned),
dark- and
light-eshed sh
0 – ≥ 6 sh serving d-1,
standardized and
validated
food-frequency
questionnaire, cohort
study with 26 y
follow-up
84,136 subjects (female)
aged 30 − 55 y, with
no known cancer,
diabetes mellitus,
angina, myocardial
infarction, stroke, or
other CVD
↓ risk of coronary heart
disease by 1-serving
sh d-1 (24%) in
subjects
Fish and poultry
intake decrease
coronary heart
disease risk
(Bernstein et al.
2010)
Wild marine deep-sea
sh fresh meat,
Commercial
preparation (mixed
proteases)
6.5 g sh collagenous
protein or placebo
(carboxymethylcellulose)
d-1 before breakfast and
bedtime
in parallel with routine
clinic drugs (T2D:
anti-diabetic drugs
(tolbutamide
500 − 3000 mg/d and or
metformin
500 − 1500 mg/d),
hypertension:
anti-hypertensive drugs
(metoprolol
50 − 100 mg/d,
verapamil 80 − 240 mg/d,
or losartan
25 − 100 mg/d), no
insulin, insulin secretion
stimulators, anti-ACE
and anti-hyperlipidemic
medicines), 3-m,
randomized double
blind study
150 subjects (100 T2D
diabetic patients
with hypertension,
50 healthy
individuals (no
current T2D,
hypertension, T1D,
infectious diseases,
current and historical
CVD, liver, kidney,
cerebrovascular
diseases, cancer) for
each group), aged
64 − 68 y, BMI:
24 − 25 kg/m2, FBG ≥
7.0 mmol/L, SBP ≥
140 mmHg, or DBP ≥
90 mmHg
↓ FBG, HbA1c, fasting
insulin, creatinine,
serum TG, TC, LDL-c,
and FFA, Cyp450, PGI2
and NO,
↑ insulin sensitivity
index, insulin
secretion, HDL-c,
bradykinin,
adiponectin compared
to patient control in
T2D and hypertension
subjects
130 − 3,000 Da (>
95%, mostly
300 − 800 Da)
Therapeutic eects
on glucose and
lipid metabolism,
insulin
sensitivity, renal
function in
Chinese patients
with T2D and
hypertension
(C.-F. Zhu, Li,
Peng, Li, etal.
2010)
Wild marine sh 6.5 g × 2 (before breakfast
and bedtime), 3-m,
blind randomized
(treatment and control
groups (50 per group))
concomitant with
antidiabetic medicines
(tolbutamide and or
metformin), and or
carboxymethylcellulose
placebo
100 T2D patients
(diagnosed when
fasting blood glucose
(FBG) concentration
was ≥ 7.0 mmol L−1)
and 50 healthy
subjects
↓ FBG, GHbA1c, fasting
blood insulin, TG, TC,
LDL-c, FFA, hsCRP and
NO,
↑ insulin sensitivity
index, HDL-c,
bradykinin, PGI2,
adiponectin in T2D
patients
95% of oligopeptides
MW 130 − 3,000 Da
(300 − 800 Da)
(C.-F. Zhu, Li, Peng,
Zhang, et al.
2010)
Table 5. (Continued).
Fish/product name and
or protein source Experimental design
Subjects and inclusion
criteria Observation
Characteristics of
material and or
peptide (AA,
sequence, and MW)
Study parameter
(reference)
(Continued)
24 S. ABACHI ETAL.
Wild marine fresh sh
Mixed proteases,
ultra-ltration,
desalination,
cryoconcentration
under vacuum at
70 °C, decolorization,
and lyophilization
6.5 g sh collagenous
protein or placebo
(water-soluble starch)
d-1 before breakfast and
bedtime in parallel with
routine clinic drugs
(T2D: anti-diabetic
drugs (tolbutamide
500 − 3000 mg/d and or
metformin
500 − 1500 mg/d),
hypertension:
anti-hypertensive drugs
(metoprolol
50 − 100 mg/d,
verapamil 80 − 240 mg/d,
or losartan
25 − 100 mg/d), no
insulin, insulin secretion
stimulators, anti-ACE
and anti-hyperlipidemic
medicines), 90-d,
random intervention
study
200 subjects (T2D
patients with/without
hypertension, 50
age-matched healthy
individuals (no
hypertension,
diabetes, coronary
heart disease, or
hyperlipemia) for
each group) subjects,
aged 62 − 68 y, FBG
≥ 7.0 mmol/L,
systolic blood
pressure (SBP) ≥
140 mmHg or
diastolic blood
pressure (DBP) ≥
90 mmHg,
↓ FFA, cytochrome P450,
hsCRP, leptin, resistin,
↑ adiponectin in T2D
with/without
hypertension subjects
130 − 3,000 Da (>
95%), 700 − 860 Da
(48%),
300 − 500 Da (28%)
(Cui-Feng etal.
2010)
Increased, improved, stimulated and or upregulated expressions are denoted as “↑”, and decreased, inhibited and or downregulated expression denoted as
“↓”. HAA: Hydrophobic Amino Acids (glycine, alanine, valine, isoleucine, leucine, phenylalanine, proline, methionine, and tryptophan), AAA: Aromatic Amino
Acids (phenylalanine, tryptophan, and tyrosine), PCAA: Positively Charged Amino Acids (arginine, histidine, lysine); NCAA: Negatively Charged Amino Acids
(aspartic acid, glutamic acid), EEA: Essential Amino Acids (phenylalanine, valine, threonine, isoleucine, methionine, histidine, leucine, lysine and tryptophan),
BCAA: Branched Chain Amino Acids (isoleucine, leucine and valine).
Table 5. (Continued).
Fish/product name and
or protein source Experimental design
Subjects and inclusion
criteria Observation
Characteristics of
material and or
peptide (AA,
sequence, and MW)
Study parameter
(reference)
glutathione peroxidase (GPX) and glutathione (GSH) activities
in liver and kidney tissues over B. mojavensis A21 digested
hydrolysate (Nasri et al. 2015). Overall, B. amyloliquefaciens
An6 fermented sardine flour was rather more hypoglycemic
and antioxidative than the B. subtilis A26 fermented muscle
proteins (Jemil, Nasri, et al. 2017).
The enzymatic hydrolysis enhanced anti-DPP-IV effect
of the non-hydrolyzed fish skin gelatins by about +5-fold
increasing it from about 10% to almost 45% − 50% (Li-Chan
et al. 2012; T.-Y. Wang et al. 2015). Similarly, enzymatic
lysis, alcalase, alcalase + flavorzyme, corolase except
PROMOD, increased the anti-DPP-IV activity of undigested
salmon proteins up to about +8-folds (Neves et al. 2017).
In agreement, enzymatic digestion, in particular with trig-
gerfish proteases, considerably enhanced the hypolipidemic
effects of undigested muscle proteins of goby fish (hepatic
TG and TC: up to 22%, serum TG: 18%, serum TC: 12%,
serum HDL cholesterol: 10%, serum LDL cholesterol: 56%,
serum VLDL cholesterol: 19%) (Nasri etal. 2018). The enzy-
matic digestion similarly enhanced the hypolipidemic and
hypoglycemic effect of thornback ray sarcoplasmic proteins
as high as 16% (TG: +16%, TC: +3%, LDL-c: +6%, VLDL-c:
+14%, HDL-c: +1%, aspartate transaminase (AST): +2%,
alanine transaminase (ALT): +14%, alkaline phosphatase
(ALP): +8%, blood glucose and α–amylase: +8%, AI: +5%)
(Lassoued et al. 2018). In contrary, enzymatic hydrolysis
lessened the metabolic benefiting effects of goby fish undi-
gested proteins, in terms of food intake, with L/A and M/G
ratios of 0.49 and 0.13 compared to the same ratios of the
triggerfish proteases digested (0.46 and 0.15) and B. mojaven-
sis A21 proteases hydrolyzed (0.58 and 0.19) fractions, by
−14% to −17% (Nasri et al. 2018). Evidently, triggerfish
crude proteases extract was a more appropriate choice in
comparison to B. mojavensis A21 proteases for isolation of
antihyperlipidemic peptides from goby fish (Nasri et al.
2018). The enzymatic hydrolysis moderately improved the
hypocholesterolemic effects of zebra blenny muscle tissue
(5% − 23%) (Ktari et al. 2015).
Glucoregulatory activity of sardine meat flour protein
was drastically improved by bacterial fermentation (Jemil,
Nasri, etal. 2017). This may be justified by lower branched
chain amino acids (BCAA), hydrophobic amino acids
(HAA), essential amino acids (EAA), L/A and M/G ratios,
and higher charged amino acids (CAA) and taurine content
of B. amyloliquefaciens An6 over B. subtilis A26 fermented
peptides (Jemil, Nasri, et al. 2017). Sardinelle and smooth
hound proteases digested fractions of zebra blenny, with
smaller degree of hydrolysis (DH), comparatively were more
potent over zebra blenny digested lysate in preventing the
hepatic damage as well as lowering the serum and hepatic
TG, TC, and LDL-c levels (Ktari etal. 2015). Nevertheless,
as observed in liver histopathological studies, hepatic damage
of zebra blenny protease hydrolyzed zebra blenny muscle
protein treated rats, but not the other lysates, was entirely
alleviated (Ktari etal. 2015). Papain comparatively enhanced
the hypocholesterolemic activity of Alaska pollock, compared
to its undigested protein, at mRNA expression level of cho-
lesterol 7 R-hydroxylase (AKA cytochrome P450 7A1)
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 25
(CYP7A1) in hypercaloric diet fed rats (Hosomi etal. 2012;
Hosomi et al. 2009).
Even though hydrolysis in many instances has improved
anti-MetS properties of fish biopeptides yet, there have
been some exceptions. Undigested proteins of bogue muscle
(L/A: 0.23, M/G: 0.26) commonly were more potent
anti-hyperlipidemic than its hydrolyzed counterpart (L/A:
0.33, M/G: 0.22) at the same concentration (500 mg kg−1
BW d−1) (Lassoued et al. 2014). Generally, selectively sep-
arated peptides, yet not always, present better anti-MetS
activity. Ultrafiltration (UF) fraction of <1,500 Da was most
potent over >2,500, and 1,500 − 2,500 fractions against
DPP-IV activity at the concentration of 1 mg mL−1 (T.-Y.
Wang et al. 2015). In an earlier study, small MW
salmon-extracted fraction (<1,000 Da) at 2 mg mL−1 simi-
larly inhibited more of DPP-IV activity over other fractions
with an inhibitory concentration 50% (IC50) value of
1.35 mg mL−1 (Li-Chan et al. 2012). The vasodilating
potency of siki head hydrolysate increased going through
different isolation and purification processes (from 4.1 to
0.01 mg of protein) by +410-times with the purification
factor of up to 79% (Martinez-Alvarez et al. 2007). Gel
filtration chromatography (GFC) slightly improved the
activity of hydrolysate by +3.8-folds (Martinez-Alvarez
etal. 2007). Nevertheless, non-fractionated extract of mack-
erel tended to be more potent hypolipidemic, up to 65%,
on plasma lipids (16% (TC), 41% (HDL-c), 65% (LDL-c))
than its fractions (Itou and Akahane 2009). Separation
techniques such as electro-separation also have been useful
in extracting potent hypoglycemic peptides with in-vitro
glucose uptake stimulatory effect from fish (Durand
et al. 2019).
Umamizyme sequentially digested spine proteins, rather
hyperlipidemic, with highest HAA, M/G and L/A ratios
(48%, 0.90 and 2.83, respectively) in comparison to other
two hydrolysates tended to increase serum and hepatic
lipids as well as liver’s fatty acid synthase (FAS) activity
and Δ9 desaturase gene expression (Vik et al. 2015). Acid
protease lysed spine proteins with moderate M/G and L/A
ratios compared to casein (0.69 vs. 1.57 and 2.12 vs. 2.97,
respectively) resulted in high hepatic polyunsaturated fatty
acids (PUFA) and ceramides levels, however, hepatic di-
and tri-acylglycerols concentrations were decreased (Vik
et al. 2015). Among the three enzymes utilized for diges-
tion of zebra blenny sarcoplasmic proteins, crude proteases
of zebra blenny viscera resulted in highest DH with lowest
L/A ratio of 0.43, and medium M/G ratio of 0.40, over
the other two (L/A and M/G ratios of crude proteases of
smooth hound and sardinelle were 0.53, 0.38, and 0.57,
0.42, respectively) (Ktari et al. 2013). Administration of
goby fish sarcoplasmic hydrolysates (B. mojavensis A21 and
gray triggerfish proteases), in particular gray triggerfish
proteases digested one with 23% DH and more smaller
size peptides, could impede weight gain better than the
daily dose of 20 mg fluvastatin per kg of body weight
(Nasri etal. 2018). L/A ratio of B. mojavensis A21 digested
hydrolysate is +21% (0.58) higher than the undigested
protein (0.48) (Nasri etal. 2015). Interestingly, while the
same hydrolysate lowered more of the plasma glucose level
in hypercaloric diet fed rats, the undigested material
increased it by +16% (Nasri et al. 2015). Almost same
trend was observed on the effectivity of hydrolysate and
undigested protein on α-amylase activity. While α-amylase
activity was significantly inhibited by hydrolysates,
Table 6. Fish peptides with bioactivities on MetS associated risk factors formulated into commercial products.
Trade name of product
Fish type and
preparation Claimed eect Manufacturer, country
Category and or
dosage form Reference
Amizate®, amino acid
(25-AA, > 120
peptides e.g., IP/LP,
KP, anserine)
complex
Fresh Norwegian
salmon, hydrolysate
(endogenous
proteases)
Benecial health
eects on diabetes
and cardiovascular
diseases
Zymtech Production
AS, Norway
Powder (Nesse etal. 2014)
Fortidium Liquamen® White sh (Molva
molva) autolysate
Lowering glycemic
index, antioxidant,
and anti-stress
Biothalassol, France Capsule (Guérard et al. 2010)
Naticol®, type-I and
type-III collagen
Warm sea sh skin,
enzymatic
hydrolysate
Obesity associated
disorders
Weishardt
International, France
Powder (Astre etal. 2018)
Nutripeptin™ Cod fresh/ frozen llet,
enzymatic
hydrolysate
Lowering glycemic
index, improving
weight loss, and
maintaining
cardiovascular
health
Copalis, France Powder (Mora and Hayes 2015)
SeaSource™, collagen Wild-caught deep-sea
sh, cod,
hydrolysate
Benecial on CVD risk
prole and bone
health
Norland Products
Incorporated,
United States
Powder (Picard-Deland etal.
2012)
Slimpro® Blue whiting
(M. poutassou), fresh
frozen muscle,
enzymatic
hydrolysate
Weight management
(↑ serum GLP-1 and
CCK levels)
Compagnie des Pêches
Saint Malo Santé
(France)
Commercial food
supplement
(Nobile et al. 2016)
Wellnex®,
food grade type-D
collagen
Tilapia (Oreochromis
sp.) scale,
enzymatic
hydrolysate
Diabetes treatment Nitta Gelatin Inc.,
Japan
Powder (Iba et al. 2016)
26 S. ABACHI ETAL.
undigested material increased its activity (Nasri et al.
2015). Source of fish-collagen and preparation techniques
seem to be important on particular parameters of
anti-obesogenic proteins (E. J. Lee et al. 2017; Woo etal.
2018). Tuna skin byproduct collagenous material, prepared
by subcritical water, decreased epididymal adipocytes’ size
while commercial collagenous skate skin perpetration had
negligible effect on epididymis adipose tissue weight in
high fat diet fed obese rats and effects were tissue depen-
dent (E. J. Lee etal. 2017; Woo etal. 2018).
Treatment and prevention of MetS with sh and
sh biopeptides
As one of the main risk factors of MetS, dyslipidemia could
have primary (genetical mutations) or secondary
(lifestyle-related and other factors) causes (Chan, Barrett,
and Watts 2004). Beside sedentary lifestyle as the main
cause, other common ones could be diabetes mellitus, alco-
hol abuse, chronic kidney disease, hypothyroidism, primary
biliary cirrhosis and other cholestatic liver diseases, cigarette
smoking, anabolic steroids, human immunodeficiency virus
infection, and nephrotic syndrome (Chan, Barrett, and Watts
2004). Lipid abnormality and elevated plasma triglyceride
(TG) levels may be genetically acquired, primary hypertri-
glyceridemia, or be of secondary type in which high-fat
diet, obesity, diabetes, hypothyroidism, and some medica-
tions trigger the condition. Obesity may be the most com-
mon stimulant of dyslipidemia yet, type 2 diabetes (T2D)
and high alcohol intake are too frequent. Dyslipidemia, one
of the most significant and common risk factors of cardio-
vascular diseases (CVD) that characterizes insulin resistance,
is an important hallmark of MetS and in the long run
advances into T2D. Abnormal levels of atherogenic lipid
and lipoprotein would be diabetic dyslipidemia with a char-
acteristic overproduction of large very low-density lipopro-
tein (VLDL) particles that would recruit a series of changes
in lipoprotein levels and develop into T2D within several
years. Over time cholesterol, predominantly low-density
lipoprotein (LDL), buildup initiates the oxidization of vas-
cular endothelium’s particles triggering the establishment of
tumor necrosis factor-alpha (TNF-α) producing atheroscle-
rotic plaques that adhere to the arterial wall promoting
arteriosclerosis originating inflammation (Kawanishi et al.
2013). In response to inflammatory mediators, TNF-α, endo-
thelium expresses cell adhesion molecules (intercellular
adhesion molecule 1 (ICAM-1), vascular cell adhesion pro-
tein 1 (VCAM-1), and endothelial-leukocyte adhesion mol-
ecule 1 (ELAM-1)) through translocation of nuclear factor
kappa-light-chain-enhancer of activated B cells (NF-kB) (K.-
W. Choi et al. 2010). For successful management of dyslip-
idemia, visceral fat mass and hepatic lipogenesis must be
reduced while improving the insulin sensitivity. This treat-
ment can be approached by reducing hepatic secretion
improving catabolism of VLDL, improving hepatic secretion
reducing catabolism of high-density lipoprotein (HDL) and
or speeding the clearance of LDL up (Chan, Barrett, and
Watts 2004). Prescription of specific therapeutic route for
the treatment of hypertriglyceridemia has not generally been
easy due to occurrence of cardiovascular disease risk factors
e.g., low HDL-c, MetS, obesity, T2D, proinflammatory and
prothrombotic biomarkers along with the condition. In addi-
tion to CVD, more severe cases of dyslipidemia could poten-
tially increase the risk of acute pancreatitis therefore the
condition should be mediated by therapeutic lifestyle changes
followed by medication in a timely manner (Shemesh and
Zafrir 2019). In both MetS and T2D, dysfunctional lipopro-
tein lipase activity, elevated cholesteryl ester transfer protein
activity, plasma VLDL (with or without chylomicronemia)
and hepatic free fatty acid (FFA) flux all play significant in
the development of hypertriglyceridemia. It is noteworthy
that abdominal adiposity, a feature of ectopic fat syndrome
and obesity, is strongly associated with low grade chronic
inflammation along with abnormal hormone secretion and
several metabolic disorders. Likewise, hypercholesterolemia
could be diet-induced or a genetically acquired condition
(familial or pure hypercholesterolemia). High plasma LDL
cholesterol (LDL-c) concentration in familial hypercholes-
terolemia increases the risk of premature coronary heart
disease (CHD). Mono- or combination-therapies in conjunc-
tion with dietary adjustments could alleviate dyslipidemia.
Fibrates, statins, niacin, cholesterol-absorption inhibitors and
handful emerging medications are regularly practiced for
the treatment of hypertriglyceridemia (Yuan, Al-Shali, and
Hegele 2007). Similar drugs (hydroxy-3
-methylglutaryl-coenzyme A (HMG-CoA) reductase inhib-
itors (statins) along with niacin, bile acid sequestrants,
fibrates, and omega-3 fatty acids) and mechanical means of
LDL-c removal are common therapies for hypercholesterol-
emia (Raal and Santos 2012).
Long term insulin resistance would lead to the develop-
ment of hyperglycemia and hyperinsulinemia, the two main
predictors of T2D. Moreover, they would indicate future
CVD and metabolic impairments (Paneni, Costantino, and
Cosentino 2014). Endothelial dysfunction in addition to
the lipid triad of dyslipidemia (emergence of VLDL-c, high
plasma TG and low HDL-c) induced by irregular insulin
signaling contributes to plaque formation and build up
within arteries (Paneni, Costantino, and Cosentino 2014).
Obesity, dyslipidemia, and insulin resistance comorbidities
are frequently associated with CVD (Paneni, Costantino,
and Cosentino 2014). Non-adipose tissue lipid accumulation
in muscle and the liver takes part in pathogenesis of insulin
resistance and recent studies have confirmed the role of
muscle-specific insulin resistance in promotion of hepatic
lipogenesis, nonalcoholic fatty liver disease, and atherogenic
dyslipidemia (Jornayvaz, Samuel, and Shulman 2010).
Persistent insulin resistance leads to impaired glucose and
lipid metabolism inducing oxidative stress followed by sub-
sequent immune response and cell damage. Impairment of
insulin signaling, and hyperglycemia are stressors of early
atherosclerotic lesion formation (Paneni, Costantino, and
Cosentino 2014). These lesions in diabetics, compared with
similar lesions of nondiabetics, advance into the ones with
large necrotic cores and higher macrophage content which
rather are correlated with glycated hemoglobin A1c
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 27
(GHbA1c) than lipid concentrations (Burke et al. 2004).
According to a community-based study, glycated hemoglo-
bin (≥ 6.0%) is greatly associated with the risk of CVD
than is with diabetes hence proven to be a better diagnostic
measure over fasting glucose for the evaluation of long-term
risk of successive CVD (Selvin et al. 2010). T2D enforces
significant economic burden on societies worldwide. T2D
related complications cost France €8.5 billion annually
(Emery et al. 2020). In the year 2003, direct medical costs
of T2D in France were estimately about €19.5 billion
(Emery et al. 2020).
One of the most common ways for treatment of diabetes
is the inhibition of enzymes involved in the digestion of
carbohydrates, α-amylase, and α-glucosidase, and or dipep-
tidyl peptidase 4 (DPP-IV) with diverse active and inactive
binding sites (supplementary Table 2). Diabetes is also
treated with glucagon-like peptide 1 (GLP-1) analogues,
sulfonylureas, meglitanides, basal insulins, thiazolidinediones
and sodium/glucose cotransporter 2 (SGLT2) inhibitors as
mono- or combination-therapies. Anti-DPP-IV medications
for example can be prescribed in combination with met-
formin and or insulin to control T2D and reduce GHbA1c
levels (Emery et al. 2020).
Statins (HMG-CoA reductase inhibitors) are rather
well-tolerated medications and among the most common
lipid-lowering compounds, yet this class of drugs are asso-
ciated with skeletal muscle, metabolic, neurological, and
other viable adverse effects. These side effects limit their
use for medication of hypercholesterolemia and manage-
ment of CVD risks. Per survey, ∼60% of former consumers
of the drug reported statin-associated muscle symptoms
which eventually made it impossible to continue the statin
therapy. The noncompliant patients taking less than 80%
of the prescribed therapy were 15% more in the risk of
CVD events not to mention the 45% increase in all-cause
mortalities (Thompson et al. 2016). Furthermore, many
adverse drug and or disease interactions have frequently
been reported for glucose lowering agents (Triplitt 2006).
This class of drug is well known for its weight gain side
effect making the management of T2D in overweight and
obese individuals difficult (Scheen and Van Gaal 2014).
Alternatively, synthetic drugs could possibly be substituted
with safe and or less damaging natural remedies and bio-
actives. In the following sections, authors will review the
in-vitro, in-vivo and human studies investigating the
anti-diabetes, anti-hyperlipidemia, and anti-obesity effects
of fish biopeptides.
Anti-diabetes peptides
In the subsequent two sub-sections, the anti-diabetic effects
of fish and fish derived proteins on mainly the enzymes
involved in glucose metabolism, fasting and postprandial
glucose and insulin levels (e.g., DPP-IV, α-amylase, and
α-glucosidase), GHbA1c, GLP-1 secretion, glucose trans-
porter type 4 (GLUT4) expression, glucose uptake and
energy expenditure in various experimental settings (in-vitro,
cell, animal, and human studies) would be discussed.
In-vitro and in-vivo studies
More than 50% (∼ 37 out of 65) of the studies reviewed
herein on the antidiabetic effect of fish biopeptides utilized
byproducts of a fish type e.g., skin, scale, frames, process
juice, etc. as substrate and starting material in their in-vitro
and in-vivo investigations (Tables 3 and 4). Many fish species
were studied for their glucoregulatory activity, yet salmon
was the most frequently tested type followed by cod, sardine,
and tuna. According to numerous observations, salmon
hydrolysates could beneficially modulate the activity of
enzymes involved in glucose metabolism, fasting and post-
prandial glucose and insulin levels, GLP-1 secretion, glucose
uptake and energy expenditure, GLUT4 expression in several
in-vitro and in-vivo studies whether in different cell lines
and or experimental animal models (Chevrier et al. 2015;
Drotningsvik et al. 2016; Drotningsvik, Pampanin, et al.
2018; Harnedy et al. 2018a; Jin 2013; Li-Chan et al. 2012;
Medenieks and Vasiljevic 2008; Neves et al. 2017; Pilon
et al. 2011; Roblet et al. 2016; Slizyte et al. 2016; J. Wang
etal. 2010). Oral dose of circulating salmon calcitonin (sCT)
has shown glucoregulatory activity affecting glucose and
insulin levels attenuating hyperglycemia along with better
islet β-cells function in diabetic and obese rats (Feigh etal.
2012; Feigh et al. 2011). Correspondingly, a 20% salmon
protein intake increased the sCT levels in hypercaloric diet
fed rats which may partially be the reason for beneficial
effects of this fish (Pilon etal. 2011). Anti-obesogenic effects
of sCT by means of reducing food intake and increasing
energy expenditure thus controlling body weight are also
of note (Lutz etal. 2000). Insulinotropic activity of salmon
was via ATP-sensitive potassium (KATP ) channel-dependent
and protein kinase A (PKA) pathways hence boosting the
membrane depolarization and intracellular calcium and
cyclic adenosine monophosphate (cAMP) concentration in
BRIN-BD11 cells (Harnedy et al. 2018a).
Salmon skin gelatinous hydrolysate diet eased the dia-
betic symptoms in rats. Polyphagia of streptozotocin (STZ)-
induced diabetic rats was significantly reduced by about
20% compared with the control group throughout 5-weeks
experiment period (Hsieh et al. 2015). Nevertheless, water
intake during the analysis insignificantly differed between
the normal non-diabetic rats and the fish-protein fed dia-
betic animals (Hsieh et al. 2015). Salmon skin gelatinous
hydrolysate diet reduced postprandial blood glucose level
to that of non-diabetic normal group thus area under curve
of fish and or normal diet fed groups were insignificantly
different from one another (Hsieh et al. 2015). The same
salmon diet tended to increase the plasma active GLP-1
levels in diabetic rats compared to diabetic and non-diabetic
control groups without inducing the secretion of hormones
(Hsieh etal. 2015). In previous studies, DPP-IV inhibitors
(e.g., sitagliptin, ASP8497 vildagliptin, and valine pyrroli-
dide), comparable to gelatinous hydrolysate, have demon-
strated protective effect and prevented the degradation of
active GLP-1 by DPP-IV thus improving its circulating
plasma levels and exerting glycemic control in similar dia-
betic experimental animal models (Hsieh et al. 2015; S.-J.
Kim, Nian, etal. 2009; Larsen etal. 2003; Matsuyama-Yokono
28 S. ABACHI ETAL.
etal. 2009). Moreover, gelatinous salmon hydrolysate, sim-
ilar to a hypoglycemic DPP-IV inhibitor (ASP8497), could
reduce the non-fasting blood glucose levels effectively in
rats (Hsieh et al. 2015; Matsuyama-Yokono et al. 2009).
Percent DPP-IV activity in diabetic fish-gelatin diet fed rats
was reduced by 32.9% in comparison to the diabetic normal
diet fed rats and in another study comparable effect (50%
inhibition) was observed on equivalent experimental model
(STZ-induced diabetic rat) by long-term administration of
sitagliptin, an orally administered DPP-IV inhibitor (Hsieh
etal. 2015; S.-J. Kim, Nian, etal. 2009). Five-weeks admin-
istration of fish-gelatin hydrolysate diet may reverse the
pancreatic β-cell destructive hyperglycemic causing feature
of streptozotocin thus inducing insulin secretion in diabetic
mice comparable to that of commercial DPP-IV inhibitors
(ASP8497, vildagliptin, sitagliptin and isoleucine thiazoli-
dide) which have been reported for their positive qualitative
and quantitative effect on small pancreatic islets,
glucose-dependent insulin excretion and subsequent blood
glucose depressing effects (Hsieh et al. 2015; S.-J. Kim,
Nian, etal. 2009; Matsuyama-Yokono etal. 2009; Pospisilik
et al. 2003). Plasma insulin-to-glucagon ratio was ∼40%
lower in salmon skin hydrolysate diet fed diabetic rats (∼7)
compared with normal control group (∼12) and ∼4-times
higher compared with diabetic control (∼1.7) thus proving
beneficial on hypoinsulinemia (Hsieh etal. 2015).
Cod’s glucoregulatory effect was rather like salmon.
According to the observations, cod protein could, similar
to salmon, beneficially modulate fasting and postprandial
glucose and insulin levels, GLP-1 secretion, glucose clearance
and energy expenditure in several in-vitro and in-vivo studies
yet to the knowledge of authors its activity on carbohydrate
digesting enzymes and or DPP‐IV has not been tested
(Geraedts et al. 2011; I.-J. Jensen et al. 2016; Lavigne,
Marette, and Jacques 2000; Lavigne et al. 2001; Myrmel
etal. 2019; Tastesen etal. 2014; von Post-Skagegård, Vessby,
and Karlström 2006). Though cod protein did not affect
insulin-mediated glucose infusion rates (GIR60–120) in obese
rats, its effects were by some means tissue specific (Lavigne
etal. 2001). Cod protein increased insulin-stimulated glucose
uptake in white tibialis, white gastrocnemius, red gastroc-
nemius, quadriceps, extensor digitorum longus (EDL) mus-
cle, heart and as well slightly in brown adipose tissue (BAT)
(Lavigne etal. 2001). Contrarily, in the study of Drotningsvik
etal. according to biochemical analysis neither of the diets,
cod- nor casein-diet (20% protein from casein/whey (90%
casein, 10% whey), could demonstrate glucoregulatory effect
(glucose and insulin concentrations, glucose to insulin ratio,
serum α-amylase) in obese Zucker fa/fa rats (Drotningsvik
et al. 2015).
Other fish types exerted similar effects to salmon and
cod. All three zebra blenny hydrolysates were potent
α-amylase inhibitors, and their activities were only insig-
nificantly different from one another (zebra blenny crude
protease digested hydrolysate with lowest IC50 of 90 μg mL−1)
(Ktari etal. 2013). Blue whiting muscle proteins stimulated
the secretion of CCK secretion from STC-1 cells, but
non-hydrolyzed material tended to be ineffective (Cudennec
etal. 2012). Tilapia collagen peptide at 1.7 g kg−1 BW could
positively affect the diabetic rat better than metformin in
terms of diabetic symptoms and hyperglycemia (R. Zhang,
Chen, Chen, etal. 2016). Fish proteins like goby fish lysates
could also enhance renal function and attenuate hyperfil-
tration of uric acid treating hypercaloric-diet induced hyper-
glycemia in liver and kidney of experimental animals (Nasri
et al. 2015).
Clinical studies
Bioavailability and bioefficacy of glucoregulatory fish bio-
peptides, processed and unprocessed, were further tested in
several controlled human studies. Of all the fish types, cod
was tested the most for its health effects in healthy and ill
human subjects. Cod successfully exerted its health effects
on various diabetes factors (e.g., insulin sensitivity (M/I),
disposition index (β-cell function × (M/I)), fasting and post-
prandial glucose and insulin, GLP-1 and HbA1c) in numer-
ous sets of populations (Eli K Aadland et al. 2016; Eli
Kristin Aadland et al. 2015; Dale et al. 2018; Mortensen
et al. 2009; Ouellet et al. 2007; Ouellet et al. 2008; Ramel,
Parra, et al. 2009; Vikøren et al. 2013). Cod fillet diet
enhanced insulin sensitivity in overweight obese
insulin-resistant human subjects compared to lean beef,
pork, veal, eggs, milk, and milk products (BPVEM) (Ouellet
et al. 2007; Ouellet et al. 2008). Additionally, cod diet
exerted anti-inflammatory effects on high-sensitivity
C-reactive protein (hsCRP), an inflammation marker known
to be associated with T2D and CVD risk, in a similar pop-
ulation as previous study (Ouellet etal. 2007; Ouellet etal.
2008). Cod protein, as part of a composite meal (45 g pro-
tein), in a randomized meal study showed glucoregulatory
effects on glucose and insulin responses in healthy subjects
(von Post-Skagegård, Vessby, and Karlström 2006).
Throughout the double-blind, randomized, controlled inter-
vention study, ingestion of 3 g codfish tableted protein per
day did not affect fasting insulin, fasting insulin C-peptide
and homeostatic model assessment of insulin resistance
(HOMA-IR), however, 2-h postprandial glucose levels at the
time point of 8-weeks were substantially lower in fish con-
sumed overweight adults group compared to the placebo
group (Vikøren etal. 2013). Opposite to triggerfish hydro-
lysates which decreased GHbA1c level in serum and liver
alloxan-induced diabetic rats, upon 8-weeks consumption
of cod protein the hemoglobin’s level was significantly
increased (Siala etal. 2016; Vikøren etal. 2013). Additionally,
cod muscle proteins exhibited glucoregulatory and
anti-obesogenic activity tending to decrease fasting and post-
prandial serum glucose and fructosamine/albumin ratio,
increasing fasting adiponectin concentration compared to
casein/whey in overweight subjects (Hovland et al. 2019).
Single cod protein dose (6.6 mg g−1 of protein), compared
to casein, however, could just depress the postprandial insu-
lin secretion but wasn’t effective on blood glucose response
or GLP-1 levels in middle-aged healthy population (Dale
et al. 2018).
In the studies of Zhu etal., collagen and gelatin prepa-
rations from various fish presented hypoglycemic and anti-
diabetic effects in diabetic patients with and without primary
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 29
hypertension (C.-F. Zhu, Li, Peng, Li, etal. 2010; C.-F. Zhu,
Li, Peng, Zhang, etal. 2010). A commercial small molecular
weight fish collagenous hydrolysate preparation demonstrated
therapeutic effects on glucose and lipid metabolism, insulin
sensitivity as well as renal function in Chinese patients with
T2D and hypertension (C.-F. Zhu, Li, Peng, Li, etal. 2010).
Effects were similar in diabetes-only subjects where fasting
glucose and insulin as well as GHbA1c decreased in patients
with the intake of 13 g collagen per day (C.-F. Zhu, Li, Peng,
Zhang, et al. 2010). Moreover, comparable findings were
confirmed in another study in which similar fish collagenic
preparation beneficially modulated the molecules involved
in pathogenesis of diabetes and hypertension (Cui-Feng
et al. 2010).
Anti-hyperlipidemia peptides
In the succeeding two sub-sections, anti-hyperlipidemia
effects of fish and fish derived proteins, mainly on the
enzymes involved in lipid catabolism and metabolism,
hepatic expression of lipogenic genes, cholesterol homeosta-
sis associated hepatic genes, hepatic and serum lipid levels,
hepatic FA desaturase indices, BA excretion, AI and CIR,
hepatic and renal tissue damage prevention and protection,
in various experimental settings (in-vitro, cell, animal and
human studies) would be discussed.
In-vitro and in-vivo studies
Of all the studies focusing on hypolipidemic effects of fish
peptides about 40% (25 out of 62) made use of fish byprod-
ucts (Tables 3–5). Numerous fish were investigated for their
anti-hyperlipidemic activities; however, the most studied
type was Alaska pollock followed by sardine and salmon,
respectively. In-vivo analysis of Alaska pollock
anti-dyslipidemia peptides has shown to effectively control
lipid metabolism and levels in liver and plasma, cholesterol
homeostasis associated hepatic genes, hepatic FA desaturase
indices, fecal BA excretion and mRNA levels of Ileal Bile
Acid Transporter (IBAT) in pigs, rats, mice and or in fish
(Cai et al. 2015; Hosomi et al. 2010; Hosomi et al. 2011,
2012, 2013; Kato etal. 2011; Maeda etal. 2015; Shukla etal.
2006; Spielmann et al. 2009; Xu et al. 2016; Zheng et al.
2014). Sardine peptides similarly modulated the hepatic
enzymes involved in lipid metabolism, hepatic and plasma
lipid parameters, lipid vacuole formation, AI and CRI,
hepatic and renal tissue damage triggering enzymatic activ-
ities in various rat models (Affane et al. 2018; Athmani
et al. 2015; Benomar et al. 2015; Jemil, Abdelhedi, et al.
2017; Jemil, Nasri, et al. 2017; Khaled et al. 2012; Madani
et al. 2012). Hypolipidemic biopeptides of salmon alone or
in combination with fish oil as single or mixed fish protein
diet acted similar to Alaska pollock and sardine diets in
regulating the lipid parameters, lipid catabolism, lipid bio-
synthesis associated enzymes and their activity as well as
the hepatic expression of lipogenic genes in experimental
mice (Ait-Yahia et al. 2003; Drotningsvik et al. 2016; Saito
etal. 2009; Vik etal. 2015; Wergedahl etal. 2009; Wergedahl
et al. 2004; Dalila Ait Yahia et al. 2003; D Ait Yahia
et al. 2005).
Alaska pollock fillet protein not only modulated the
expression of hepatic genes involved in the lipid metabolism
but also affected serum and hepatic lipid levels in normal-fat
and high-fat hypercholesterolemic diet fed mice (supple-
mentary Table 3) (Hosomi et al. 2009). Alaska pollack
hydrolysate was more effective on liver lipid indices of
hypercholesterolemic diet fed rats (cholesterol: −27%, TG:
+6%) than normal diet fed ones (cholesterol: +2%, TG:
−12%) compared to casein, regardless of its significance
(Hosomi etal. 2012). Liver of hypercholesterolemic fed rats
had higher levels of cholesterol (+13-fold and +10-fold in
casein and fish diets, respectively) and TG (4-fold and 5-fold
in casein and fish diets, respectively) which may have been
the reason for higher organ weight (Hosomi et al. 2012).
Serum, liver, and fecal biochemical parameters as well as
liver FA (C16:0, C16:1n-7, C18:1n-9, C18:2n-6, C20:3n-6,
and C20:4n-6) and FA desaturase indices (C16:1/C16:0 and
C18:1/C18:0) were considerably modulated by different pro-
tein dietary sources (casein and Alaska pollock) (Maeda
et al. 2015). Nonetheless, growth parameters, organ weight,
hepatic fatty acid metabolism related activities of enzymes
and relative mRNA expression levels were not as much
affected by the purified protein diets, except for the signif-
icant downregulation of stearoyl-CoA desaturase 1 (SCD-1)
by fish proteins (positively correlated with hepatic C18:1/
C18:0 and C16:1/C16:0 ratios) in KK-Ay rats (Maeda etal.
2015). Findings of Maeda et al. are in comparative agree-
ment with Hosomi etal.’s observations (Hosomi etal. 2013;
Hosomi et al. 2009; Maeda et al. 2015). Water-insoluble
proteins of Alaska pollock comparably exhibited hypocho-
lesterolemic effect compared to casein (M/G: 1.22, L/A: 2.7)
in cholesterol-free fed ovariectomized rats (Kato etal. 2011).
Smaller M/G ratio, compared to smaller L/A value, played
more vital for hypocholesterolemic effect of Alaska pollock
protein (L/A: 2.0, M/G: 0.38 (low-Met) and 0.76 (high-Met))
versus casein (L/A: 2.7, M/G: 1.22) (Kato et al. 2011).
Water-soluble proteins of some fish types such as blue whit-
ing similarly tend to demonstrate significant hypocholester-
olemic effect in obese animal models (Drotningsvik, Vikøren,
et al. 2018).
Inclusion of small amount of Alaska pollock could also
make significant changes in the hyperlipidemic state of
animal models. In the study of Hosomi et al., a diet of
10% Alaska pollock fillet protein significantly enhanced
the activity of carnitine palmitoyl transferase 2 (CPT-2),
however, its effect on acyl-CoA oxidase (ACOX), FAS and
glucose-6-phosphate dehydrogenase (G6PDH) were insig-
nificant compared to casein diet in mice models (Hosomi
etal. 2013). In accord, relative mRNA expression levels of
lipid metabolism related enzymes and transporters (i.
ATP-binding cassette transporter A1 (ABCA1), ii.
3-hydroxy-3-methylglutaryl coenzyme A reductase
(HMGCR), iii. ABC transporter G5 and G8 (ABCG5 and
ABCG8), iv. CYP7A1, v. LDL receptor (LDLR), and vi.
scavenger receptor B1 (SRB1)) were marginally affected by
30 S. ABACHI ETAL.
fish diet fed rats compared to casein, except SCD1 which
was downregulated by 8% (Hosomi etal. 2013). In addition
to hepatic cholesterol levels, relatively similar to the study
of Hosomi et al., relative mRNA concentrations of genes
involved in fatty acid metabolism in liver and adipose
tissue of fish protein fed pigs (acetyl-CoA carboxylase
(ACC) and FAS in liver and adipose tissue, peroxisome
proliferator-activated receptor alpha (PPARα) (and its target
genes ACOX and CPT-1a) in hepatic fatty acid oxidation),
except CPT‐1a, were insignificantly affected by raw Alaska
pollack fillet diet (Spielmann et al. 2009). Unlike undi-
gested protein, effect of papain digested protein of the
same fish was more prominent (+36%) on the relative
mRNA expression level of CYP7A1 than other cholesterol
metabolism associated genes (Src homology region 2
domain-containing phosphatase-1 (SHP-1), HMGR,
acetyl-CoA acetyltransferase (ACAT-1), LDLR, sterol reg-
ulatory element-binding protein 2 (SREBP-2), farnesoid X
receptor alpha (FXRα), liver receptor homolog-1 (LRH-1))
compared to casein in hypercholesterolemic diet fed rats
(Hosomi et al. 2012).
In addition to upregulation of antioxidation enzymes,
sardine muscle proteins at high and low doses in short-and
long-term controlled animal studies alleviated hyperlipidemia
in hypercaloric fed diet hyperglycemic and oxidative stressed
rats (Affane etal. 2018; Athmani etal. 2015; Benomar et al.
2015; Jemil, Abdelhedi, etal. 2017; Jemil, Nasri, etal. 2017;
Khaled etal. 2012; Madani etal. 2012). Interestingly, sardine
byproduct isolated proteins were more hypolipidemic than
its fillet proteins, by up to +73%, in terms of anti-obesity
effects, fecal lipid and cholesterol excretion (Affane et al.
2018). Likewise, effect of sardine byproduct was superior
(serum Paraoxonase-1 (PON-1): +119%, HDL2-PON-1:
+100%, HDL3-PON-1: +90%) to its fillet peptides conse-
quently affecting lipid peroxidation (serum thiobarbituric
acid reactive substances (TBARS): −34%, VLDL-TBARS:
−31%, LDL-HDL1-TBARS: −54%, HDL2-TBARS: −64%,
HDL3-TBARS: −63%) in obese rats (Affane et al. 2018). It
is noteworthy that lipid metabolism was more influenced
by bogue hydrolysate than sardine hydrolysate in hypercho-
lesterolemic diet fed rats (Benomar etal. 2015). Fish lysates
modulated the lipid profile of lipoproteins ((VLDL (TC: ≤
−80%, phosphatidylcholine: ≤ −60%, sphingomyelin: ≤
+248%), LDL (TC: ≤ −45%, phosphatidylcholine ≤ −50%,
sphingomyelin: ≤ +53%) and HDL (TC: ≤ −4%, phospha-
tidylcholine: ≤ −15%, sphingomyelin: ≤ +59%)) and serum
activity of HDL-associated enzymes (lecithin cholesterol
acyltransferase (LCAT) activity: +23% by bogue hydrolysate
and −35% by sardine hydrolysate) in hyperlipidemic animals
significantly yet bogue hydrolysate was more potent than
sardine (Benomar etal. 2015). Accordingly, bogue hydroly-
sate fed rats had 3.3-times higher fecal cholesterol excretion
rate than sardine (Benomar etal. 2015).
Salmon backbone hydrolysate tended to decrease lipo-
genesis involved enzymes increasing the hepatic PUFA levels
affecting the regulation of lipid and glucose metabolism
compared to casein diet in high fat fed animals (Vik et al.
2015). The same salmon off-cuts hydrolysate, at different
concentrations, in studies of Bjørndal et al. and Parolini
etal. downregulated the mRNA level of Scd1 in two different
animal models, chronically inflamed and apolipoprotein E
(ApoE)-deficient rats (Bjørndal et al. 2013; Parolini et al.
2014). Expression of acetyl-CoA carboxylase A (ACACA)
was considerably downregulated in 5% salmon spine hydro-
lysate fed ApoE-/- mice for 12-weeks while higher intake of
same diet (15%) for 2-weeks, did not affect its expression
in humanized (h)TNF-α rats (Bjørndal et al. 2013; Parolini
etal. 2014). Salmon diet increased plasma levels of carnitine
and its precursor (γ-butyrobetaine), short-chained and
medium-chained acylcarnitine esters and fatty acid compo-
sition in liver and white adipose tissue (WAT) (Bjørndal
etal. 2013). In particular, Δ5 desaturase index for n-3 fatty
acids and Δ6 desaturase index for n-3 fatty acids and n-3
index were higher in the earlier mentioned organ and tissue
of chronically inflamed rat (Bjørndal etal. 2013). A signif-
icant decrement in the lipid profile, namely TC, TG, and
LDL-c but not HDL-c, of hemodialysis patients upon car-
nitine supplementation of 750 mg per day was observed
(Naini et al. 2012).
Fatty acid metabolism of the obese animals was likewise
considerably affected by cod-diet compared to casein diet;
total n-3 PUFA level in epididymal WAT (eWAT), n-3/n-6
PUFA ratio in serum, liver and eWAT, and anti-inflammatory
fatty acid index (AIFAI) in serum, liver, skeletal muscle and
eWAT (Drotningsvik etal. 2015). Menhaden oil-cod protein
combined diet, however, could not reduce serum TG levels
compared with other protein-lipid diets in rats (Demonty,
Deshaies, and Jacques 1998). In agreement, cod diet (23%
(w/w) protein diet) had insignificant effect on fasting plasma
concentrations of non-esterified fatty acids (NEFA) and TG
in high fat diet fed rats (Lavigne etal. 2001). Nonetheless,
cod-diet was superior to casein-diet (14% and 36% higher
L/A and M/G, respectively) in reducing the serum concen-
tration of NEFA (Drotningsvik et al. 2015). In contrary,
neither cod- nor casein-diets (20% protein from casein/whey
(90% casein and 10% whey)) could have hypolipidemic
effects (insignificant effects on lipase and alanine transam-
inase concentrations, plasma TNF-α levels, serum TC, HDL/
LDL cholesterol, total BA and triacylglycerol concentrations)
in obese Zucker fa/fa rats (Drotningsvik etal. 2015). Plasma
HDL-c and LDL-c levels were heightened in cod/scallop fed
rats, as well as mRNA expression of sterol regulatory
element-binding transcription factor 1 (SREBF1) and
HMGCR, compared to low fat fed and other protein group,
however, other parameters of plasma metabolites and liver
lipids were not significantly affected (Tastesen et al. 2014).
Of all the monitored parameters only HDL: TC ratio was
non-negligibly higher in casein fed rats, than low-fat and
other protein diets (Tastesen et al. 2014). Evidently, bene-
ficial metabolic effect of 13-weeks cod/scallop diet consump-
tion was superior over chicken intake in alleviating aorta
atherosclerotic plaque burden in ApoE-/- rat (I.-J. Jensen
et al. 2016). Fatty seafood regimen (eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) rich) as well as
lean ones have repeatedly been proposed for their hypotri-
glyceridemic effects and subsequent lesser aorta
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 31
atherosclerosis (Liaset etal. 2019). Nevertheless, these effects
could not solitary be beneficial to the condition since diets
with comparable cholesterol content, but different amino
acid composition, have affected the plaque burden differently
(I.-J. Jensen etal. 2016; Tastesen et al. 2014). There seems
to be simply an association of diet type, in terms of protein
source, with metabolic benefiting effects important in pre-
vention and management of cardiometabolic syndrome.
Other fish types likewise demonstrated small and or large
hypolipidemic effects improving dyslipidemia, its associated
disorders and organ damages. Compared to Crestor
(cholesterol-lowering drug at the dosage of 10 mg kg−1 BW)
zebra blenny muscle hydrolysates more efficiently reversed
kidney (urea 19%, creatinine 2%) and hepatic damage (ala-
nine aminotransferase (ALAT) 22%, ALP 23%) while posi-
tively modulating the serum and hepatic lipids (serum: TG
+41%, TC +68%, LDL-c + 148%, HDL-c + 19%, and liver: TC
+37%, LDL-c + 23%, and HDL-c + 135%) in hyperlipidemic
animals (Ktari et al. 2015). Evidently, hepatic damage, in
histopathological analysis, was completely prevented by zebra
blenny proteins in rats (Ktari etal. 2015). Although saithe
hydrolysate significantly increased the plasma BA (not the
hepatic levels of BA), fecal BA excretion was greatest in the
soy protein fed mice (Liaset et al. 2009). Soy in another
study presented better hypolipidemic effects than the fish
biopeptides. Soy (M/G: 0.24, L/A: 0.79) and salmon frame
proteins (M/G: 0.18, L/A: 1.05) had relatively comparable
effects, with soy diet being more potent over the other, on
hepatic lipid metabolism, fatty acid composition and desat-
urases; reduced 18:1(n-9) to 18:0 ratio (increased hepatic
18:0 (decreased 18:1(n-9)), unchanged Δ9 desaturase gene
expression), reduced 18:3(n-6):18:2(n-6) and
20:4(n-6):20:3(n-6) ratios (reduced mRNA levels of Δ5 and
Δ6 desaturase (reduced activities of Δ5 and Δ6 desaturases)),
increased 20:4(n-6):18:2(n-6) ratio (increased Δ5 desaturase
activity), increased hepatic triacylglycerol-rich lipoprotein
secretion (increased hepatic lipid content), increased hepatic
22:6(n-3) (upregulated peroxisomal acyl-coenzyme A oxidase
with no effect on CPT-1 enzyme activity), and increased
cytosolic isoform of acetyl-CoA carboxylase (increased activ-
ity of lipogenic enzyme fatty acid synthase) compared to
casein diet (M/G: 1.17, L/A: 1.85, negligible health benefiting
effects) in genetically obese Zucker fa/fa rats (Wergedahl
et al. 2004).
Mixed fish diet also could beneficially affect the hyper-
lipidemia in animal models. Concentrations of plasma apo-
lipoproteins were altered by commercial fish protein
preparation compared to casein diet in spontaneously hyper-
tensive rats (SHR); HDL3 apo A-I (-38%), A-II (-55%) and
A-IV (-41%), HDL2 apo A-II (+71%) and A-IV (+41%),
VLDL apo B-48 (∼ −40%) and apo C (∼ +40%) (D Ait
Yahia et al. 2005). Total lipid, tissue lipoprotein lipase (LPL)
and hepatic triglyceride lipase (HTGL) activities were sim-
ilarly modulated in fish protein fed SHR compared to casein
diet (liver TL (-24%), and HTGL (-10%), heart TL (+14%)
and LPL (+5%), kidney TL (-6%) and LPL (+24%), gastroc-
nemius TL (-29%) and LPL (+7%), and adipose tissue TL
(-26%) and LPL (-91%)) (D Ait Yahia et al. 2005). The same
commercial fish protein preparation by Seah International
beneficially modulated fatty acid composition of microsomal
lipids, but not casein diet, in SHR animal models; 16:0
(+26%), 18:0 (+21%), 18:1(ω-9) (+20%), 20:4(ω-6) (-50%),
Saturated Fatty Acid (SFA) (+23%), total ω-6 (-29%), and
20:4(ω-6)/18:2(ω-6) (-50%) (Ait-Yahia et al. 2003; D Ait
Yahia et al. 2005).
Clinical studies
Among all fish types, cod was the type mostly tested in
human intervention studies for its anti-hyperlipidemic effect
(Table 5). Different meal sizes and or treatment dosages of
cod protein, compared to various control diets and or pla-
cebo, beneficially affected the lipid peroxidation, oxidative
stress expressed as malondialdehyde/plasma antioxidant
potential (MDA/AOP) ratio, plasma lipid parameters and
antioxidant capacity in overweight, insulin-resistant, diabetic
subjects and or healthy individuals (Gunnarsdottir et al.
2008; Hovland et al. 2019; Mortensen et al. 2009; Ouellet
etal. 2007; Ouellet et al. 2008; Parra et al. 2007; Thorsdottir
et al. 2007; Vikøren et al. 2013). Positive health effects of
control diet at times surpassed the experimental fish diets.
Accordingly, cod test meal, compared to casein, may have
positively influenced fat-induced postprandial lipemia but
its effect was not as significant as whey diet in T2D human
subjects (Mortensen etal. 2009). Mixed fish meal (lean and
or fatty fish) in controlled human interventions modulated
plasma phospholipids (PL), TL, TG, cholesterol, total SFA,
FFA and prostaglandin I2 (PGI2) levels in different types
of population (e.g., coronary heart patients, diabetics with
and or without hypertension as well as healthy subjects)
(Eli K Aadland etal. 2016; Eli Kristin Aadland et al. 2015;
Cui-Feng et al. 2010; de Mello et al. 2009; Erkkilä et al.
2014; Grieger, Miller, and Cobiac 2014; Zaribaf etal. 2014;
C.-F. Zhu, Li, Peng, Li, etal. 2010). Collagenous hydrolysate
preparation, dosage of 13 g daily, could decrease TG, TC,
LDL-c and FFA while increasing PGI2 and HDL-c in T2D
patients (C.-F. Zhu, Li, Peng, Li, et al. 2010). In a more
sophisticated study, fish gelatinous diet supplemented with
or without n-3 PUFA showed hypolipidemic yet rather
sex-dependent activity in free-living insulin-resistant men
and women (Picard-Deland etal. 2012).
Anti-obesity peptides
In the following two sub-sections, effects of fish and
fish-derived products on appetite suppression and regulation
of CCK release, total and organ weight gain/loss including
lipid droplet formation and accumulation as well as food
intake will be discussed in detail.
In-vitro and in-vivo studies
Not only that fish biopeptides have shown to therapeutically
affect the obesity associated comorbidities but also could
directly modulate weight gain and loss, food intake and
energy expenditure. Of all the studies reviewed herein, inves-
tigating anti-weight gain and anti-obesity attributes of
32 S. ABACHI ETAL.
biopeptides, about 44% utilized fish byproducts (about 19
out of 43) (Tables 3–5). Among so many conventional bio-
activity screening studies, Liu et al. attempted a different
approach using response surface methodology for optimizing
the reaction parameter of DH and predicting the anti-obesity
activity of Crucian carp (Carassius carassius) muscle hydro-
lysates in terms of porcine pancreas lipase (PPL) and
α-amylase inhibition effects (L. Liu etal. 2013). Many types
of fish such as Alaska pollock, tuna, blue whiting, smooth
hound, saithe, and others demonstrated anti-obesity activity,
yet cod, salmon and sardine were the most studied ones.
Cod fillet protein, in-house and or commercial preparation,
modulated CCK release, body weight gain (lean and fat
mass), liver weight and fat mass, final weight, food intake,
feed efficiency and growth in multiple in-vitro and in-vivo
experimental setting (Dort et al. 2012; Drotningsvik et al.
2015; Geraedts et al. 2011; Hosomi et al. 2017; Myrmel
et al. 2019). CCK is a hormone that among its so many
major roles, such as stimulation of pancreatic enzyme secre-
tion and growth, could also suppress appetite inducing sati-
ety via CCK1 receptors thus being significant to weight
control (Rehfeld 2017). Outcome of the studies greatly
depended on the experimental setting and the animal model.
Following a monthly 5% cod diet body weight, growth per-
centage and liver weight increased in obese Zucker fa/fa
rats (Drotningsvik et al. 2015). Accordingly, a diet of 23%
cod protein over a month, compared to tuna, increased the
weight gain, final weight, food intake in hypercholesterol-
emic diet fed rats (Hosomi etal. 2017). However, a 20 − 40%
cod protein intake decreased further weight and fat mass
gain as well as feed efficiency while increasing the lean
mass over 6 − 12 weeks in high-fat/protein fed obese mice
and low-fat fed lean C57BL/6J mice (Myrmel et al. 2019).
Furthermore, salmon with its anti-obesity effects changed
the mean growth, weight gain, feed intake as well as adi-
ponectin, leptin and resistin levels in rats and mice
(Drotningsvik etal. 2016; Pilon etal. 2011; Vik etal. 2015;
C. Zhu, Zhang, Mu, et al. 2017). Compared to 20% (w/w)
bonito, herring and mackerel protein diets only 20% (w/w)
salmon could over the period of 28-days reduce body weight
gain and visceral adiposity while increasing energy expen-
diture in high fat high sucrose (HFHS) diet fed rats (Pilon
et al. 2011). In the study of Vik et al., while 5% salmon
protein diet increased the feed intake but also prevented
body and total weight gain compared to casein in high fat
fed rats (Vik etal. 2015). Sardine more or less had similar
effects as salmon and cod protein diets. Sardine protein
averted high fructose diet induced weight gain, considerably
in liver and slightly in muscle tissues compared with casein
diet (Madani etal. 2015). Even though sardine protein diet
(with or without high fructose) effects were non-significant
on the weights of heart, kidney and skeletal muscle tissues
but liver weight was much smaller compared to high fruc-
tose diet only (Madani etal. 2015). High fructose fed rats,
supplemented with sardine muscle lysate with L/A ratio of
1.71 (16% higher L/A ratio than cod protein), concomitant
with lower food and energy intakes, gained less weight
which was more prominent in the liver tissue (Madani etal.
2015; Vikøren et al. 2013). Sardine byproduct hydrolysate
was by more than 50% more anti-obesogenic than its muscle
proteins on food intake, body weight gain, food efficiency
rate and fecal lipid excretion (Affane etal. 2018). Interestingly,
fish like saithe had tissue-specific anti-obesogenic effects.
Saithe fish fed rats (taurine and glycine rich diet, M/G:
0.20) gained less weight, pertinent in perirenal and retro-
peritoneal visceral adipose tissues but not in skeletal muscle
(gastrocnemius and plantaris) and hepatic tissues compared
to casein (taurine deficient, low glycine, M/G: 1.08) and soy
(taurine deficient, medium glycine, M/G: 0.24) diets, how-
ever, effects did not root from lower energy absorption
(Liaset etal. 2009). Diet of 20% mixed fish protein (a com-
mercial preparation) reduced absolute liver weight and body
weight gain as well as final body weight, compared with
casein, over 2-months in SHR rats (Ait-Yahia et al. 2003;
Dalila Ait Yahia et al. 2003; D Ait Yahia etal. 2005).
Final body weight of the rats fed fish collagen supple-
mented high caloric diet was +2.2-fold while hypercaloric
and normocaloric fed ones encountered 2.7- and 1.9-folds
weight increase (Raksha etal. 2018). Collagen rich in-house
prepared tuna skin product, at concentration as low as 1 mg
mL−1, prevented the accumulation of lipids and formation
of lipid droplets delaying adipogenic differentiation of pread-
ipocytes while downregulating the expression of adipogenic
(CCAAT/enhancer binding protein alpha (C/EBP-α) and
PPAR-γ) and target genes (adipocyte protein 2 (aP2)) in
3T3-L1 preadipocytes (E. J. Lee et al. 2017). Same tuna
collagenous preparation substantially reduced the
palmitate-induced lipogenesis in HepG2 cells (E. J. Lee etal.
2017). These health effects were further confirmed in obese
high fat diet fed rats where body weight gain, epididymal
adipocyte size and the expression of adipogenic genes and
its transcription factors were significantly reduced and
downregulated (E. J. Lee et al. 2017). Another commercial
collagenous preparation of skate origin exerted comparable
effects to tuna collagens in obese animal models reducing
liver, visceral and subcutaneous adipose tissue weight (but
not epididymis adipose tissue), lipid droplet size as well as
liver lipid accumulation increasing the adiponectin levels
(Woo etal. 2018). Level of adiponectin with insulin-sensitizing,
anti-inflammatory, and antiapoptotic effects are low in obese,
T2D and at CVD risk patients thus its stimulation may
reduce the prevalence of these conditions by enhancing
metabolism and uptake of glucose (Combs et al. 2001;
Guenther et al. 2014; X. Wu et al. 2003). Anti-obesogenic
activity of glycine rich marine fish collagenic preparation,
concomitant with hypoglycemic effects, may be due to CCK
modulation thus stimulating satiation (Raksha et al. 2018).
Amino acid treatment of 3T3-L1 adipocytes have previously
shown to affect the adiponectin secretion probably by acting
as substrates for the synthesis of fat cell-derived hormone
(Blümer et al. 2008).
It is of note that fish diets, whether lean- and or fatty-fish,
have not always been successful in weight gain prevention.
Like sardine, salmon diet did not change the weight of all
the tested tissues (e.g., epididymal, retroperitoneal, inguinal,
or BAT) and its beneficial effects were only significant in
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 33
the liver weight gain of obese mice (Chevrier et al. 2015;
Madani etal. 2015). Weight gain and fat tissue accumulation
of obese rats were not affected by cod diet and its
anti-inflammatory effects on TNF-α expression in muscle
and adipose tissues were insignificant (Lavigne etal. 2001).
In agreement, Alaska pollock only exerted hypolipidemic
effect with null activity on the weight gain of KK-Ay rats
(Hosomi etal. 2013; Hosomi etal. 2009; Maeda et al. 2015).
Clinical studies
Various fish diets, blue whiting, cod, salmon, and tuna as
well as mixed fish, were intervened in human studies to
further test their clinical anti-obesogenic effects (Table 5).
Fish collagenous preparation of mixed fish and cod, in addi-
tion to anti-obesity effects in rats, exerted stimulatory effects
on the adiponectin levels in T2D (with/without hyperten-
sion) or overweight subjects (Cui-Feng etal. 2010; Hovland
et al. 2019; C.-F. Zhu, Li, Peng, Li, et al. 2010). Cod pre-
sented significant anti-obesity effects in different studies by
means of reducing body weight and waist circumference,
obesity, hunger, prospective foodstuff consumption, energy
intake at the evening meal while increasing satiety and
fasting adiponectin level in healthy overweight/obese subjects
(Borzoei et al. 2006; Gunnarsdottir et al. 2008; Hovland
etal. 2019; Ramel, Jonsdottir, etal. 2009; Thorsdottir et al.
2007). While during the first 4-weeks consumption of cod
protein (with L/A ratio of 1.47) weight and muscle gain
were boosted, fat gain was significantly eased in overweight
human subjects (Vikøren et al. 2013). Blue whiting muscle
hydrolysate in tablet dosage form, at concentrations as low
as 1.4 − 2.0 g daily, significantly reduced the desire to sweet
consumption before and after experimental diet, weight and
fat mass, body mass index (BMI), extracellular water as well
as waist, hip and thigh circumference while increasing CCK
level in overweight individuals (Nobile et al. 2016; Zaïr
et al. 2014).
Multifaceted character of sh biopeptides toward
prevention and or treatment of MetS
Fish anti-diabetic, anti-obesogenic and anti-hyperlipidemic
peptides exert their beneficial effect on metabolic disorders
non-cytotoxically. Effects of fish anti-MetS peptides are
insignificant on hematological parameters (e.g., white blood
cell (WBC), red blood cell (RBC), total hemoglobin (Hb),
hematocrit (Htc), mean corpuscular volume (MCV), mean
corpuscular hemoglobin (MCH), and mean corpuscular
hemoglobin concentration (MCHC), platelet count (PLT),
and lymph) making them appropriate enough as therapeutic
options for the treatment of MetS (Cudennec et al. 2008;
Y. M. Kim et al. 2015; E. J. Lee et al. 2017; Nasri et al.
2015). Among the studies screening fish peptides for their
anti-diabetic, anti-obesogenic and anti-hyperlipidemic effects,
many have shown to be multi-functional of which few
demonstrated anti-CVD activities. Bogue protein while being
hypolipidemic could also reduce atherosclerotic plaques pre-
venting the formation of foam cells in hypercholesterolemic
diet fed rats (Lassoued et al. 2014). Sardine peptides had
rather similar effects in hypercaloric diet fed rats reducing
plasma AI, CRI, hypertrophy of cells in infarction of heart
tissue, lipid deposition within intima of aorta and lesion
development in aortic wall (Jemil, Abdelhedi, et al. 2017).
Salmon extracted collagen exerted anti-CVD activity and
prevented endothelial thinning and exudative inflammation
in carotid-artery vascular endothelial cells of dietary-induced
diabetic rats (C. Zhu, Zhang, Mu, et al. 2017). Lean fish
meal in 8-weeks intervention study significantly reduced
soluble ICAM-1 (sICAM-1), a biomarker of CVD, in CHD
patients (de Mello et al. 2009). Of the total peptides from
Atlantic herring (Clupea harengus L.) skin and residual
material byproducts proteinic extracts, identified by a com-
bination of MS (Orbitrap), bioinformatics and database
(BioPepDB and Teleost) search, about half were related to
motifs with possible effects on cardiovascular system (EL,
AFL, AIYK+, ALEP, ALPM, APL, AVF, FAL, FY, GPL, HHL,
HLP, IAE, IAP, IAPG, IHPF, IKP, IIAEK+, IKW, IPP, IPY,
IVVE+, IW, KFYG, LGP, LKP, LQGMP, LRP, NIPP, PLPLL,
PPK, PSYVAF, VIKP, VIY, VK, VPP, YN, YNKL, YP, YPK,
YQEP+, YQY) (Pampanin et al. 2012). Furthermore, histo-
pathological analysis has shown that fish bioactive peptides
could preserve kidneys and liver from MetS-associated organ
damages. Hypoglycemic, hypolipidemic, antioxidant and
anti-obesity goby fish hydrolysate prevented renal and
hepatic damages by improving kidney and liver architecture
in hypercaloric fed mice (Nasri et al. 2018; Nasri et al.
2015). Sardine anti-diabetic and antioxidant peptides likewise
decreased renal glomerular atrophy and prevented hepatic
tissue damage in diabetic and oxidative stressed animals
(Jemil, Nasri, etal. 2017). Hypoglycemic and hypolipidemic
zebra blenny hydrolysates exerted comparable effects as sar-
dine and goby fish in diabetic and hypercaloric diet fed rats
(Ktari etal. 2015; Ktari etal. 2013). Another example could
be mackerel hydrolysate peptides demonstrating significant
in-vitro hypotensive and immunoregulatory effects with neg-
ligible in-vivo anti-diabetes and anti-obesity attributes at the
tested concentrations (Soheila Abachi et al. 2022;
Hokmabadinazhad etal. 2022). Many fish-extracted peptides
with dual- and multi-functional activities in animal and
human studies have been reviewed in this work (Tables
4 and 5).
Nonetheless, MetS benefiting health effects (glucose and
lipid metabolism) of the fish diets are rather divergent
depending on the characteristics of the under study popu-
lation and study design (Dale et al. 2018; Hovland et al.
2019). Various marine fish collagenous preparations had
affected T2D patients, with and or without high blood pres-
sure, in different human intervention study settings
(Cui-Feng etal. 2010; C.-F. Zhu, Li, Peng, Li, etal. 2010).
Serum levels of hsCRP, a metabolic regulator, and adipokine
(leptin and resistin) were beneficially modulated in the study
of Cui-Feng etal. by a marine collagen product yet some-
what similar preparation exerted null effect on the same
parameters in a similar randomized double-blind study of
Zhu et al. (Cui-Feng et al. 2010; C.-F. Zhu, Li, Peng, Li,
et al. 2010). Various fish diets (e.g., tuna and cod) reduced
34 S. ABACHI ETAL.
MetS (same criteria defined by health organizations) in over-
weight and obese subjects (supplementary Table 1) (Ramel,
Jonsdottir, et al. 2009; Zaribaf et al. 2014). Logically, meal
and or dosage size were important in the health effects
hence fish ought to be ingested in adequate amounts to
exert significant beneficial therapeutical activity. Accordingly,
in the study of Grieger etal., a 2-months low fish diet could
not significantly modulate the cardiovascular biomarkers in
a healthy elderly population (Grieger, Miller, and
Cobiac 2014).
Structure activity relationship and stability
Scientific community agrees on the fact that certain features
of the bioactive material play vital in their positive biological
activity. For instance, fish hypotensive and immunomodu-
latory peptides commonly possessed smaller molecular
weight, short chain, and certain compositional factors yet
presence or absence of a feature did not necessitate its effec-
tiveness and or ineffectiveness. The topics have been thor-
oughly reviewed by the authors. More or less same applies
to anti-diabetes, anti-hyperlipidemia, and anti-obesity fish
biopeptides as discussed in the following paragraphs. For
example, food-derived oligopeptides of small molecular
weight and shorter amino acid sequences have repetitively
been reported as effective DPP-IV inhibitors (R. Liu, Cheng,
and Wu 2019). Among numerous reported food-derived
DPP-IV inhibitors, up to 2019, more than 88.4% have MW
smaller than 1,000 Da, and around 47% are hydrophobic
indicating the importance of physicochemical properties of
the biopeptides in their bioavailability and bioefficacy (R.
Liu, Cheng, and Wu 2019). Both hydrophobic and hydro-
philic peptides could inhibit the activity of DPP-IV although
chance of a hydrophobic peptide (hydrophobicity index of
larger than 0) being an anti-DPP-IV is higher (Nongonierma
and FitzGerald 2013). Presence of N-terminus HAA and or
aromatic AA (AAA) has been a good indication of a food
derived anti-DPP-IV peptide yet other features also come
into play for successful inhibition of the enzyme’s activity
(Nongonierma and FitzGerald 2014). In addition to molec-
ular mass and hydrophobicity, presence and or absence of
particular amino acids in certain positions of the sequences
seem to fully and or partially contribute to the anti-MetS
activity of fish biopeptides. Anti-MetS affecting features of
peptides have been evidently documented in many studies
by comparing the experimental peptide and or diet to ref-
erence proteins such as casein (supplementary Table 4).
Occurrence of proline as N-terminus penultimate residue
along with HAA as N-terminus ultimate residue seems to
be rather important characteristics of a food-originated
DPP-IV inhibitor (R. Liu, Cheng, and Wu 2019). In an
in-silico study aiming to predict food derived DPP-IV inhib-
itors, potential candidate peptides had N-terminal trypto-
phan with proline at penultimate position (Nongonierma
and FitzGerald 2014). Therefore, in addition to the occur-
rence of proline at the penultimate point of N-terminal,
presence of HAA at the C-terminal and N-terminal ultimate
position appears to facilitate the glucoregulatory effect of a
biopeptide (R. Liu, Cheng, and Wu 2019; Matsui, Oki, and
Osajima 1999). N-terminal tryptophan of barbel-extracted
tri-peptide, WSG, also played significant in its anti-DPP-IV
activity (Assaad Sila et al. 2016). While whey isolated LLF
and LV were impotent anti-DPP-IV peptides, LL and LA
potently inhibited the activity of the same enzyme noting
the significance of N-terminus position 3 residue along with
ultimate and penultimate motifs (Tulipano et al. 2011). In
the study of Huang etal., N-terminal proline was as import-
ant as N-terminal penultimate proline for the DPP-IV inhi-
bition (S.-L. Huang et al. 2012). Interestingly, replacement
of leucine with tyrosine in the same YPL sequence, tyrosine
at both N- and C-terminals, decreased the potency by about
7-fold, from IC50 of 3.9 mM to 25.8 mM (S.-L. Huang etal.
2012). In-vitro DPP-IV inhibition of 3 mg mL−1 tilapia and
milkfish skin gelatin hydrolysates, with a higher amount of
imino acids, were by about 8% greater than halibut and
hake skin gelatin hydrolysates (T.-Y. Wang et al. 2015). In
agreement, proline or hydroxyproline (a metabolite of pro-
line) supplementation has shown to enhance the perfor-
mance and weight gain of vertebrates and invertebrates (G.
Wu etal. 2011). Accordingly, proline and HAA are present
at the same positions as of salmon, halibut and tilapia oli-
gopeptides (Li-Chan et al. 2012; T.-Y. Wang et al. 2015).
Glycine in free form, as a supplement, has demonstrated
many health effects (e.g., anti-inflammation, immunomod-
ulation, cytoprotection, etc.) through glycine-gated chloride
channel activation in various cell types in the in-vivo exper-
iments. Glycine exerts various cardioprotective and vascular
health effects such as GLP-1 and glucagon secretion stim-
ulation, downregulation of Kupffer cell activation controlling
fructose-induced steatosis, and sucrose-induced MetS inhi-
bition (Table 1). This may be the reason for the glucoreg-
ulatory, anti-hyperlipidemia and anti-obesogenic activities
of glycine rich tilapia, salmon, flathead gray mullet and
marine fish collagenic preparations and hydrolysates (H.-S.
Kim, Nian, et al. 2009; Raksha et al. 2018; J. Wang et al.
2010; R. Zhang, Chen, Chen, et al. 2016; C.-F. Zhu, Zhu,
and Zhou 2013; C. Zhu, Zhang, Mu, et al. 2017). Glycine
and sulfur-containing amino acids (methionine, cysteine,
homocysteine, and taurine) have long been known as poten-
tial lipid metabolism modulators, increasing HDL-c and
decreasing VLDL-c, at appropriate concentrations conceiv-
ably via [1] altering the enzymatic and transcriptional activ-
ity by reduced form of glutathione and stimulating cholesterol
degradation and its clearance from blood circulation, [2]
changing the posttranslational modification pattern of ligand
binding to nuclear receptors and phosphorylation/dephos-
phorylation regulatory proteins, and [3] inducing CYP7A1
and Apo A-I gene expressions (Oda 2006). However, diets
of varying richness and deficiency of glycine and or M/G
as well as taurine behave differently on weight gain, specif-
ically adipose tissue, and not skeletal muscle, of rats.
Correspondingly, taurine and glycine rich saithe fish (rather
balanced M/G) was more anti-obesogenic than casein and
soy (Liaset et al. 2009). Higher amounts of these amino
acids in saithe hydrolysate also enhanced the hepatic secre-
tion of BA and its consequent excretion into plasma which
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 35
seemed to be more affected by glycine than taurine since
organic anion transporting polypeptide (OATP) 1, bile acid
coenzyme A: amino acid N-acyltransferase (BAAT), and
ABC subfamily C member 3 (ABCC3) hepatic expressions
were not modulated by taurine-rich diet (downregulating
hepatic ABCC4 protein levels, hepatic expression of, OATP1
and OATP4 significant in cholestasis) (Liaset et al. 2009).
Expression of BA transporters and BA fecal secretion have
been shown to be sensitive to taurine and glycine of the
treatment diet (Liaset etal. 2009). While higher fecal excre-
tion of BA in soy diet has been theorized to be due to
irreversible binding of its indigestible fractions to BA, higher
plasma BA in saithe diet fed rats may be because of taurine
and glycine making the conjugation of BA possible hence
improving their solubility and liver secretion to the blood
(Liaset et al. 2009). According to Iwami et al.,
anti-hypercholesteremic peptides in part owe their effectivity
to the enhanced binding of hydrophobic plant biopeptides
to BA in the digestive tract (Iwami, Sakakibara, and Ibuki
1986). In the study of Liaset et al., hepatic expression of
OATP1, BAAT and ABCC3 weren’t as much affected by
taurine, however, overall those may have been sensitive to
glycine (Liaset et al. 2009). Interestingly, taurine deficient
(casein with low glycine) and high taurine (saithe with high
glycine) diets downregulated the hepatic expression of
OATP1 (Liaset et al. 2009). In contrary, hepatic expression
of BAAT and ABCC3 were upregulated by soy (taurine
deficient, medium glycine) and saithe (taurine and glycine
rich) diets (Liaset etal. 2009). Beneficial effects of fish diet
could as well possibly be explained by its satiety attributes
over chicken and beef intake which have been related to
the presence and absence of certain amino acids such as
taurine (Uhe, Collier, and O’Dea 1992). Amino acid com-
position of a satiating fish diet was relatively different from
beef and chicken (fish: CAA 27 > HAA 23 > BCAA 11 > Tau
1.5 g 50 g−1 protein, L/A 1.69 and M/G 0.53, chicken: CAA
20, HAA 20 > BCAA 10 > Tau 0.2 g 50 g−1 protein, L/A 1.74
and M/G 0.60, beef: CAA 24 > HAA 22 > BCAA 11 > Tau
0.2 g 50 g−1 protein, L/A 1.59 and M/G 0.25) with relatively
high CAA, high taurine, balanced L/A and M/G ratios (Uhe,
Collier, and O’Dea 1992). Beef, pork, veal, eggs, milk, and
milk products (BPVEM) diet was to a small fraction richer
in BCAA, HAA, and EAA, up to 11%, with higher L/A
ratio (7%) compared to cod diet with stimulatory effect on
insulin sensitivity in human subjects (Ouellet et al. 2007).
The importance of L/A ratio peptides was pointed out some
decades ago by Kritchevsky et al. demonstrating the ath-
erogenicity power of different diets with parallel lysine but
variable arginine levels. Diet with highest arginine thus low-
est L/A presented the least atherogenicity in rabbits
(Kritchevsky etal. 1982). Typically, low M/G and L/A ratio
diets have repeatedly demonstrated anti-atherogenic,
anti-hyperlipidemic and anti-obesogenic effects in many
studies and various experimental settings (Gudbrandsen
etal. 2005; Kern etal. 2002; Morita etal. 1997; Rajamohan
and Kurup 1990; Vega-López et al. 2010). In a study, bal-
anced L/A (1.1) diet fed cobia performed better than high
(1.8) and low (0.8) L/A diet fed fish (Van Nguyen et al.
2014). Overall, weight gain of cobia (lipid and protein gain)
were lower in imbalanced L/A diet fed fish (Van Nguyen
etal. 2014). Similar finding was observed in a human inter-
vention study where L/A and M/G ratios of casein/whey
diet (EAA 1255 > HAA 1201 > CAA 1183 > BCAA 587 > imino
acids 262 mg d−1) were considerably higher (2.41, 1.53) than
anti-diabetic fish protein diets (Hovland et al. 2019). Yet,
zebra blenny may among other assumptions, owe its hypo-
glycemic, antihyperlipidemic and other possible health effects
to its high BCAA and CAA mainly leucine (15%), glutamic
acid and arginine (20%), approximately accounting for 35%
of the total (Ktari etal. 2013). It is of note that oral sup-
plementation of arginine in free form, a CAA, to acute
myocardial infarction patients with 3 g of the amino acid
daily improved their dyslipidemia conditions, decreasing
serum TC and TG while increasing HDL-c, during the
2-weeks period of study (Tripathi, Misra, and Pandey 2012).
It should be noted that along with beneficial effects there
are various examples of proline, charged and aromatic amino
acids having negative effect on the glucoregulatory attributes
of fish biopeptides and same have been valid for
anti-hyperlipidemic activities of fish proteins.
Leucine, comparable to glycine with glucoregulatory
effects, has been known for its stimulatory effect on pan-
creatic insulin secretion via activation of mammalian target
of rapamycin (mTOR) pathway successively downregulating
the surface expression of adrenergic α2A receptor and
enhancing cAMP production (Table 1) (Yang et al. 2012).
In addition, leucine, in free form, like several other amino
acids, tended to modulate MetS-induced insulin resistance,
hepatic steatosis reversing the inflammation of adipose tissue
over 2-months consumption of dietary supplements in obese
rats (Macotela et al. 2011). Presence of leucine at the
C-terminal and tyrosine at the N-terminal, contrary to
DPP-IV inhibitors, have been reported vital for the inter-
action of a biopeptide with active binding sites of
α-glucosidase attenuating its activity (Yu Zhang, Chen, Chen,
et al. 2016). Collectively, molecular weight, chain length,
compositional and structural features of a fish biopeptide
are important for anti-MetS effects. Additionally, amino acid
composition and their respective bioactivities may vary
depending on the starting material and type of fish. For
instance, white muscle of cod tended to be a relatively more
potent hypocholesterolemic protein than tuna red muscle
protein which may be due to compositional differences of
diets (Hosomi et al. 2017).
Structural dierences between dierent sh and
control diets aecting their bioactivities
In the following sub-sections, authors have attempted to
focus on the compositional differences of biopeptides based
on most investigated fish types, where possible, for better
understanding of the structure-activity relationship.
Alaska pollock
Importance of either extremities of a biopeptide in gluco-
regulatory activity of fish hydrolysate was examined by frag-
menting an Alaska pollack-originated (myosin(548–556))
36 S. ABACHI ETAL.
oligopeptide, ANGEVAQWR, to tri-peptides; ANG, EVA,
and QWR (Ayabe et al. 2015). Interestingly, at 1 mg kg−1
C-terminal tri-peptide QWR had glucose lowering effect in
diabetic rats while its di-peptide fragments (QW, and WR)
were ineffective (Ayabe et al. 2015). Another C-terminus
Alaska pollack-originated pentapeptide, YNELR, and
tri-peptide, ELR, tended to lower the blood glucose levels
at the dosage of 1 mg kg−1 in animal models, while the main
identified actin(87–97) associated oligopeptide
(IWHHTFYNELR) had negligible effects (Ayabe etal. 2015).
Glucose uptake rates in mouse skeletal muscle C2C12 cells
were tested to further elucidate the structure activity rela-
tionship of fish glucoregulatory peptides (Ayabe etal. 2015).
Tripeptides, QWR, ELR and pentapeptide, YNELR, enhanced
the uptake of glucose in cells (Ayabe et al. 2015). At con-
centrations up to 500 μM QWR dose-dependently activated
the insulin-independent glucose uptake in skeletal muscle
cells (Ayabe etal. 2015). Potency of Alaska pollock hydro-
lysate may be related to glycine content of the diet as it
composed of 2-fold glycine compared to casein yet suppos-
edly both diets were taurine deficient (not listed in AA
composition of diets) (Hosomi et al. 2012). Casein with
ineffective attributes on hepatic TG and FA desaturase indi-
ces of obese T2D KK-Ay mice model compared to Alaska
pollock muscle proteins has higher proline (+3.2-times), yet
lower glycine (-0.47-times) (Maeda etal. 2015). Briefly, pres-
ence of arginine at C-terminus and polar amino acids at
N-terminus position as well as high glycine or less proline
content may play significant in bioactivity of Alaska pollock
oligopeptides on glucose uptake and level.
Salmon
Amino acid compositions of salmon spine and backbone/
head diets, regardless of molecular weight distribution, were
to some extent comparable, yet their beneficial metabolic
attributes greatly differed from one another (Vik etal. 2015).
Backbone lysate of salmon contained least of BCAA and
CAA, whilst was richest in imino acids with least M/G and
L/A (0.35 and 1.13, respectively) (Vik et al. 2015).
Accordingly, inadequate sub-optimal methionine diet fed
animal model (Atlantic salmon) compared to adequate opti-
mal amount fed ones, led to increased liver weight, FAS
activity, 18:1/18:0 FA ratio, hepatic TG concomitant with
decreased hepatic taurine and total fecal and plasma BA
(descriptive of nonalcoholic fatty liver disease development
in rats) (Espe etal. 2010). For example, umamizyme salmon
spine lysate, with rather high M/G, tended to be hyperlip-
idemic than being hypolipidemic (Vik et al. 2015). Salmon
hydrolysate, compared to herring, in the study of
Drotningsvik etal., presented different patterns of bioactivity
on MetS markers being more hypoglycemic and
anti-obesogenic than hypolipidemic in an obese and diabetic
animal model (Zucker fa/fa rat) (Drotningsvik etal. 2016).
Salmon and herring byproduct hydrolysates contained com-
parably similar amounts of HAA, CAA and BCAA yet their
taurine quantities, L/A and M/G ratios significantly diverged
from one another and from the casein/whey control diet
(taurine deficient) (Drotningsvik et al. 2016). Of the
nineteen tested hypocholesterolemic and/or antidiabetic
sequences (ALPMH, GGV, GLDIQK, GPAE, GPGA, GPL,
HIRL, IAVPGEVA, IIAEK, IPI, LPGP, LPYPR, PGPL,
RPLKPW, VAWWMY, VGVI, VGVL, VPDPR, VVYP, VW,
VYVEELKPTPEGDLEILLQK, YPFVV, and YYPL) only few
were present in the herring and salmon hydrolysates (her-
ring: GPL, IPI, VW, GPAE and LGPG (antidiabetic motifs),
IIAEK (hypocholesterolemic motif), PGPL (hypocholester-
olemic and antidiabetic motif), salmon: GPL, IPI and VW
(antidiabetic motifs), PGPL (hypocholesterolemic and anti-
diabetic motif)) (Drotningsvik et al. 2016). In conclusion,
type of salmon as well as extraction technique and/or type
of enzyme seem to be effectual on its anti-MetS attributes.
Moreover, presumably adequate taurine level as well as M/G
and L/A ratios define the bioactivity of salmon
biopeptides.
Cod
Specific amino acid arrangement of cod may be the source
of its metabolic health effects on insulin secretion or insulin
excretion rates in the liver (von Post-Skagegård, Vessby, and
Karlström 2006). Glucoregulatory effects of cod muscle pro-
teins compared to soy and casein-fed animals in the study
of Lavigne etal., on glucose and insulin dynamics, may be
explained by its balanced L/A and M/G ratios (1.50 and
0.37, respectively) (Lavigne, Marette, and Jacques 2000). The
amino acid composition of all three diets were comparable
except that casein contained significantly higher amounts
of proline (1.9-times) compared to cod and soy (Lavigne,
Marette, and Jacques 2000). In another study, comparable
anti-obesogenic effects were observed by similar diets on
high fat fed rats (relatively parallel amino acid composition
of diets with significantly different L/A, M/G ratios) on
obesity-induced muscle insulin resistance and
insulin-stimulated glucose uptake in skeletal muscle cells
(Lavigne etal. 2001). In both of Madani etal. and Chevrier
et al. studies, with insufficient effects of experimental diets
on weight gain, the L/A ratio of casein hydrolysate compared
to salmon and sardine lysates was higher (Chevrier et al.
2015; Madani et al. 2012; Madani et al. 2015). In another
sturdy, casein diet with negligible antidiabetic and
anti-obesogenic effect on obesity prone rats had almost
+4-times more proline than cod/scallop diet (Tastesen et al.
2014). Similar to the studies of Madani etal. and Tastesen
etal., the ineffective casein diet on weight gain, plasma and
liver lipid and cholesterol levels was rich in CAA, BCAA,
AAA and proline (+100%) with higher L/A ratio, yet
glycine-deficient compared to purified fish protein (Ait-Yahia
et al. 2003; D Ait Yahia et al. 2005). L/A and M/G ratios
of diets varied greatly from one another (in the decreasing
order of casein > chicken and > cod/scallop) (Tastesen et al.
2014). This agrees with the study of Van Nguyen et al. in
which balanced L/A ratio fed cobia performed better than
high and low L/A ratio fed fish (Van Nguyen et al. 2014).
It is noteworthy that plasma TC, HDL-c and LDL-c as well
as liver TG and total neutral lipid concentrations, concom-
itant with increased mRNA expression of lipogenic gene
diacylglycerol acyltransferase 1 (DGAT1), were higher in
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 37
chicken diet (with medium taurine) fed rats (Tastesen
et al. 2014).
In accordance, taurine and glycine concentrations could
have possibly been high enough in cod/scallop diet for
beneficial management of lipid metabolism in various
animal experimental models (I.-J. Jensen et al. 2016;
Tastesen et al. 2014). In the study of Tastesen et al.,
glycine and sulfur containing amino acid concentration
of the cod/scallop regimen with anti-obesogenic and glu-
coregulatory activity was relatively different from other
experimental diets (glycine (mmol per kg of diet); cod/
scallop 192 > chicken 109 > casein 47 and sulfur containing
amino acids (mmol per kg of diet); cod/scallop
137 > chicken 85 > casein 70) (Tastesen et al. 2014). A
similar trend was observed in the study of Jensen et al.
testing the metabolic beneficiary effect, mainly on ath-
erosclerotic lesions, of cod/scallop dietary intake over
3-months on high fat fed ApoE−/− rats (mg of glycine per
g of diet); cod/scallop 10.1 > chicken 5.7, and sulfur con-
taining amino acids (mg per g of diet); cod/scallop
13.7 > chicken 8.3) (I.-J. Jensen et al. 2016). It is worthy
of note that taurine has also been documented as an
amino acid with satiating effects which would decrease
food intake while lowering weight gain yet non-hydrolyzed
and hydrolyzed goby fish proteins, taurine-deficient, had
similar effects (Nasri et al. 2018). Single dose of cod
taurine-rich (6.6 mg per g of protein) enzymatic hydro-
lysate, compared to taurine-deficient casein intake with
high L/A and M/G ratios, however, could only depress
postprandial insulin secretion with null effect on blood
glucose response or GLP-1 levels (Dale et al. 2018).
Contrary to oral administration of single cod dose to
middle-aged healthy individuals with slight glucoregula-
tory effect, an 8-weeks mixed low-fish diet only minimally
affected cardiovascular biomarkers in the healthy elderly
population (Grieger, Miller, and Cobiac 2014). Taurine
concentration was significantly higher in cod/scallop with
beneficial effect on HDL-c, 61 mmol kg−1 of diet, than in
chicken and casein ones (Tastesen et al. 2014). Casein
diet, with glucose tolerance reduction effect, had the high-
est BCAA (14 − 39%) compared to cod/scallop and chicken
diets (Tastesen et al. 2014). Contrary to casein, chicken
with 290 mmol of BCAA, 630 mmol of EAA and 611 mmol
of CAA per kg of diet, boosted the plasma insulin in the
obesity-prone animals (Tastesen et al. 2014). In compar-
ison to chicken diet, cod/scallop had correspondingly by
about up to −15% less CAA, EAA and BCAA with smaller
L/A and M/G ratios (-18% and −44%, respectively), how-
ever, its taurine content was +53-times higher (I.-J. Jensen
etal. 2016). Taurine rich cod/scallop and taurine deficient
casein diets had higher EAA but lower CAA content than
chicken (Tastesen et al. 2014). Following 7-weeks of dif-
ferent protein diet regimens, compared to chicken fed
group, seafood and casein diet decreased the efficiency
of feed and adiposity in obesity-prone rats (Tastesen et al.
2014). In Brief, adequate amount of proline, glycine, tau-
rine, BCAA, CAA and AAA as well as balanced L/A ratio
are positively correlated with anti-MetS properties of cod
biopeptides.
Sardine
Similar compositional factors were important for sardine’s
hypoglycemic, hypolipemic and anti-obesity effects.
Alpha-glucosidase inhibition effectivity of truncated sardine
muscle extracted peptide (YPL) was insignificantly different
from the original tetra-peptide (YYPL) indicating the impor-
tance of YPL sequence for glucoregulatory activity of the
biopeptide (Matsui, Oki, and Osajima 1999). Even though
shorter in length, synthetic di-peptide analogues of the same
sequence, YP and PL, were negligibly potent against
α-glucosidase (Matsui, Oki, and Osajima 1999). Substitution
of Leucin, a HAA, with another hydrophobic one, glycine,
in the Tyr-Pro-Leu sequence slightly decreased its activity
(Matsui, Oki, and Osajima 1999). Both of sardine diets,
hypolipidemic byproduct and fillet proteins, as well as casein
control diet composed of comparable amounts of CAA,
HAA and BCAA, however, byproduct extracted diet con-
tained the highest amount of taurine and glycine while its
proline was lowest of all (-29% and −78% compared to fillet
and casein diets, respectively) (Affane et al. 2018). Taurine
contents of sardine diets were +2.9-times and +1.7-times
higher (sardine byproduct and or fillet respectively) than
that of casein one (Affane etal. 2018). In addition to tau-
rine, the higher efficacy of sardine byproduct diet on hyper-
lipidemia, obesity, atherogenicity and oxidation, may be due
to its lower M/G rate compared to sardine fillet protein and
casein by about −31% and −64%, correspondingly (Affane
et al. 2018). More potent hypolipidemic bogue hydrolysate,
with −25% lower L/A and −56% less BCAA, particularly
was taurine- (+2.46-times) and glycine-rich (+1.33-times)
and had more sulfur containing amino acid (+1.95-times)
in comparison to sardine hydrolysate with slightly smaller
anti-dyslipidemia activity (Benomar et al. 2015). Clinical
oral dose of l-arginine (3 g daily) has exerted antihyperlip-
idemic effects, modulating the lipid profile, in elderly
patients diagnosed with acute myocardial infarction (Tripathi,
Misra, and Pandey 2012). Therefore, superiority of bogue
in lipid metabolism modulation, compared to sardine, may
be due to its high arginine content (1.5-times) (Benomar
et al. 2015). Both fish diets, sardine and bogue, had com-
parable M/G ratios (0.41 and 0.42, respectively) (Benomar
et al. 2015). Amino acid composition of casein, with null
effect on weight gain of obese rats, and sardine slightly
differ from one another. Though abundance of negatively
CAA in both is relatively comparable, casein has +2.5-fold
more proline than sardine and its L/A was higher than
sardine (Madani et al. 2015). In conclusion, presence of
polar amino acids at N-terminal along with branched chain
and/or hydrophobic amino acids at C-terminal influence
anti-MetS activity of sardine oligopeptides. Furthermore,
balanced L/A and M/G ratios plus adequate taurine and
glycine as well as low proline play rather a vital role in the
bioactivity of sardine similar to other types of fish discussed
earlier.
Tilapia
Metabolite of proline, hydroxyproline, seemed to play a
rather significant role on the GLP-1 secretory and
38 S. ABACHI ETAL.
anti-DPP-IV activity of fish biopeptides. Imino acid rich
tilapia and or halibut induced GLP-1 secretion, unlike
salmon gelatinous hydrolysate with insignificant stimulatory
effect on the same incretin, in diabetic rats (Hsieh et al.
2015; T.-Y. Wang et al. 2015) (Hsieh et al. 2015). Tilapia
hydrolysate inhibited plasma DPP-IV activity by 28% where
sitagliptin hindered this activity by 63% in diabetic rats
(T.-Y. Wang etal. 2015). Furthermore, the same hydrolysate
was more efficient than halibut and sitagliptin in stimulat-
ing the secretion of GLP-1 in comparison to the diabetic
control group where the substrate’s secretion was signifi-
cantly lower than non-diabetic normal animals (T.-Y. Wang
etal. 2015). Tilapia hydrolysate with higher imino acid was
as potent as sitagliptin in enhancing the secretion of insulin
in experimental rats where halibut hydrolysate’s effect was
marginal (T.-Y. Wang et al. 2015). Both tilapia and halibut
identified sequences contained the well-known GLP-1 secre-
tion stimulatory motifs (LGG, GL and GP) which exert
their effect via proton-coupled uptake and the
calcium-sensing receptor (Diakogiannaki etal. 2013) (T.-Y.
Wang etal. 2015). Halibut- and salmon-originated peptides
also contain glutamine (Q) which has repeatedly been
reported as a strong GLP-1 secretagogue (Reimann et al.
2004) (Harnedy etal. 2018a). Bester sturgeons, halibut, and
salmon oligopeptides contain a well-known anti-DPP-IV
biopeptide (GPAG) while GPA was also a common motif
in many of antidiabetic fish peptides reviewed herein (Hsu
et al. 2013; Sasaoka et al. 2018; T.-Y. Wang et al. 2015; C.
Zhu, Zhang, Mu, et al. 2017). The same tri-peptide, GPA,
has been reported as a DPP-IV inhibitor and the same
motif has occurred in few of the fish anti-DPP-IV biopep-
tides (Bauvois 1988; Hatanaka, Kawakami, and Uraji 2014;
Li-Chan et al. 2012; Neves et al. 2017; Ying Zhang, Chen,
Chen, et al. 2016). In closing, tilapia biopeptides may owe
their anti-diabetic properties to the presence of hydrophobic
amino acids at both extremities.
Herring
In the study of Durand etal., while herring milt hydrolysate
had insignificant stimulatory effect on the glucose uptake,
its Electrodialysis with Ultrafiltration membrane (EDUF)
fraction (non-charged peptides) tended to significantly
increase the in-vitro glucose uptake of skeletal muscle cells
(Durand etal. 2019). In contrary, positively charged peptides
of herring milt hydrolysate decreased the glucose uptake
rate (≤ −9.9%) in the same cells and similar analytical con-
ditions (Durand et al. 2019). Examining the amino acid
composition of the EDUF herring milt fractions, obviously
the most potent one has the least CAA (32 g 100 g−1 of
peptides versus 45 and 49 g 100 g−1 of peptide for cationic
and anionic fractions respectively) while having highest tau-
rine content (1.3 g 100 g−1 of peptide versus 0.58 and 1.13 g
100 g−1 of peptide for cationic and anionic fractions respec-
tively) with rather balanced L/A ratio (0.13 versus 0.10 and
0.29 for cationic and anionic fractions respectively) (Durand
et al. 2019). Not only that taurine harbors hypolipidemic
and satiating properties but also has repeatedly demonstrated
hypoglycemic effects in different experimental platforms and
the topic has been reviewed by Ito etal. (Ito, Schaffer, and
Azuma 2012; Kulakowski and Maturo 1984; Tenner, Zhang,
and Lombardini 2003). Hence, the potent effect of herring
EDUF non-charged fraction may be due to its relatively
higher taurine content rather than the charge of peptides
(Durand et al. 2019). It is noteworthy that the effective
fraction of herring milt hydrolysate and the non-dialyzed
hydrolysate had similar amino acid composition properties
except for its lower taurine (-5%) and higher L/A ratio
(+15%) (Durand et al. 2019). Atlantic herring is rich in
anti-CVD peptide motifs in which alanine at N- and or
penultimate position of N-terminal, proline at C- and or
penultimate point of C-terminal and leucine rarely in
C-terminal and generally at N- or penultimate position of
N-terminal are situated (Pampanin etal. 2012). These obser-
vations demonstrate the fact that certain conformational
structure, chemical, physical, and biochemical properties
affect the bioactivity of fish biopeptides. It could be con-
cluded that adequate amount of charged amino acids and
presence of hydrophobic amino acids at N- or C-terminals
as well as their penultimate positions could explain anti-MetS
effects of tilapia biopeptides. Furthermore, taurine content
of the fish may also be imperative for its biological activities
against MetS.
Stability of peptides to gastrointestinal digestion
Almost all of anti-hyperlipidemic and anti-obesity along
with the majority of anti-diabetic fish biopeptides were
tested in animal studies presenting significant hypoglyce-
mic, hypolipidemic and anti-obesogenic potencies meaning
they could resist the harsh environment of the digestive
tract and be highly bioavailable within the tract of exper-
imental models such as fish, pigs, sheep, rats, and mice.
Human studies intervening fish diets in many different
healthy and or ill subjects are also confirmatory of those
studies demonstrating successful effects against diabetes,
obesity, CVD and MetS (Table 5). In line, few studies
followed the same approach in cell and or in-vitro settings
testing the stability of anti-MetS fish biopeptides in static
and dynamic stimulated gastrointestinal digestion systems.
To reveal the bioavailability of fish hypocholesterolemic
peptides Hosomi et al. lysed Alaska pollock muscle and
casein proteins to soluble and insoluble fractions by diges-
tive proteases and tested BA binding capacity and micellar
solubility of cholesterol (Hosomi et al. 2011). In a simu-
lated intestinal digestion (pepsin and pancreatin hydrolysis)
model, soluble and insoluble fractions of Alaska pollock
proteins tended to reduce the micellar solubility of cho-
lesterol, compared to casein fractions, which may explain
the higher fecal cholesterol excretion rates in rats (Hosomi
et al. 2011). A shark liver peptide (S‐8300) with great
hepatoprotective effects was susceptible to static GI diges-
tion (susceptible to trypsin and proteinase K, resistant to
DNase, RNase, heat, acid and alkali) (F. Huang and Wu
2005, 2010; F. J. Huang & Wu, 2010). Moreover, the same
peptide showed significant anti-MetS activity in animal
studies which may be due to the fact that GI proteolytic
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 39
activity may have lysed the rather big S‐8300 molecule
into more potent smaller size oligopeptides (F. Huang and
Wu 2005, 2010; F. J. Huang & Wu, 2010). Similar approaches
were taken to assess the stability of anti-diabetes
biopeptides.
In another attempt, glucoregulatory effects of salmon
byproduct biopeptides were put to test in a static GI digestion
(pepsin and corolase PP) model (Harnedy etal. 2018a). Skin
gelatin lysates were relatively susceptible to the digestive
enzymes (insulin secretion from BRIN-BD11 cells +3.2- and
+8.0-times pre- and post-digestion, GLP-1 secretion from
enteroendocrine GLUTag cells +3.2- and +0.4-times pre- and
post-digestion, DPP-IV activity IC50 0.90 and 1.19 mg mL−1
pre- and post-digestion) (Harnedy et al. 2018a). However,
trimming hydrolysates rather resisted the GI protease activity
(insulin secretion from BRIN-BD11 cells +3.0- and +4.2-times
pre- and post-digestion, GLP-1 secretion from enteroendo-
crine GLUTag cells +2.4- and +2.3-times pre- and
post-digestion, DPP-IV activity IC50 0.84 and 1.00 mg mL−1
pre- and post-digestion) (Harnedy etal. 2018a). Insulin stim-
ulatory potency of the salmon biopeptides was notably
enhanced by digestion, however, their anti-DPP-IV and
GLP-1 induction activities were reduced or unaltered
(Harnedy et al. 2018a). Hydrolysate of blue whiting muscle
behaved similar in the simulated digestion (pepsin and coro-
lase PP DH: 33%) analysis (insulin secretion from BRIN-BD11
cells +3.8- and +4.2-times pre- and post-digestion, DPP-IV
activity IC50 1.28 and 1.49 mg mL−1 pre- and post-digestion,
membrane depolarization +6.4-times, [Ca2+]i and cAMP con-
centration in BRIN-BD11 cells post-digestion) (Harnedy etal.
2018b). Blue witting hydrolysate was further lysed, to
pre-examine its in-vivo permanence, by the proteolytic activ-
ity of GI enzymes to di- and tri-peptides (<500 Da peptides:
65%) altering the behavior of post-digestion lysate on insulin
secretion, DPP-IV and membrane potential (Harnedy et al.
2018b). In accordance, boarfish GI proteases (pepsin and
corolase PP) subjected sarcoplasmic hydrolysate was fairly
resistant to the digestion (insulin secretion from BRIN-BD11
cells +4.2- and +5.3-times pre- and post-digestion, GLP-1
secretion from enteroendocrine GLUTag cells +1.3-times
post-digestion, DPP-IV activity IC50 1.18 and 1.21 mg mL−1
pre- and post-digestion, glucose uptake in 3T3‐L1 adipocytes
+1.3-times post-digestion) (Parthsarathy etal. 2019). Digestive
enzyme lysed boarfish hydrolysate was rich in <1,000 Da
(92%) oligopeptides (di- to penta-peptides) (Parthsarathy
et al. 2019). DPP-IV inhibition activities of tuna cooking
juice protease XXIII hydrolysate-extracted oligopeptides,
PGVGGPLGPIGPCYE and CAYQWQRPVDRIR, were
enhanced up to 12% post-GI digestion yet the efficacy of
orientase hydrolysate-isolated PACGGFYISGRPG was not
different pre- and post-digestion (S.-L. Huang et al. 2012).
Immunoreactive calcitonin gene-related peptide (im-CGRP)
like molecules of siki hydrolysate were stable to digestion
and proteases but not the CGRP-like molecules with specific
CGRP binding sites interaction capacity (Martínez-Alvarez
etal. 2012). CGRP neuropeptide molecules have a wide range
of bioactivities of which some also surpass the potencies of
conventional drugs. Among many bioactivities these com-
pounds have great immunomodulating, vasodilating and
satiety effects (Pilon et al. 2011). Levels of CGRP are fairly
low in diabetic and coronary artery patients (L. Wang et al.
2012). Thus, pharmacological properties of these peptides
Table 7. Drug-likeness and ADME analysis of selected sh anti-MetS oligopeptides by Lipinski’s rules.
Lipinski’s rule of ve
Molecular
weight (g mol−1)
Lipophilicity
(MLog P)
Hydrogen bond
acceptors
Hydrogen bond
donors
No. of rule
violations Drug-likeness
Sequence
Less than 500
Dalton Less than 5 Less than 5 Less than 10
Less than two
violations
Follows
Lipinski’s rule
Bioavailability
score*
DP 230.22 −1.27 641Ye s 0.56
FF 312.36 1.9 430Ye s 0.55
I/LD 246.26 −0.58 641Yes 0.56
I/LH 268.31 −0.94 541Yes 0.55
PP 212.25 −0.07 420Yes 0.55
VC 220.29 −0.3 430Yes 0.55
VP 214.26 −0.07 430Ye s 0.55
VW 303.36 0.56 440Yes 0.55
YP 278.3 0.22 541Yes 0.55
FSD 367.35 −1.23 861Yes 0.11
FVA 335.4 0.61 541Ye s 0.55
GPA 243.26 −1.38 531Ye s 0.55
GPL 285.34 −0.53 531Yes 0.55
IPI 341.45 0.48 531Yes 0.55
WSG 348.35 −1.48 661Yes 0.55
APA G 314.34 −1.78 661Yes 0.55
GGYE 424.41 −1.67 971Ye s 0.11
GPAE 372.37 −2.07 851Yes 0.11
GPAV, LGPG 342.39 −1.26 641Ye s 0.55
GPGA 300.31 −2.06 641Yes 0.55
PGPL 382.45 −0.53 631Yes 0.55
YYPL 554.63 0.33 862No 0.17
GEYGP 521.52 −2.11 10 8 2 No 0.11
IIAEK 572.69 −1.13 10 8 2 No 0.17
Drug likeness of selected di-, tri-, tetra- and penta-peptides were predicted according to Lipinski’s rule of ve using SwissADME web tool. *Abbot bioavailability
score: probability of a compound to have at least 10% oral bioavailability in rat.
40 S. ABACHI ETAL.
are possibly ideal for the research and development of
anti-MetS drugs and selected ones have been analyzed for
their ADME properties (Table 7).
Conclusion and possible future directions
Fish biopeptides derived by a wide range of techniques,
mostly enzymatic hydrolysis, membrane filtration as well as
chromatographic ones, have shown to prevent and alleviate
MetS and its main associated risk factors in great number
of studies. About half of the studies made efficient use of
fish byproducts and processing leftovers. Nevertheless, more
attention shall be given to the problem of food security and
environmental protection act including greenhouse gas emis-
sion thus exploiting food byproducts and underutilized spe-
cies of fish in as many studies as possible and contributing
to the related global strategies. It is noteworthy that many
of the peptides reviewed herein are of multifunctional nature
thus of high importance to the researchers and product
developers whether in pharmaceutical, nutraceutical and/or
food industry. Mortality and morbidity rates of metabolic
diseases are significant and the prevention and/or the ther-
apy options are limited due to several reasons such as non-
compliance issue and side effects making the natural
non-cytotoxic therapeutic treatments important in this era.
Hypoglycemic, hypolipidemic and anti-obesogenic fish bio-
active peptides exert their effect via different mechanisms
of which many are yet not well studied and understood.
These biomolecules could be involved as drug leads in drug
discoveries and/or simply as active ingredients in nutraceu-
ticals applicable to clinical nutrition and/or to functional
food. Bioavailability of the fish peptides was high in many
of the studies we have reviewed and discussed in this article
since integrity of the biomolecules was not negatively
affected and/or hindered by the digestive enzymes in various
animal models and human subjects. Yet, for a definite con-
clusion full capacity of fish anti-MetS peptides must be
tested in human subjects including ill and healthy ones.
Disclosure statement
No potential conict of interest was reported by the authors.
Funding
is project was made possible by Natural Sciences and Engineering
Research Council of Canada (NSERC) under the name of Strategic
Partnership Grants for Projects grant STPGP/479527-2015.
ORCID
Lucie Beaulieu http://orcid.org/0000-0001-8120-1039
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