Access to this full-text is provided by Springer Nature.
Content available from BMC Pediatrics
This content is subject to copyright. Terms and conditions apply.
Fatahietal. BMC Pediatrics (2022) 22:527
https://doi.org/10.1186/s12887-022-03590-x
RESEARCH
The eects ofchitosan supplementation
onanthropometric indicators ofobesity, lipid
andglycemic proles, andappetite-regulated
hormones inadolescents withoverweight
orobesity: arandomized, double-blind clinical
trial
Somaye Fatahi1, Ali Akbar Sayyari2, Masoud Salehi3, Majid Safa4, Mohammadhassan Sohouli5,
Farzad Shidfar1* and Heitor O. Santos6
Abstract
Background: Chitosan is one of dietary fiber that has received great attention in improving obesity-related markers,
but little is known on its effects on adolescents.
Objectives: To analyze the effects of chitosan supplementation on obesity-related cardiometabolic markers and
appetite-related hormones in adolescents with overweight or obesity.
Methods and analysis: A randomized clinical trial was performed on 64 adolescents with overweight and obe-
sity, who were randomly allocated to receive chitosan supplementation (n = 32) or placebo as control (n = 32) for
12 weeks. Anthropometric measures, lipid and glycemic profiles, and appetite-related hormones were examined.
Results: Sixty-one participants completed study (chitosan = 31, placebo = 30). Chitosan supplementation
significantly improved anthropometric indicators of obesity (body weight: − 3.58 ± 2.17 kg, waist circumfer-
ence: − 5.00 ± 3.11 cm, and body mass index: − 1.61 ± 0.99 kg/m2 and − 0.28 ± 0.19 Z-score), lipid (triglycerides:
− 5.67 ± 9.24, total cholesterol: − 14.12 ± 13.34, LDL-C: − 7.18 ± 10.16, and HDL-C: 1.83 ± 4.64 mg/dL) and glycemic
markers (insulin: − 5.51 ± 7.52 μIU/mL, fasting blood glucose: − 5.77 ± 6.93 mg/dL, and homeostasis model assess-
ment of insulin resistance: − 0.24 ± 0.44), and appetite-related hormones (adiponectin: 1.69 ± 2.13 ng/dL, leptin
− 19.40 ± 16.89, and neuropeptide Y: − 41.96 ± 79.34 ng/dL). When compared with the placebo group, chitosan sup-
plementation had greater improvement in body weight, body mass index (kg/m2 and Z-score), waist circumference,
as well as insulin, adiponectin, and leptin levels. Differences were significant according to P-value < 0.05.
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco
mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Open Access
*Correspondence: shidfar.f@iums.ac.ir
1 Department of Nutrition, School of Public Health, Iran University of Medical
Sciences, Tehran, Iran
Full list of author information is available at the end of the article
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 2 of 9
Fatahietal. BMC Pediatrics (2022) 22:527
Introduction
Adolescent obesity has emerged as a serious health issue
worldwide [1]. Obesity in children and adolescence is
often complicated primarily by an early association with
a range of other noncommunicable diseases [2–4]. ere
is a close link between childhood and adult obesity, so
much so that a recent systematic review stated that chil-
dren with obesity had a five times greater risk of having
obesity in the adulthood compared with children with
normal-weight [5]. Childhood obesity often extends into
adulthood, in which approximately 80% of children with
obesity have obesity in the adulthood [6].
Lifestyle-based interventions (diet, exercise, and behav-
ioral therapy) together with medications are the most
traditional treatments for obesity, leading to reduced
caloric intake and increased energy expenditure [7–9].
Nutrition-based therapies associated with a drastic
reduction in energy and nutrient intake, however, may
be less effective in children and adolescents in virtue of
lack of adherence, hence with ensuing weight gain as well
as micronutrient deficit [10–14]. Instead of the concept
of food restriction, an increment of functional foodstuffs
or supplements may be conceivable in this setting. For
example, high-fiber foods or fiber supplementation can
elicit several improvements in cardiometabolic param-
eters in different populations [15, 16]. It is no wonder
that proper fiber intake is recognizably associated with
reduced risk of obesity and seems to be viable in manag-
ing the pediatric population [17, 18].
Among the types of fiber, chitosan is one of them that
has received great attention in preventing fat absorption
[19]. It is a cationic polysaccharide derived from crusta-
cean cuticles such as shrimp and lobster, or fungal wall by
distillation (hydrolysis of N-acetyl-D-glucosamine units)
of chitin biopolymer [20]. In animal models, chitosan
upregulates the hepatic low-density lipoprotein (LDL)
receptor mRNA expression and increases the excretion
of fecal bile acids, thus decreasing total cholesterol and
low-density lipoprotein cholesterol (LDL-C) levels [21].
Additionally, chitosan can increase leptin concentra-
tions and reduce expression of the neuropeptide Y (NPY)
gene in the jejunal region, which is an potent satiety and
an appetite-stimulating hormone, respectively, favoring
therefore weight loss [22, 23].
Despite the myriad metabolic effects of chitosan, fur-
ther human research is deemed of paramount importance
primarily in the pediatric population, including teenag-
ers. In light of this wisdom, this randomized clinical trial
(RCT) was conducted in order to analyze the effects of
chitosan supplementation on appetite-related hormones,
anthropometric indicators of obesity, and lipid and gly-
cemic profiles in adolescents with overweight or obesity.
Material & Methods
Participants
A double-blind RCT was conducted during 2021–2022,
involving adolescents with overweight or obesity referred
to the Obesity Clinic of the Mofid Children’s Hospi-
tal, Tehran, Iran, who were selected based on inclu-
sion and exclusion criteria. e ethics committee of the
Iran University of Medical Sciences approved the study.
Moreover, this clinical trial was registered on the Ira-
nian Registry of Clinical Trials (www. irct. ir) website
(IRCT20091114002709N57; registration date: 2021-06-
20). e flow chart of the study design and the schedule
of the project are shown in Fig.1.
Inclusion andexclusion criteria
Inclusion criteria included the following items: 1) Will-
ingness to cooperate and sign the informed consent form
after full knowledge of the objectives and method of the
study; 2) Adolescent girls and boys with overweight and
obesity, aged 10 to 19 years; 3) body mass index (BMI)
Z-score higher than 1 and less than 3 based on age and
sex (according to the definition of World Health Organi-
zation (WHO) [24, 25]). Also, adolescents were not
included in the study if they meet the following criteria:
1) Use of probiotic supplements, prebiotics, symbiot-
ics or any foods fortified with these supplements during
the last 3 months; 2) Use of any antibiotics for 3 months
before the study; 3) History of type 1 or 2 diabetes, car-
diovascular, hepatic, gastrointestinal (celiac disease,
irritable bowel syndrome, and inflammatory bowel dis-
ease) or renal diseases and metabolic disorders includ-
ing maple syrup urine disease and phenylketonuria, urea
cycle disorders; 4) History of gastrointestinal surgery;
5) Use medications or supplements that affect appetite,
weight, or metabolism at least 3 months before the study
(such as medications that affect carbohydrate, protein,
or fat metabolism, and also medications that reduce or
increase appetite or food intake, including herbal supple-
ments); 6) Adherence to weight loss diet or any type of
Conclusion: Chitosan supplementation can improve cardiometabolic parameters (anthropometric indicators of
obesity and lipid and glycemic markers) and appetite-related hormones (adiponectin, leptin, and NPY) in adolescents
with overweight or obesity.
Keywords: Chitosan, Obesity, Lipids, Appetite, Adolescents
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 3 of 9
Fatahietal. BMC Pediatrics (2022) 22:527
heavy exercise program during the last 6 months; 7) Preg-
nant and lactating adolescents; 8) Smoking (more than
one cigarette in the last week or more than 200 cigarettes
in Lifespan); 9) Having any allergy to chitosan or crabs
and shrimp. We also excluded those who with any acute
illness, the occurrence of any accident that affects a per-
son’s health, the use of antibiotics during the study, fail-
ure to follow the supplement based on personal reasons
or other reasons, and migration. Furthermore, the admis-
sion rate of patients after the intervention period was cal-
culated using the following formula, and patients whose
admission rate is less than 80% were excluded from the
study. Acceptance rate = number of packages received
at the beginning of the study/number of packages con-
sumed at the end of the study * 100.
Sample size calculation
Given the absence of a study that investigated the effect
of chitosan on weight loss in children and adolescents
with overweight or obesity, we used a method of Reinehr
etal. in order to calculate the sample size by consider-
ing the BMI Z-score as the primary outcome, as these
authors examined the effects of prebiotics on overweight
and overweight children. In this way, considering the dif-
ference of 0.066 units in the mean BMI Z-score at the
end of 12 weeks of intervention, assuming S1 = 0.07 and
S2 = 0.09, and with the type I of error probability level of
5% (α = 0.05) and the type II error probability level of is
20% (β = 0.20, power = 80%), the number of samples was
calculated based on the sample size formula below 24
participants in each group. Assuming 30% of the possible
loss, 32 participants in each group and a total of 64 par-
ticipants were included in our study.
Study design andintervention
In this randomized double-blind randomized clinical trial
with 12 weeks of intervention, 64 adolescents with over-
weight or obesity who meet the inclusion criteria were
randomly divided into two groups receiving chitosan
supplement and placebo (maltodextrin). e appropri-
ate amount of chitosan supplementation in most studies
is approximately 3 g/d [26–28]. Since no toxicity of this
substance has been reported to mammals in the FDA
[29], the participants received 1.5 g (Twice a day a total
of 3 g) of chitosan powder (intervention group) or malto-
dextrin (placebo group) daily 30 minutes to 1 hour before
lunch and dinner for 12 weeks. Standard fruit flavorings
were added to these supplements, taking into account
the possibility of individuals not consuming raw chitosan
powder. Parents were advised to add the recommended
Fig. 1 Consort flow diagram for the trial
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 4 of 9
Fatahietal. BMC Pediatrics (2022) 22:527
amount of powder for each person to 250 ml of water.
e supplements were provided by Karen Pharmaceuti-
cals and Vital-Food Supplements Company. e powders
were given to the parents at the beginning of the study
and at the end of the fourth eighth week, and they are
asked to bring empty packages of cans at the end of the
fourth, eighth and twelfth weeks to check the acceptance
rate of supplements.
At baseline, all study participants received recommen-
dations for gradual weight loss (0.5 to 1 kg per month).
According to age, sex, height, and BMI Z-score, the
energy consumption was calculated according to the
formulas proposed in Krauss’s book and a slight reduc-
tion of 200 kcal per person is considered [30]. e caloric
distribution of the diet was estimated at 30% fat (7%
saturation), 50% carbohydrate, and 20% as protein and
the maximum amount of cholesterol and 300 mg per
day. Dietary recommendations were the same for both
groups, and both groups are asked not to consume for-
tified sources of probiotics, symbiotics, or prebiotics or
supplements during this study.
Randomization andallocation
To ensure the uniform distribution of the main vari-
ables can have a great impact on the results (BMI Z-score
and gender) in two groups, we used random allocation
by Stratified Randomization and Permuted block rand-
omization method. Based on the sample size of present
study (64 subjects), we produced the double block and
quadruple block using the online site (www. seale denve
lope. com). At the beginning of the study, sets of packages
containing chitosan powder were prepared by someone
other than the researcher due to the double-blindness of
the study, and the placebo was similar in appearance to
chitosan powder. All of the researchers from the alloca-
tion of participants in each of the groups (intervention
and control group) until the end of the intervention, were
not know the groups whereby the patients were rand-
omized. In order to apply concealment in the randomi-
zation process, we used unique codes which generated
by the company receiving the supplements and placebos
on the medicine boxes. So, none of the participants and
researchers know which of the two groups received the
supplement or placebo with this method. Upon each per-
son entering the study, based on the sequence generated,
the medicine boxes in which the code is recorded was
assigned to the participants.
Evaluation ofpersonal information
At the beginning of the study, personal information
including name, age, sex, dietary supplements, and his-
tory other diseases were completed using the face-to-face
interview technique (person or parents). Maturity status
is determined by a trained individual using Marshall and
Tanner tables [31].
Anthropometric andphysical activity measurements
Anthropometric variables were measured before and
at the end of the study. Adolescents’ height and weight
were measured with minimal clothing and without shoes.
e weight of all subjects was measured twice with the
Seca digital scale (made in Germany) with an accuracy
of 0.01 kg. e height of the participants in the study was
recorded standing using a tape measure, without shoes
and with an accuracy of 0.5 cm at the beginning and end
of the study; measures were collected twice each time
and their average was recorded). BMI was determined as
weight in kilograms divided by height in meters squared.
Patients’ waist circumference was measured using a non-
elastic tape measure with a maximum error of 0.5 cm,
considering the middle half of the body below the ribs of
the chest.
e BMI Z-score, also known as the standard deviation
for BMI score, is a measure of relative weight and height
that is set for age and gender in a reference standard.
ese scores are considered more suitable for determin-
ing longitudinal changes in body weight and obesity, and
are also a superior criterion for comparing the mean val-
ues of the group [32]. erefore, BMI Z-score was used
to assess changes in body weight in participants. e
level of physical activity at the beginning and end of the
study was assessed by the International Physical Activity
Questionnaire (IPAQ) in Persian. e amount of physical
activity was calculated as small continuous data taking
into account the coefficients related to the activity, and
recorded as Met-min/week. e Met coefficient for walk-
ing is 3.3, for moderate activity is 4, for heavy activity is
8, which is multiplied by the duration of the activity in
minutes and the number of days in the activity week, and
its sum as the amount of physical activity in the week is
set [33].
Biochemical measurements
At the beginning of the study and at the end of the twelfth
week, after 12 to 14 hours of fasting, 5 cc of a venous
blood sample was taken from the patients while sitting on
a chair. ese samples were centrifuged at room temper-
ature for 10 minutes at 3700 rpm to separate their serum.
e isolated serum was placed in 1.5 cc microtubules to
measure biochemical factors was stored in a freezer at
− 80 °C until testing.
Serum total cholesterol and triglyceride (TG) lev-
els were measured using Pars Azmoon commercial kits
(Tehran, Iran) by a biochemistry autoanalyzer, and serum
high-density lipoprotein cholesterol (HDL-C) were meas-
ured after deposition of apolipoprotein B-containing
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 5 of 9
Fatahietal. BMC Pediatrics (2022) 22:527
lipoproteins with phosphotungstic acid solution. In cases
where the triglyceride level was less than 400 mg/ml,
serum LDL-C levels were calculated using the Friedewald
Equation [34]: LDL-C = total cholesterol -TG/6 - (HDL-
C). In other cases, commercial kits were used as a sur-
rogate measure.
Pars Azmoon commercial kits (Tehran, Iran) were used
to measure fasting blood glucose (FBG) by a biochemis-
try autoanalyzer and serum insulin levels by the immuno-
turbidimetry method. Homeostatic model assessment of
insulin resistance (HOMA-IR) was calculated as fasting
insulin (mU/L) × FBG (mmol/L)∕405. Serum NPY was
assessed using an ELISA kit (Crystal Day Biotech Co,
Shanghai, China). Leptin and adiponectin were measured
by using an ELISA kit (Mediagnost Co, Germany).
Dietary assessment
Evaluation of dietary intake at the beginning and end of
the study and each time using a 24-hour dietary recall
questionnaire of 3 days (2 normal days and 1 day off) was
done interviewing the adolescents or parents. Related
data, including energy intake, macronutrients, and
some micronutrients were determined by Nutritionist 4
software.
Statistical analysis
SPSS-24 software (IBM Corp. IBM SPSS Statistics for
Windows, Armonk, NY) was used to obtain statisti-
cal analyses. Quantitative variables were reported as
mean (standard deviation) and qualitative variables were
reported as numbers (percentage). Because the data was
not normal, Mann-Whitney test were used to compare
the results between baseline and end of the intervention
between groups. As well as Wilcoxon test, were used to
analyze within-group data. ANCOVA test was used to
estimate any differences in treatment group at the end of
trial with adjusting for covariates. Also, Chi-square test
were used to compare qualitative factors. Significant lev-
els for all tests were considered as P-value < 0.05.
Results
Characteristics oftheparticipants
From 93 pediatric patients with overweight or obesity eli-
gible for inclusion, 64 were selected and 61 participants
completed study and entered the final analysis (31 in the
intervention group and 30 in the placebo/maltodextrin
group) (Fig.1).
e baseline characteristics of the participants are pre-
sented in Table1. e mean age of the participants was
13.51 years in the intervention group and 13.12 years in
the control group. e mean and standard deviation of
BMI (Z-score) of the participants group was 1.52 (0.26)
in the chitosan and 1.67(0.32) in the placebo group which
was not statistically significant. Also, there was no signifi-
cant difference between the two groups in terms of age,
gender, waist-circumference, physical activity and multi-
vitamin supplement consumption distribution (P = 0.891
and P = 0.893, P = 0.196, P = 0.778 and P = 0.704,
respectively).
Dietary intake is indicated in Table2. Based on the
findings of the 24-h dietary recall questionnaire and
comparing the beginning with the end of the study, the
analysis of findings shows that although intake of energy
(P = 0.039), protein (P = 0.031), total fat (P = 0.018),
saturated fat (P < 0.001), polyunsaturated fat Saturation
(P = 0.015), vitamin E (P = 0.036) and zinc (P = 0.001)
showed a significant decrease after the intervention in the
chitosan supplement group, however, these changes were
not significant between the two groups. Regarding the
intake of other macronutrients and micronutrients, no
statistically significant difference was observed between
the two groups before and after the intervention.
Table 3 depicts the mean values of anthropometric
indicators of obesity, lipid and glycemic profiles, and
appetite-regulated hormones at baseline and after inter-
vention. Chitosan supplementation caused a signifi-
cant improvement of weight (P < 0.001), BMI (P < 0.001),
BMI Zscore (P < 0.001), waist (P < 0.001), fasting blo od
glucose level (P < 0.001), HOMA-IR (P < 0.001), insu-
lin (P = 0.001), total cholesterol (P < 0.001), triglyceride
(P < 0.001), HDL -C (P = 0.04), LDL-C (P < 0.001), adi-
ponectin (P < 0.001), leptin (P < 0.001) and neuropeptide
Y (P = 0.009) in individuals. is decrease for waist cir-
cumference, height (P = 0.011), HOMA-IR (P = 0.001),
total cholesterol (P < 0.001), trig lyceride (P = 0.001)
Table 1 Baseline characteristics of participants
BMI Body mass index, DBP Diastolic Blood Pressure, SBP Systolic Blood Pressure,
WC Waist circumference
a Data obtained from Mann-Whitney Test for continuous variables and Chi-
square for categorical variables
Variables Groups, mean (SD) P-valuea
Chitosan (n = 31) Control (n = 30)
Age(y) 13.51 (2.15) 13.12 (2.02) 0.891
Female (n, %) 14 (48.4) 15 (46.7) 0.893
Height (cm) 148.74 (9.15) 152.21 (8.48) 0.130
Weight (kg) 56.12 (7.20) 57.67 (9.34) 0.702
BMI (kg/m2)25.31 (1.79) 24.71 (1.86) 0.098
BMI (Z-score) 1.52 (0.26) 1.67 (0.32) 0.064
Waist-circumference
(cm) 88.48 (15.15) 93.40 (16.39) 0.196
Physical Activity
(met.h/wk) 472.14 (225.33) 528.28 (327.04) 0.778
Multivitamin use
(n, %) 6 (19.4) 7 (23.3) 0.704
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 6 of 9
Fatahietal. BMC Pediatrics (2022) 22:527
Table 2 Energy, macronutrient, and micronutrients intake at baseline and at the end of study
Data are expressed as Mean (SD)
PUFA Polyunsaturated fatty acid, SFA Saturated fatty acid, MUFA Monounsaturated fatty acid
a P value for within-group comparison of non-parametric quantitative data using Wilcoxon signed-rank test
b P value for between-group comparison of non-parametric quantitative data using Mann–Whitney U-test
Chitosan Placebo P-valueb
Baseline After P-valueaBaseline After P-valuea
Energy (kcal/d) 2181.43 (204.41) 1896.10 (233.05) 0.021 1961.79 (244.82) 1887.78 (311.85) 0.171 0.906
Carbohydrate (g/d) 276.95 (67.57) 271.35 (71.01) 0.754 262.18 (78.22) 262.58 (80.90) 0.177 0.433
Protein (g/d) 72.51 (19.99) 69.65 (21.96) 0.031 71.50 (14.40) 69.78 (15.31) 0.069 0.812
Fat (g/d) 59.43 (13.94) 55.65 (16.43) 0.018 55.17 (19.88) 57.94 (17.75) 0.254 0.812
SFA (g/d) 20.20 (6.11) 16.67 (5.49) < 0.001 18.69 (4.97) 18.41 (5.66) 0.854 0.624
MUFA (g/d) 19.55 (6.77) 17.49 (6.79) 0.053 16.87 (6.96) 17.33 (6.50) 0.430 0.988
PUFA (g/d) 20.76 (8.88) 17.58 (8.06) 0.015 19.64 (8.60) 20.40 (9.03) 0.629 0.319
Cholesterol (mg/d) 182.14 (81.94) 175.85 (66.63) 0.991 183.18 (64.99) 175.46 (67.97) 0.517 0.956
Fiber (g/d) 17.92 (6.45) 17.29 (6.88) 0.094 17.74 (8.13) 17.67 (8.50) 0.419 0.891
Vitamin B12 (mcg/d) 1.47 (0.90) 1.41 (0.70) 0.621 1.37 (0.74) 1.37 (0.78) 0.894 0.415
Folate (mcg/d) 249.88 (104.34) 237.25 (97.72) 0.122 280.98 (132.91) 270.07 (133.81) 0.035 0.466
Magnesium (mg/d) 207.40 (57.45) 196.33 (56.41) 0.469 200.38 (75.90) 200.37 (64.16) 0.393 0.971
Vitamin A (RE) 945.9 (557) 1022.9 (162.8) 0.312 894.5 (490.9) 963.2 (318) 0.447 0.593
Vitamin E (mg/d) 10.4 (4.9) 8.3 (6.1) 0.036 11.4 (5) 9.8 (7.4) 0.042 0.810
Vitamin C(mg/d) 90.8 (43) 90.1 (54) 0.701 86.1 (35.3) 97.6 (33.3) 0.670 0.502
Vitamin D (mcg/d) 8.7 (6) 9.1 (3.6) 0.481 8.8 (5.3) 9.6 (5.7) 0.268 0.471
Selenium (mg/d) 60.9 (39.1) 71.8 (34.1) 0.069 68.2 (30.5) 70.3 (41.7) 0.109 0.482
Zinc (mg/d) 12.8 (3.3) 9.7 (2.7) 0.001 9.5 (4.2) 9.3 (4.8) 0.802 0.059
Table 3 Anthropometric characteristics and laboratory markers at baseline and at the end of study
Data are expressed as Mean (SD)
Abbreviations: BMI Body mass index, FBG Fasting blood glucose, HDL-C High density lipoprotein-cholesterol, HOMA_IR Homeostatic model assessment-insulin
resistance, LDL-C Low density lipoprotein-cholesterol, NPY Neuropeptide Y, TC Total cholesterol, TG Triglycerides, WC Waist circumference
a P-values for comparison of within-group dierences by Wilcoxon signed-rank test
b P value for between-group comparison using analyses of covariance (ANCOVA), considering baseline values (weight, BMI, WC, TG, TC, physical activity, adiponectin,
and energy) as covariate
Chitosan Placebo P-valueb
Baseline After Change P-valueaBaseline After Change P-valuea
Weight (kg) 56.12 (7.20) 52.54 (7.07) −3.58 (2.17) < 0.001 57.67 (9.34) 57.40 (9.45) −0.27 (1.85) 0.252 < 0.001
BMI (kg/m2)25.31 (1.79) 23.70 (1.93) −1.61 (0.99) < 0.001 24.71 (1.86) 24.60 (2.05) −0.10 (0.86) 0.102 < 0.001
BMI (Z-score) 1.52 (0.26) 1.24 (0.36) −0.28 (0.19) < 0.001 1.67 (0.32) 1.65 (0.35) −0.02 (0.12) 0.247 < 0.001
WC (cm) 88.48 (15.15) 83.48 (15.18) −5.00 (3.11) < 0.001 93.40 (16.39) 92.40 (16.56) −1.00 (2.37) 0.011 < 0.001
FBG (mg/dL) 96.19 (10.15) 90.41 (8.81) −5.77 (6.93) < 0.001 95.26 (9.89) 94.40 (9.82) −0.86 (3.92) 0.237 0.131
HOMA-IR 2.37 (0.89) 2.13 (0.70) −0.24 (0.44) < 0.001 2.89 (1.37) 2.51 (0.93) −0.38 (0.70) 0.001 0.370
Insulin (μIU/mL) 23.23 (11.85) 17.71 (8.44) −5.51 (7.52) 0.001 22.11 (14.64) 23.95 (12.49) 1.84 (11.57) 0.206 0.006
TC (mg/dL) 182.09 (27.40) 167.96 (26.22) −14.12 (13.34) < 0.001 167.90 (21.92) 163.93 (21.62) −3.96 (5.39) < 0.001 0.071
TG (mg/dL) 149.64 (45.70) 143.96 (40.43) −5.67 (9.24) < 0.001 125.56 (29.84) 121.70 (28.54) −3.86 (5.31) 0.001 0.847
HDL-C (mg/dL) 43.54 (9.58) 45.38 (8.53) 1.83 (4.64) 0.041 43.96 (8.34) 44.46 (8.16) 0.50 (1.73) 0.162 0.116
LDL-C (mg/dL) 114.43 (33.82) 107.25 (37.06) −7.18 (10.16) < 0.001 120.60 (26.21) 115.86 (25.29) −4.73 (10.16) 0.016 0.714
Adiponectin (ng/
mL) 7.55 (4.20) 9.24 (5.42) 1.69 (2.13) < 0.001 10.09 (5.32) 8.93 (3.81) −1.15 (3.06) 0.075 0.028
Leptin (ng/mL) 47.66 (35.13) 28.25 (20.73) −19.40 (16.89) < 0.001 50.04 (44.59) 40.90 (33.80) −9.26 (26.78) 0.382 0.046
NPY (ng/mL) 207.56 (123.54) 165.59 (99.45) −41.96 (79.34) 0.009 228.24 (155.04) 233.62 (155.82) 5.38 (45.99) 0.910 0.278
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 7 of 9
Fatahietal. BMC Pediatrics (2022) 22:527
and LDL-C. (P = 0.01) was also observed in the placebo
group. However, comparing the changes of these vari-
ables after adjusting the confounders of weight, BMI,
WC, TG, TC, physical activity, adiponectin, and energy
between the two groups of participants only for weight
(P < 0.001), BMI (P < 0.001), BMI Zscore (P < 0.001), waist
circumference (P < 0.001), insulin (P = 0.006), adiponec-
tin (P = 0.02) and leptin (P = 0.04) was significant follow-
ing the twelve-week intervention. e change in other
risk factors was not different among the groups.
Discussion
Due to the fact that chitosan is not fully digested and
absorbed in the body, it has been suggested as a fac-
tor in improving weight and cardiovascular risk factors
[35]. Chitosan and its derivatives are widely distributed
in various health stores and pharmacies and are used by
the general public, especially adults [36]. However, its use
at an early age has not yet been fully explored. For this
reason, in this study, we examined the effects of chitosan
supplementation in adolescents with overweight or obe-
sity. In general, our study showed that chitosan at 3/g/d
for 12 weeks improved all obesity-related cardiometa-
bolic markers (anthropometric indicators of obesity and
lipid and glycemic markers) assessed as well as appetite-
related hormones (adiponectin, leptin, and NPY). When
compared with the placebo group, chitosan supplemen-
tation had greater improvement in body weight, BMI (kg/
m2 and Z-score), waist circumference, as well as insulin,
adiponectin, and leptin levels.
Regarding the weight-loss effect, we found a signifi-
cant intragroup decrease in body weight of ~ 3.6 kg for
chitosan supplementation, while body weight did not
change in the placebo group. Such a reduction is higher
than the overall result of a meta-analysis (14 selected
RCTs) addressing adults with overweight or obesity [37],
whereby there was a weight loss of ~ 1 kg (WMD 1.01,
95% CI: − 1.67 to − 0.34) for the chitosan group versus
placebo. Moreover, we found a mean BMI decrease of
1.6 kg/m2 (− 1.54 ± 1.66) and no change in the placebo
group, whose result is similar to the overall BMI differ-
ence of − 1.27 kg/m2 (95% CI − 1.96 to − 0.57) for the
between-group results of the meta-analysis.
Despite our similar results with this aforementioned
meta-analysis [37], we observed significant improve-
ments in traditional lipid markers (mean decreases of
14 mg/dL for TC, 7 mg/dL for LDL-C and 6 mg/dL for
TG, and 2 mg/dL increase for HDL-C levels) that can
be deemed clinically modest, whereas the meta-analysis
found expressive reductions in TC (− 54 mg/dL), LDL-C
(32 mg/dL), and TG (94 mg/dL) levels. e chitosan dos-
age of our study is within the dosing range of the meta-
analysis, in which a mean of 2 g/d (0.34–3.4 g/d) was used
for 17 weeks (4–52 weeks); thus, we tested a feasible ther-
apeutic dosage regimen.
Beyond the scientific scrutiny of assessing meta-anal-
yses, it is crucial to consider well-controlled RCTs apart
in order to investigate specific conclusions. In contrast
to our study, an RCT consisting of middle-aged patients
(n = 130 at randomization period) with borderline/mild
hypercholesterolemia (186–263 ng/dL) did not find lipid-
lowering effects of chitosan supplementation (2.4 g/d
over 10-month intervention with alternating periods
according to the crossover design) [38]. In line with our
findings, in an RCT consisting of adults with obesity
(n = 94), 2.5 g/d of chitosan supplementation for 3 months
led to a mean body weight decrease of 3 kg accompanied
by reductions in BMI (− 1.20 kg/m2), body fat (− 0.98%),
visceral fat (− 1.28%), upper abdominal circumference
(− 2.17 cm), hip circumference (− 2.07 cm), and waist
circumference (− 1.97 cm) compared to placebo. Of note,
chitosan was also able to lower HbA1c to less than 6% in
those with higher baseline levels [19]. Such a study is of
pivotal importance taking into account the relevance of
examining the weight-loss effect and related outcomes of
chitosan supplementation in patients with obesity.
Concerning the lipid-lowering effects of chitosan, the
action on the gastrointestinal tract is the central tenet,
where chitosan, due to the cationic nature, binds to nega-
tively charged lipids and thus reduces their absorption,
yielding potential to reduce lipid markers and anthro-
pometric indicators of obesity thanks to fecal excretion
of fats [39]. e binding of chitosan to fats and bile acids
can also be beneficial for various metabolic factors [40].
More specifically, chitosan dissolves in the stomach and
afterward binds to intestinal fat through fat emulsions
and gel formation, thereby impairing fat absorption [27,
41]. With respect to the anti-diabetic potential, changes
in the expression regulation of peroxisome prolifera-
tor-activated receptors (PPAR), in the paraventricular
nucleus, have been observed in animals supplemented
with chitosan [23]. Recognizably, PPAR activation in
patients with type 2 diabetes enhances insulin and glu-
cose levels [42].
e benefits in obesity-related markers that we
found can be strongly associated with a mean reduc-
tion of ~ 200 kcal/d (from 2181.43 ± 204.41 to
1896.10 ± 233.05 kcal/d) in the chitosan group, while
the energy intake did not alter in the placebo group.
Such a result may be associated with the appetite-sup-
pressing properties of chitosan, as our study provides
evidence that chitosan supplementation can modulate
appetite-related hormones. We observed a significant
increase and decrease in adiponectin and leptin lev-
els, respectively, which reached both within-group and
between-group differences. Furthermore, we noted a
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 8 of 9
Fatahietal. BMC Pediatrics (2022) 22:527
significant within-group decrease in NPY levels after chi-
tosan supplementation, that, despite the lack of statistical
between-group difference, the ~ 42 ng/mL reduction for
chitosan supplementation is clinically meaningful, while
concentrations tend to increase by ~ 5 ng/mL in the pla-
cebo group.
Taken together, many animal studies furnish the role of
leptin, adiponectin, and NPY in appetite modulation and
systematic effects on obesity. Chitosan administration
has anti-obesity and anti-diabetic effects in ob/ob mice,
with related improvement in adiponectin resistance and
its plasma concentrations, as well as increased expres-
sion in adipose tissue of PPAR-gamma, a key regulator of
adiponectin production [43]. Serum leptin concentration
and its receptor expression in adipose tissue increased in
chitosan fed-pigs compared with animals receiving basal
diet, and increased expression of NPY in the hypothalamic
nuclei and in the jejunum [23]. In addition to the anorexi-
genic (i.e., appetite suppressant) role of leptin, experimen-
tal data also provide a theoretical basis for systemic effects
on chitosan administration by increasing the expression
of liver leptin receptor b-L (LepRb) and phosphorylation
of JAK2 and STAT3 [44], in which chitosan activates the
JAK2-STAT3 signaling pathway and hence reduces leptin
resistance while partly suppressing adipogenesis.
Strengths andlimitations
e main strength of this study is the RCT design and nov-
elty, given that this study was the first human research that
examined the effects of chitosan supplementation on ado-
lescents with overweight or obesity. However, our studies
have limitations that serve as perspectives. First, we did
not assess body fat, which should preferably be examined
by a reliable method. Second, although we measured some
appetite-related hormones, we did not assess ghrelin levels
or perform appetite questionnaires. ird, we encourage
further RCT to assess these markers, as well as crossover
acute studies using transabdominal ultrasound to allow
the examination of the gastric emptying on meal tests with
and without chitosan supplementation. At last, further
research is also required to better understand the effects of
chitosan on the gut microbiota, as well as on advanced bio-
markers of the lipid profile (e.g., lipoprotein (a) and small
dense low-density lipoprotein-cholesterol) and inflamma-
tory and oxidative status due to their emerging scientific
attention to disease management [45, 46].
Conclusion
In general, our study showed that chitosan supplementa-
tion can improve cardiometabolic parameters (anthro-
pometric indicators of obesity and lipid and glycemic
markers) and appetite-related hormones (adiponec-
tin, leptin, and NPY) in adolescents with overweight or
obesity. However, the effects must be considered as an
adjuvant instead of a magic bullet for the management of
obesity. Preferably, such a strategy ought to be planned
mainly in combination with a hypocaloric diet and physi-
cal exercise supervised by proper heathy professionals.
Acknowledgements
We express our gratitude to the participants of this study. This article is taken
from disease registry, titled "Evaluation of obesity and overweight in Iranian
children" and code number IR.SBMU.RICH.REC.1398.030 from ethic committee,
that was supported by deputy of research and technology in Shahid Beheshti
university of medical sciences (http:// dregi stry. sbmu. ac. ir)
Authors’ contributions
S.F.and F.Sh. contributed to the conception, design, and statistical analysis. S.F.,
M.S., M. S, H.S and Mh.S contributed to data collection and manuscript draft.
A.S and F.Sh supervised the study. H.S contributed to the manuscript draft and
critical revision. All authors approved the final version of the manuscript.
Funding
No funding.
Availability of data and materials
The data that support the findings of this study are available from “ Department
of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran,
Iran” but restrictions apply to the availability of these data, which were used
under license for the current study, and so are not publicly available. Data are
however available from the authors upon reasonable request and with permis-
sion of “Dr. Farzad Shidfar, Department of Nutrition, School of Public Health, Iran
University of Medical Sciences, Tehran, Iran. E-mail: shidf ar.f@ iums. ac. ir“.
Declarations
Ethics approval and consent to participate
This study was approved by the research council and ethics committee Iran Uni-
versity of Medical Sciences, Tehran, Iran (NO: IR.IUMS.REC.1400.104). The study has
been registered in IRCT (IRCT20091114002709N57; registration date: 2021-06-20).
Consent for publication
Not applicable.
Competing interests
The authors declare that have no competing interests.
Author details
1 Department of Nutrition, School of Public Health, Iran University of Medical
Sciences, Tehran, Iran. 2 Pediatric Gastroenterology, Hepatology, and Nutrition
Research Center, Research Institute for Children’s Health, Shahid Beheshti Universi ty
of Medical Sciences, Tehran, Iran. 3 Department of Biostatistics, School
of Public Health, Iran University of Medical Sciences, Tehran, Iran. 4 Depar tment
of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University
of Medical Sciences, Tehran, Iran. 5 Student Research Committee, Department
of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology,
Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6 School of Medicine,
Federal University of Uberlandia (UFU), Uberlandia, Minas Gerais, Brazil.
Received: 29 April 2022 Accepted: 1 September 2022
References
1. Fryar CD, Carroll MD, Ogden CL. Prevalence of overweight, obesity, and
severe obesity among children and adolescents aged 2–19 years: United
States, 1963–1965 through 2015–2016; 2018.
2. Flegal KM, Wei R, Ogden C. Weight-for-stature compared with body mass
index–for-age growth charts for the United States from the Centers for
Disease Control and Prevention. Am J Clin Nutr. 2002;75(4):761–6.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 9 of 9
Fatahietal. BMC Pediatrics (2022) 22:527
3. Boyer BP, Nelson JA, Holub SC. Childhood body mass index trajecto-
ries predicting cardiovascular risk in adolescence. J Adolesc Health.
2015;56(6):599–605.
4. Baker JL, Olsen LW, Sørensen TI. Childhood body-mass index and
the risk of coronary heart disease in adulthood. N Engl J Med.
2007;357(23):2329–37.
5. Simmonds M, Burch J, Llewellyn A, Griffiths C, Yang H, Owen C, et al.
The use of measures of obesity in childhood for predicting obesity and
the development of obesity-related diseases in adulthood: a systematic
review and meta-analysis. Health Technol Assess (Winchester, England).
2015;19(43):1–336.
6. Cali AM, Caprio S. Obesity in children and adolescents. J Clin Endocrinol
Metab. 2008;93(11_supplement_1):s31–s6.
7. Baños RM, Cebolla A, Botella C, García-Palacios A, Oliver E, Zaragoza I,
et al. Improving childhood obesity treatment using new technologies:
the ETIOBE system. Clin Pract Epidemiol Mental Health. 2011;7:62.
8. Santos HO, Lavie CJ. Weight loss and its influence on high-density lipo-
protein cholesterol (HDL-C) concentrations: a noble clinical hesitation.
Clin Nutr ESPEN. 2021;42:90–2.
9. Santos HO, Macedo RC. Impact of intermittent fasting on the lipid profile:
assessment associated with diet and weight loss. Clin Nutr ESPEN.
2018;24:14–21.
10. Field AE, Austin S, Taylor C, Malspeis S, Rosner B, Rockett HR, et al. Relation
between dieting and weight change among preadolescents and adoles-
cents. Pediatrics. 2003;112(4):900–6.
11. Fisher JO, Birch LL. Restricting access to foods and children’s eating.
Appetite. 1999;32(3):405–19.
12. Fisher JO, Birch LL. Restricting access to palatable foods affects chil-
dren’s behavioral response, food selection, and intake. Am J Clin Nutr.
1999;69(6):1264–72.
13. Kirby M, Danner E. Nutritional deficiencies in children on restricted diets.
Pediatr Clin. 2009;56(5):1085–103.
14. García OP, Long KZ, Rosado JL. Impact of micronutrient deficiencies on
obesity. Nutr Rev. 2009;67(10):559–72.
15. Lee DPS, Peng A, Taniasuri F, Tan D, Kim JE. Impact of fiber-fortified food
consumption on anthropometric measurements and cardiometabolic
outcomes: a systematic review, meta-analyses, and meta-regressions of
randomized controlled trials. Crit Rev Food Sci Nutr. 2022:1–19.
16. Ranaivo H, Thirion F, Béra-Maillet C, Guilly S, Simon C, Sothier M, et al.
Increasing the diversity of dietary fibers in a daily-consumed bread modi-
fies gut microbiota and metabolic profile in subjects at cardiometabolic
risk. Gut Microbes. 2022;14(1):2044722.
17. Papathanasopoulos A, Camilleri M. Dietary fiber supplements: effects
in obesity and metabolic syndrome and relationship to gastrointestinal
functions. Gastroenterology. 2010;138(1):65–72 e2.
18. Kimm SY. The role of dietary fiber in the development and treatment of
childhood obesity. Pediatrics. 1995;96(5):1010–4.
19. Trivedi V, Satia M, Deschamps A, Maquet V, Shah R, Zinzuwadia P, et al.
Single-blind, placebo controlled randomised clinical study of chitosan for
body weight reduction. Nutr J. 2015;15(1):1–12.
20. Ospina NM, Alvarez SPO, Sierra DME, Vahos DFR, Ocampo PAZ, Orozco
CPO. Isolation of chitosan from Ganoderma lucidum mushroom for
biomedical applications. J Mater Sci Mater Med. 2015;26(3):135.
21. Xu G, Huang X, Qiu L, Wu J, Hu Y. Mechanism study of chitosan on lipid
metabolism in hyperlipidemic rats. Asia Pac J Clin Nutr. 2007;16(Suppl
1):313–7.
22. Considine RV, Cooksey RC, Williams LB, Fawcett RL, Zhang P, Ambrosius
WT, et al. Hexosamines regulate leptin production in human subcutane-
ous adipocytes. J Clin Endocrinol Metab. 2000;85(10):3551–6.
23. Egan ÁM, O’Doherty JV, Vigors S, Sweeney T. Prawn shell chitosan exhibits
anti-obesogenic potential through alterations to appetite, affecting feed-
ing behaviour and satiety signals in vivo. PLoS One. 2016;11(2):e0149820.
24. Organization WH. Overweight and obesity. 2020.
25. De Onis M. World Health Organization reference curves. The ECOG’s
eBook on child and adolescent Obesity, vol. 19; 2015.
26. Ho S, Tai E, Eng P, Tan C, Fok A. In the absence of dietary surveillance, chi-
tosan does not reduce plasma lipids or obesity in hypercholesterolaemic
obese Asian subjects. Singap Med J. 2001;42(1):006–10.
27. Kaats GR, Michalek JE, Preuss HG. Evaluating efficacy of a chitosan prod-
uct using a double-blinded, placebo-controlled protocol. J Am Coll Nutr.
2006;25(5):389–94.
28. Santas J, Lázaro E, Cuñé J. Effect of a polysaccharide-rich hydrolysate from
Saccharomyces cerevisiae (LipiGo®) in body weight loss: randomised,
double-blind, placebo-controlled clinical trial in overweight and obese
adults. J Sci Food Agric. 2017;97(12):4250–7.
29. Baldrick P. The safety of chitosan as a pharmaceutical excipient. Regul
Toxicol Pharmacol. 2010;56(3):290–9.
30. Baranowski T, Taveras EM. Childhood obesity prevention: changing the
focus. New Rochelle: Mary Ann Liebert, Inc; 2018.
31. Morrison JA, Lask arzewski PM, Rauh JL, Brookman R, Mellies M, Frazer M,
et al. Lipids, lipoproteins, and sexual maturation during adolescence: the
Princeton maturation study. Metabolism. 1979;28(6):641–9.
32. Must A, Anderson S. Body mass index in children and adolescents:
considerations for population-based applications. Int J Obes.
2006;30(4):590–4.
33. Bryant R, Ooi S, Schultz C, Goess C, Grafton R, Hughes J, et al. Low muscle
mass and sarcopenia: common and predictive of osteopenia in inflam-
matory bowel disease. Aliment Pharmacol Ther. 2015;41(9):895–906.
34. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration
of low-density lipoprotein cholesterol in plasma, without use of the
preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.
35. Jull AB, Mhurchu CN, Bennett DA, Dunshea-Mooij CA, Rodgers A.
Chitosan for overweight or obesity. Cochrane Database Syst Rev.
2008;3:1–64.
36. Lehtimäki T, Metso S, Ylitalo R, Rontu R, Nikkil M, Wuolijoki E, et al. Micro-
crystalline chitosan is ineffective to decrease plasma lipids in both apoli-
poprotein E ε4 carriers and non-carriers: a Long-term placebo-controlled
trial in Hypercholesterolaemic volunteers. Basic Clin Pharmacol Toxicol.
2005;97(2):98–103.
37. Moraru C, Mincea MM, Frandes M, Timar B, Ostafe V. A meta-analysis on
randomised controlled clinical trials evaluating the effect of the dietary
supplement chitosan on weight loss, lipid parameters and blood pres-
sure. Medicina. 2018;54(6):109.
38. Metso S, Ylitalo R, Nikkilä M, Wuolijoki E, Ylitalo P, Lehtimäki T. The effect
of long-term microcrystalline chitosan therapy on plasma lipids and glu-
cose concentrations in subjects with increased plasma total cholesterol:
a randomised placebo-controlled double-blind crossover trial in healthy
men and women. Eur J Clin Pharmacol. 2003;59(10):741–6.
39. Mhurchu CN, Poppitt S, McGill A, Leahy F, Bennett D, Lin R, et al. The
effect of the dietary supplement, chitosan, on body weight: a ran-
domised controlled trial in 250 overweight and obese adults. Int J Obes.
2004;28(9):1149–56.
40. Sugano M, Fujikawa T, Hiratsuji Y, Nakashima K, Fukuda N, Hasegawa Y. A
novel use of chitosan as a hypocholesterolemic agent in rats. Am J Clin
Nutr. 1980;33(4):787–93.
41. Sciutto A. Lipid-lowering effect of chitosan dietary integrator hypocaloric
diet in obese subjects. Acta Toxicol Ther. 1995;16:215–30.
42. Leonardini A, Laviola L, Perrini S, Natalicchio A, Giorgino F. Cross-talk
between PPAR and insulin signaling and modulation of insulin sensitivity.
PPAR Res. 2009;2009:1–12.
43. Kumar SG, Rahman MA, Lee SH, Hwang HS, Kim HA, Yun JW. Plasma pro-
teome analysis for anti-obesity and anti-diabetic potentials of chitosan
oligosaccharides in Ob/Ob mice. Proteomics. 2009;9(8):2149–62.
44. Pan H, Fu C, Huang L, Jiang Y, Deng X, Guo J, et al. Anti-obesity effect of
chitosan oligosaccharide capsules (COSCs) in obese rats by ameliorating
leptin resistance and adipogenesis. Marine Drugs. 2018;16(6):198.
45. Santos HO, Earnest CP, Tinsley GM, Izidoro LFM, Macedo RCO. Small
dense low-density lipoprotein-cholesterol (sdLDL-C): analysis, effects
on cardiovascular endpoints and dietary strategies. Prog Cardiovasc Dis.
2020;63(4):503–9.
46. Zhu C, Yan H, Zheng Y, Santos HO, Macit MS, Zhao K. Impact of cinnamon
supplementation on cardiometabolic biomarkers of inflammation and
oxidative stress: a systematic review and Meta-analysis of randomized
controlled trials. Complementary therapies in medicine. 2020;53:102517.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com
Available via license: CC BY 4.0
Content may be subject to copyright.