Effects of Non-nutritive Sweeteners on Sweet Taste Processing and Neuroendocrine Regulation of Eating Behavior

Abstract

Purpose of review:
Non-nutritive sweeteners (NNS) are increasingly used as a replacement for nutritive sugars as means to quench the desire for "sweets" while contributing few or no dietary calories. However, there is concern that NNS may uncouple the evolved relationship between sweet taste and post-ingestive neuroendocrine signaling. In this review, we examine the effects of NNS exposure on neural and peripheral systems in humans.

Recent findings:
NNS exposure during early development may influence sweet taste preferences, and NNS consumption might increase motivation for sweet foods. Neuroimaging studies provide evidence that NNS elicit differential neuronal responsivity in areas related to reward and satiation, compared with caloric sweeteners. Findings are heterogenous regarding whether NNS affect physiological responses. Additional studies are warranted regarding the consequences of NNS on metabolic outcomes and neuroendocrine pathways. Given the widespread popularity of NNS, future studies are essential to establish their role in long-term health.

Full text

NUTRITION AND THE BRAIN (J NASSER, SECTION EDITOR)
Effects of Non-nutritive Sweeteners on Sweet Taste Processing
and Neuroendocrine Regulation of Eating Behavior
Alexandra G. Yunker
1,2
&Reshma Patel
1,2
&Kathleen A. Page
1,2
#Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
Purpose of Review Non-nutritive sweeteners (NNS) are increasingly used as a replacement for nutritive sugars as means to
quench the desire for “sweets”while contributing few or no dietary calories. However, there is concern that NNS may uncouple
the evolved relationship between sweet taste and post-ingestive neuroendocrine signaling. In this review, we examine the effects
of NNS exposure on neural and peripheral systems in humans.
Recent Findings NNS exposure during early development may influence sweet taste preferences, and NNS consumption might
increase motivation for sweet foods. Neuroimaging studies provide evidence that NNS elicit differential neuronal responsivity in
areas related to reward and satiation, compared with caloric sweeteners. Findings are heterogenous regarding whether NNS affect
physiological responses.
Summary Additional studies are warranted regarding the consequences of NNS on metabolic outcomes and neuroendocrine
pathways. Given the widespread popularity of NNS, future studies are essential to establish their role in long-term health.
Keywords Non-nutritive sweeteners .Low-calorie sweeteners .Sweeteners .Artificial sweeteners .Sweet taste .Hormones .
Obesity .Insulin .Incretins .GLP-1 .Brain .fMRI .Neuroimaging .Obesity .Reward .Satiety .Food intake .Feeding
behavior .Appetite .Hypothalamus .Striatum .Insula .Amygdala
Introduction
A growing body of evidence has linked increased caloric sug-
ar consumption with obesity risk [1–3]. Accordingly, non-
nutritive sweeteners (NNS) have become a popular alternative
for added sugar intake, satisfying the craving for “sweets”
while providing few or no calories. NNS use is rapidly in-
creasing; currently, over 40% of US adults and 25% of ado-
lescents and children are habitual NNS consumers [4].
Notably, among American children and adolescents, NNS in-
take has increased by 200% since 1999 [4]. Furthermore,
given the widespread distribution of NNS in drinks and foods,
consumers are often unaware that they are even ingesting
NNS [5,6]. Despite the increasing usage of NNS, and NNS
being largely marketed as strategic tools for weight manage-
ment, the prevalence of obesity and associated metabolic dis-
orders has not decreased; rather, rates of the co-epidemics of
obesity and type 2 diabetes (T2DM) have continued to rise
over the past several decades [7,8]. Notably, a recent advisory
from the American Heart Association recommended against
prolonged consumption of NNS beverages by children, while
also concluding that NNS beverages could potentially be a
useful replacement strategy for adult chronic high consumers
of sugar-sweetened beverages [9]. In addition, while epidemi-
ological evidence suggests that NNS exposure throughout the
lifespan (and as early as in utero) can contribute to risk for
weight gain [10–13] and risk for metabolic derangements,
including type 2 diabetes [14], other studies using experimen-
tal designs have reported that NNS have neutral or beneficial
effects regarding body weight [15–18] and glucose metabo-
lism [19]. Given the equivocal evidence regarding the efficacy
of NNS, and the paradoxical increase in prevalence of both
NNS use and metabolic disorders, it is imperative that the
This article is part of the Topical Collection on Nutrition and the Brain
*Kathleen A. Page
kpage@usc.edu
1
Division of Endocrinology, Department of Medicine, Keck School of
Medicine, Diabetes and Obesity Research Institute, University of
Southern California, 2250 Alcazar Street; CSC 209, Los
Angeles, CA 90089, USA
2
Diabetes and Obesity Research Institute, Keck School of Medicine,
University of Southern California, Los Angeles, CA 90089, USA
Current Nutrition Reports
https://doi.org/10.1007/s13668-020-00323-3

potential neural and peripheral implications of NNS consump-
tion throughout the lifespan are understood (Fig. 1). The pur-
pose of this article is to review and summarize the current
literature, and to address the gaps in knowledge regarding
the effects of both acute and chronic NNS exposure across
the lifespan on glucose metabolism, sweet taste perception
and preference, and neural systems involved in appetite and
reward, with an emphasis on findings from human studies.
NNS and Sweet Taste
While caloric sugars and NNS have varying chemical struc-
tures, they all interact with the heterodimeric sweet taste re-
ceptor complex, T1R2/T1R3 [20]. Notably, sweet taste per-
ception plays a role in carbohydrate metabolism and reward
[21], and sweet taste preference has been linked to the likeli-
hood of children becoming overweight or obese [22].
Additionally, sweet-liking is predictive of weight gain over
time in some adult populations [23,24]. Given the potential
metabolic consequences of heightened hedonic liking for
sweet, it is important that the possible influences of NNS on
taste perception and preference are well understood.
A growing body ofevidence in rodents,and a limited num-
ber of studies in humans, suggests that NNS exposure or con-
sumption during early development may influence sweet taste
processing. The formation of taste preferences, including pref-
erence for sweet, begins before birth; both rodent and human
studies havedemonstrated that maternal diets during pregnan-
cy and lactation, in addition to the offspring’sdietduringthe
first months of life, influence flavor learning, conditioning,
and acceptance [25–27]. The effects of in utero and early-
life exposure to NNS on offspring sweet taste learning, per-
ception, and preference have in large part been elucidated by
rodent studies. Rosales-Gomez et al. recently reported that
young mice who habitually consumed oral sucralose directly
after weaning had heightened preference for sweetened water
and increased weight gain at approximately 15 weeks of life
[28]. Other rodent studies have addressed how in utero and
lactational NNS exposure influences offspring taste prefer-
ence. Mouse pups exposed to acesulfame potassium (aceK)
prenatally and during lactation via maternal diet exhibit great-
er sweet taste preference in adulthood compared with control
Fig. 1 Downstream potential
effects of NNS intake on
neuroendocrine systems involved
in appetite regulation and eating
behavior. The taste of a sweet
substance activates sweet taste
receptors, including in the oral
cavity and brain. Exposure to
NNS, which uncouple sweet taste
and energy content, may
dysregulate sweet taste signaling
pathways and affect brain and
metabolic processes across the
lifespan, which, in turn, may
contribute to altered eating
behavior, T2DM, and chronic
disease. Figure created with
BioRender
Curr Nutr Rep

mice [29,30], and furthermore, infusion of aceK during the
early postnatal stage promoted unfavorable gustatory system
changes in young mice [31].
Together, these findings in animal models have particular
clinical implications for pediatric populations. NNS are fre-
quently ingested by nursing infants; it has been shown that
saccharin, sucralose, and aceK were present in 65% of breast
milk samples from twenty lactating mothers, independent of
the mothers’NNS dietary intake [32]. However, the specific
magnitude and prevalence of fetal NNS exposure in humans
remains unknown [33•]. Studies in children examining the
effects of habitual NNS consumption on dietary preference
for sweet foods are limited to cross-sectional analyses. A
study among UK children and adolescents (ages 4–18) found
that boys who reported any dietary consumption of artificially
sweetened beverage(s) (ASBs) had higher dietary intake of
sugar from solid foods when compared with boys who report-
ed consuming only sugar-sweetened beverages (SSBs) or
those who were non-consumers of either SSBs or ASBs
[34]. However, the majority of this cohort consumed both
SSBs and ASBs (43%), while a subset of 18% consumed only
ASBs [34]. More recently, Sylvetsky et al. reported the first
results from a US study that used 2011–2016 National Health
and Nutrition Examination Survey (NHANES) data to exam-
ine associations between NNS beverage consumption and di-
etary intake in children and adolescents. They found that con-
sumers of low-calorie sweetened beverages, whether con-
sumed alone or in conjunction with SSBs, displayed higher
energy, carbohydrate, total sugar, and added sugar intake
compared with children and adolescents who were classified
as only water consumers [35••]. In a separate study that used
NHANES data, Sylvetsky and colleagues also demonstrated
positive associations between dietary NNS consumption and
obesity in adolescents [36]. It should be noted that the
NHANES data were limited to self-reported dietary intake,
based on only a single or two-day recall, and that given the
cross-sectional nature of the studies, confounding by reverse
causation is possible. Nevertheless, the findings from
Sylvetsky et al. are consistent with one of the proposed mech-
anisms by which early-life NNS exposure may impact future
body composition via dysregulation of the developmental pro-
gramming of taste preferences. Chronic NNS consumption
may uncouple the functionality of sweet taste to signal the
post-ingestive caloric consequences of eating sweet foods, in
turn, enhancing sugar intake [37–41]. Taken together, further
studies examining the effects of early-life NNS exposure on
taste preference, dietary intake, and body weight regulation
are warranted. Future areas of study include replication of
findings in animal models and studies that include more rig-
orous experimental methods in humans.
Few human studies have addressed how NNS consumption
influences sweet taste preferences in adulthood. A study by
Casperson etal. aimed to determine the effects of consuming a
SSB or NNS beverage on the reinforcing value of sweet foods.
Young adults ingested either acute oral sucralose (Splenda®)
or sucrose, matched for sweetness and pleasantness, with a
standardized meal. Consumption of sucralose, but not sucrose,
heightened the motivation to gain access to sweet foods post
meal [42•]. Sucralose increased the relative reinforcing values
of sweet snacks, compared with salty or savory snacks, sug-
gesting that acute NNS consumption might alter desire for
sweet foods and eating behavior [42•]. In contrast, a recent
industry-funded study reported that among French adults, wa-
ter and low-calorie sweetened (LCS) beverage ingestion did
not have differential effects on the selection of, or motivation-
al ratings towards, sweet foods [43]. Furthermore, appetite for
sweet foods was neither affected by acute nor longer-term
exposure to the LCS beverage [43]. It is important to note that
the respective experimental studies by Casperson et al. and
Fantino et al. utilized different NNS methodologies, the latter
employing a LCS lemonade that included several NNS (aceK,
aspartame, and sucralose) in combination with other com-
pounds. Hill and colleagues examined the acute effects of
consuming a SSB (Sprite®), a NNS beverage (Sprite
Zero®), or an unsweetened beverage (carbonated water), in
combination with a standardized meal, on subsequent product
choice and subjective responses to a sugar-sweetened food
among young adults. They found that participants who con-
sumed the NNS drink, relativeto those who had consumed the
SSB or water, were more likely to choose a high calorie food
item (specifically, candy) during a food product choice task,
compared to other food options [44]. In addition, participants
who consumed the NNS beverage felt less satisfied after eat-
ing a sugar-sweetened snack (cookies), compared with sub-
jects who consumed the SSB or water [44]. Taken together,
these studies provide equivocal evidence for the impact of
NNS consumption on adult sweet taste preference and eating
behavior, and future experimental studies are warranted.
NNS and Metabolic Hormones
There has been much debate regarding whether NNS have
effects on metabolic hormones. In vitro studies showed that
NNS bind with high affinity to the T1R3 subunit of the sweet
taste receptor complex, which is expressed on the tongue and
throughoutthe digestive tract [45–47], and that NNS stimulate
incretin and insulin release in both the enteroendocrine cells in
the gut as well as beta cells in the pancreas [20,48–52]. While
evidence from in vitro studies has been compelling, in vivo
studies testing the effects of NNS on metabolic hormone se-
cretion have produced mixed results. Studies in rodent models
have been reviewed elsewhere [53], and in this review, we
highlight human studies that have examined the effects of
NNS on metabolic hormones (Table 1).
Curr Nutr Rep

Table 1 Summary of findings from human studies examining NNS effect on hormone levels, specifically insulin, glucagon like peptide 1 (GLP-1), peptide YY (PYY), gastric inhibitory polypeptide
(GIP), leptin, ghrelin, and glucagon
Author Year Age Group/
Size
Participant
Characteristics
NNS Used Dosage and Method
of Delivery
Insulin C-
peptide
GLP-1 PYY GIP Leptin Ghrelin Glucagon
Abdallah et al. 1997 12 Male
Adults
Lean Aspartame 18mg aspartame,
tasted
Decreased n/a n/a n/a n/a n/a n/a No effect
Ahmad et al. 2019 17 Adults
(10F)
Lean Aspartame,
Sucralose
425mg aspartame,
136mg sucralose,
ingested for 2 weeks
No effect n/a No effect n/a n/a No effect n/a n/a
Anton et al. 2010 31 Adults 19 Lean, 12 Obese Stevia,
Asparta-
me,
Sucrose
400g preload meal
with stevia,
aspartame or
sucrose
Lower with stevia
and aspartame
than sucrose
n/a n/a n/a n/a n/a n/a n/a
Argyri et al. 2013 70 Adults
(28F)
T2DM Diabetic
dessert
Not specified, ingested No effect No effect n/a n/a n/a n/a n/a n/a
Bonnet et al. 2018 50 Adults
(28F)
28 Lean, 22
Overweight
Aspartame+
aceK
129mg aspartame +
13mg aceK for 12
weeks, 4 week
washout, then 258
mg aspartame +
26mg aceK for 12
weeks
No effect n/a n/a n/a n/a n/a n/a n/a
Brown, R et al. 2009 22
Adolesce-
nts and
Young
Adults
(12F)
Overweight Sucralose+
aceK
68mg sucralose +
41mg aceK (Diet
Rite Cola), then
OGTT
No effect n/a Increased n/a n/a n/a n/a n/a
Brown, R et al. 2012 44
Adolesce-
nts and
Young
Adults
(27F)
25 Overweight
(Nondiabetic),
9 T1DM lean,
10 T2DM
obese
Sucralose+
aceK
68mg sucralose +
41mg aceK (Diet
Rite Cola), then
OGTT
n/a No effect Increased in
T1DM and
nondiabetic
overweight
groups, not
T2DM group
No effect n/a n/a n/a n/a
Brown, A et al. 2011 8 Female
Adults
Lean Sucralose 42mg sucralose drink,
42mg sucralose +
50g sucrose drink,
then standard meal
No effect n/a n/a n/a n/a n/a No effect No effect
Dhillon et al. 2017 64 Adults
(41F)
Obese Sucralose Not specified, in solid
and liquid form;
taste vs. ingestion
Early rise higher
with taste of
solid
n/a n/a n/a n/a n/a n/a n/a
Ford et al. 2011 8 Adults
(7F)
Lean Sucralose 2mmol/L in water, or
2mmol/L in water
with maltodextrin,
tasted and ingested
No effect n/a No effect No effect n/a n/a n/a n/a
Grotz et al. 2003 128 Adults
(42F)
Obese Sucralose 667mg sucralose, via
ingested capsule, 13
week exposure
n/a No effect n/a n/a n/a n/a n/a n/a
Grotz et al. 2017 Lean Sucralose No effect No effect n/a n/a n/a n/a n/a n/a
Curr Nutr Rep

Table 1 (continued)
Author Year Age Group/
Size
Participant
Characteristics
NNS Used Dosage and Method
of Delivery
Insulin C-
peptide
GLP-1 PYY GIP Leptin Ghrelin Glucagon
47 Male
Adults
667mg sucralose, via
ingested capsule, 12
week exposure
Higgins and
Mattes
2019 154 Adults
(87F)
85 Overweight, 69
Obese
Saccharin,
Asparta-
me,
Stevia,
Sucralose
73mg saccharin, 58mg
aspartame, 66mg
stevia, 16mg
sucralose, via drink,
12 week exposure
No effect n/a n/a n/a n/a n/a n/a n/a
Higgins et al. 2018 100 Adults
(50F)
Lean Aspartame 0, 350, 1050mg
aspartame, via
drink, 12 week
exposure
No effect n/a No effect n/a No effect No effect n/a n/a
Lertrit et al. 2018 15 Adults
(11F)
8 Lean, 1
Overweight, 6
Obese
Sucralose 200mg sucralose, via
capsule, 4 week
exposure
Decreased n/a Increased n/a n/a n/a n/a n/a
Ma et al. 2009 7 Adults Lean Sucralose 80mg sucralose,
800mg sucralose,
via NG tube
No effect n/a No effect n/a No effect n/a n/a n/a
Ma et al. 2010 10 Adults
(2F)
Lean Sucralose 960mg sucralose, via
NG tube
n/a n/a No effect n/a n/a n/a n/a n/a
Nichol et al. 2019 21 Adults
(17F)
10 Lean, 11 Obese Sucralose 48mg sucralose, t aste
vs. ingestion then
OGTT
Increased in taste
vs. ingestion
for both weight
groups, late
increase in
obese group
during OGTT
No effect n/a n/a No effect n/a n/a n/a
Overduin et al. 2016 20 Adults
(10F)
10 Lean, 10 Obese Erythritol+
Sucralose
8g erythritol, 4mg
sucralose in drink
and meal, compared
to sucrose control
No effect n/a Increased
compared to
sucrose
Increased
compared to
sucrose
n/an/an/an/a
Pepino et al. 2013 17 Adults
(15F)
Obese Sucralose 48mg sucralose,
ingested, followed
by OGTT
Increased Increased No effect n/a No effect n/a n/a No effect
Romo-Romo et al. 2018 66 Adults
(49F)
Lean Sucralose 12mg sucralose
consumed 3x/day,
via drink, 14 day
exposure
Decreased insulin
sensitivity,
increased acute
insulin
response
n/a n/a n/a n/a n/a n/a n/a
Sakurai et al. 2012 21 Male
Adults
Lean Sucralose,
aceK,
Asparta-
me,
Erythritol
Not specified, mixed
with 5mg sucrose
via drink,
co-ingested with a
meal
n/a n/a No effect n/a n/a n/a n/a n/a
Curr Nutr Rep

Table 1 (continued)
Author Year Age Group/
Size
Participant
Characteristics
NNS Used Dosage and Method
of Delivery
Insulin C-
peptide
GLP-1 PYY GIP Leptin Ghrelin Glucagon
Steinert et al. 2011 12 Adults
(6F)
Lean Sucralose,
Asparta-
me, aceK
169mg aspartame,
220mg aceK, 62mg
sucralose, via NG
tube
No effect n/a No effect No effect n/a n/a No effect n/a
Sylvetsky et al. 2016 61 Adults
(34F)
Overweight Sucralose,
Sucralos-
e+aceK
Experiment 1: 68mg,
170mg and 250mg
sucralose;
Experiment 2: Diet
Rite Cola: 68mg
sucralose + 41mg
aceK; Diet
Mountain Dew:
18mg sucralose,
18mg aceK, 57mg
aspartame; 68mg
sucralose + 41mg
aceK dissolved in
seltzer water, all
preloads to OGTT
No effect No effect Increased after
sucralose +
aceK, Diet Rite
Cola, and Diet
Mountain Dew;
no effect of
sucralose alone
n/a No effect n/a n/a n/a
Temizkhan et al. 2015 16 Adults
(8F)
8Obese,8Obese
T2DM
Aspartame,
Sucralose
72mg aspartame,
24mg sucralose,
ingested, then
OGTT
No effect No effect Increased after
sucralose
n/a n/a n/a n/a n/a
Tey et al. 2017 30 Male
Adults
Lean Aspartame,
Monk
fruit,
Stevia
440mg aspartame,
630mgmonkfruit,
330mg stevia, via
drink, prior to test
meal, sucrose as a
positive control
Increased acutely
after test meal,
no difference in
AUC
n/a n/a n/a n/a n/a n/a n/a
Wu et al. 2012 10 Adults
(3F)
Overweight Sucralose 60mg sucralose drink,
followed by test
meal
No effect n/a No effect n/a No effect n/a n/a n/a
Wu et al. 2013 10 Male
Adults
Overweight Sucralose,
aceK,
Sucralos-
e+aceK
52mg sucralose,
200mg aceK, 46mg
sucralose + 26mg
aceK, then OGTT
No effect n/a No effect n/a n/a n/a n/a n/a
Curr Nutr Rep

The effects of acute ingestion of NNS on incretin and in-
sulin responses have been studied using a variety of delivery
methods as well as different dosages and types of NNS
[54–66]. Interestingly, Diet Rite Cola®, which contains sucra-
lose and aceK, among other colorants and preservatives, was
found to increase GLP-1 secretion when compared with a
water or a seltzer control when consumed prior to an oral
glucose tolerance test (OGTT) in overweight and obese indi-
viduals [54–56]. However, studies examining the effects of
NNS dissolved solely in water have been mixed, with the
majority showing no effect of acute NNS consumption on
hormone secretion [56,57,59,64]. While Temizkhan et al.
observed an increase in GLP-1 levels when sucralose vs. wa-
ter was consumed prior to glucose ingestion, these effects
were not observed with an aspartame preload [57].
Sylvetsky and colleagues found no significant difference be-
tween varying concentrations of sucralose dissolved in water
compared with water alone when consumed prior to an oral
glucose load on peripheral insulin, glucose, C-peptide, or
GLP-1 levels in overweight individuals [56•]. Likewise,
Ford and colleagues found no difference between sucralose
compared with water preloads on insulin or GLP-1 responses
to oral glucose [64]. Additionally, Wu and colleagues found
no effect of sucralose or aceK, when consumed alone or in
combination, on peripheral insulin or GLP-1 concentrations
before or during an OGTT [59]. Future work is needed to
determine if some of the observed NNS effects on peripheral
GLP-1 are attributable to the colorants or preservative present
in diet soda given that the majority of studies that found an
effect on GLP-1 secretion utilized Diet Rite Cola®.
The studies mentioned above utilized acute glucose inges-
tion as a caloric load, whereas other studies used a standard-
ized meal to examine the effects of NNS consumption on
hormone responses in a more “real-life”scenario. These stud-
ies have largely found no effects of acute NNS ingestion on
hormone responses to standardized meals [60,65,67,68]. Wu
and colleagues examined the effects of sucralose on the hor-
monal response to a mashed potato meal in overweight indi-
viduals and found no significant effect of a sucralose preload
on insulin, GLP-1, or GIP [60]. Likewise, NNS co-ingested
with a meal of chicken soup and biscuits had no effect on
GLP-1 levels in lean males [67]. Similarly, Brown and col-
leagues found no effect of a sucralose preload on insulin,
ghrelin, and glucagon levels in response to a standardized
breakfast in lean females [68]. More recently, Tey and col-
leagues showed that the consumption of drinks containing the
NNS, aspartame, stevia, or monk fruit extract when compared
with drinks containing sucrose resulted in higher insulin levels
at 120 min after lunch, but reported no difference between the
four drinks on insulin or glucose area under the curve (AUC)
over the 3-h period after lunch [65•].
The longer-term effects of NNS consumption on metabolic
regulation in humans have also been examined with no clear
consensus on their physiological effects. Two recent studies
suggested that sucralose ingestion may negatively affect insu-
lin sensitivity [69,70]. Lertrit and colleagues showed that 4-
week consumption of sucralose (in capsule form) vs. an empty
capsule increased peripheral GLP-1 levels and decreased in-
sulin sensitivity in lean, overweight, and obese adults [69].
This finding was replicated by another study showing that a
14-day ingestion of sucralose in beverage form led to de-
creased insulin sensitivity in lean adults [70]. In contrast, other
studies have shown no effect of longer-term NNS consump-
tion on metabolic hormones [18,71–73]. Ahmad and col-
leagues found no change in insulin, GLP-1, or leptin levels
and no change in insulin sensitivity in lean adults exposed for
12 weeks to aspartame or sucralose mixed in water [71•].
Higgins and Mattes tested 12-week exposure to aspartame,
sucralose, saccharin, and stevia in overweight and obese
adults and showed no change in insulin levels with any of
the NNS examined [18•]. Similarly, another study showed
no effects of aspartame and aceK administered in differing
dosages over 12 weeks on insulin levelsin response to glucose
ingestion [72]. Furthermore, Grotz et al. found no difference
in glucose, C-peptide, or hemoglobin A1c after ingestion of
sucralose in a capsule vs. cellulose placebo over 12–13 weeks
in obese and lean adults [74,75].
Collectively, the current evidence provides equivocal evi-
dence on the effects of NNS consumption on hormones in-
volved in appetite regulation and glucose homeostasis. More
work is necessary to determine the specific concentrations and
types of NNS that may elicit hormone secretion, whether ef-
fects of NNS are dependent on delivery method, and whether
consumption of NNS in isolation or in the presence of carbo-
hydrate produces different effects. Future studies should con-
sider how individual characteristics, including habitual NNS
consumption, age, sex, adiposity, and insulin resistance, affect
metabolic hormone responses to NNS consumption.
Of note, while the majority of work has been done in
adults, recent evidence suggests that NNS may affect fetal
development and potential programming later in life.
Exposure to NNS in utero and during early life was associated
with risk of metabolic syndrome later in life in mice [76,77].
A longitudinal study in children demonstrated that mothers
with gestational diabetes who consumed daily NNS compared
with NNS non-consumers had children who were larger for
gestational age at birth as well as a higher BMI z-score and
increased risk of obesity at 7 years [13]. These results were
corroborated by a longitudinal cohort study showing that daily
consumption of NNS was linked with a 0.2 unit increase in
infant BMI z-score as well as a greater risk for being over-
weight at 1 year of age [11•], suggesting that maternal pro-
gramming with NNS exposure may affect a child’smetabolic
development. These studies further underscore the need for
studies on the effects of NNS in early development and
childhood.
Curr Nutr Rep

NNS and Neural Systems Involved in Appetite
and Reward
There has been increasing interest towards elucidating the
effects of NNS on brain regulation of appetite and reward. A
growing body of evidence reported via fMRI studies suggests
that NNS can provoke differential brain responses in humans,
compared with nutritive sweeteners. Frank et al. reported that
taste pathways in the brain can distinguish nutritive versus
non-nutritive sweet taste; sucrose, relative to sucralose, elicit-
ed stronger blood oxygen level–dependent (BOLD) brain re-
sponse activation of regions involved in reward processing,
such as the main gustatory complex (frontal operculum/
anterior insula) and the contralateral insula and midbrain, in-
cluding the ventral tegmental area (VTA),and substantia nigra
[78]. In accordance with these findings, Smeets et al. demon-
strated that small tastes of sucrose provoked increased BOLD
activation in the striatum, while in contrast, small tastes of a
mix of several NNS (aspartame, aceK, sodium cyclamate, and
sodium saccharin) led to heightened activation in the amyg-
dala, among lean adult males [79]. Taken together, these find-
ings support that either small or large tastes of NNS, when
compared with caloric sugars, can evoke differential re-
sponses within neural areas involved in processing of reward
and primary regions of taste activation.
Notably, several fMRI studies indicate that NNS may have
dampened hypothalamic satiety signaling effects, compared
with nutritive sugars. The hypothalamus is a brain region that
regulates appetite and energy homeostasis. Prior fMRI studies
have consistently shown a reduction in hypothalamic activa-
tion following the ingestion of glucose, which is interpreted as
a biomarker of satiety [80–82], and obesity is associated with
an altered glucose-linked hypothalamic response [83,84]; fur-
thermore, alterations in glucose-linked hypothalamic activa-
tion predicted longitudinal weight gain in children [85].
Smeets and colleagues first established that decreases in hy-
pothalamic activation in response to sweetened beverages
might be dependent on both sweet taste and energy content.
They found that among young adults, glucose ingestion pro-
voked a signal reduction in the hypothalamus, while water,
maltodextrin, and aspartame had no effect on hypothalamic
activation [86]. Most recently, Van Opstal et al. investigated
the hypothalamic response to acute ingestion of sucralose,
relative to nutritive sugar; sucralose led to the smallest de-
crease in BOLD activity in the hypothalamus, similar to water,
when compared with glucose, fructose, and sucrose ingestion
[87]. Another recent fMRI study also demonstrated that con-
sumption of a fat/protein milkshake sweetened with glucose
resulted in a widespread effect on the brain: decreased BOLD
signal in the posterior cingulate cortex, brainstem, VTA, and
insula and also decreased voxel based connectivity in the hy-
pothalamus and VTA [88••]. In contrast, shakes containing
allulose and sucralose showed no effect on BOLD signaling
within any of the regions of interest indicating that the NNS
had no immediate effect on the activation of brain areas related
to eating behavior [88••]. This finding further supports that
sweet taste, in the absence of nutritive carbohydrates, may
not lead to hypothalamic connectivity changes that are typi-
cally linked to satiation. It is important to note that there is an
abundant expression of sweet taste receptors within the hypo-
thalamus; RNA expression levels of the sweet taste receptor
complex (T1R2/T1R3) in the hypothalamus are significantly
higher than those in other brain regions implicated in eating
behavior, such as the cortex or hippocampus [89]. Given that
NNS interact with the sweet taste receptor complex, future
areas of investigation could consider how sweet taste prefer-
ence impacts neural satiety signaling in response to sugars and
NNS.
Other recent findings from Creze and colleagues utilize
electroencephalographic (EEG) methods to assess whether in-
gestion of sucrose and NNS drinks would elicit different neu-
ral responses to food cues and subsequent food intake at an ad
libitum buffet. The acute ingestion of a NNS beverage (con-
taining a mix of cyclamate, aceK, and aspartame) produced
differential neural activity in response to food cues, compared
with sucrose and water ingestion. Sucrose or water, but not
NNS, led to increased insula activation, whereas NNS con-
sumption increased neural activity in ventrolateral prefrontal
regions associated with inhibition of reward, consistent with
prior findings in humans [79,90]. The investigators concluded
that their findings showing differential brain responses to
acute NNS consumption may be indicative of early-stage ad-
aptation to taste-calorie uncoupling [90••]. However, there
was no difference in food intake during the buffet between
the water and NNS conditions, which the investigators pro-
posed could be due to limitations in experimental design and
that the design may not have been sensitive enough to capture
all secondary outcome differences between the NNS and wa-
ter groups [90••]. Another recent EEG study by Creze et al.
featured an interventional design; daily consumers of SSB
were asked to undergo a 3-month replacement period with
NNS beverage equivalents, which contained a varying mix
of NNS, such as aspartame, cyclamate, aceK, and sucralose.
Participants neither experienced weight loss over the replace-
ment period nor changes in food liking towards visual cues;
however, neural activity in response to high-fat, sweet food
cues was decreased in prefrontal regions linked to impulse
control after the intervention period [91]. Interestingly, the
post-intervention neural modulations in prefrontal areas were
predictive of weight loss failure, implying individual dimin-
ished ability over food intake control [91].
Additional studies in humans utilizing fMRI methods sug-
gest that frequent dietary consumption of NNS may condition
altered neural processing of sweet taste. Rudenga and Small
showed a negative association between self-reported chronic
NNS use and amygdala response, with a similar trend in the
Curr Nutr Rep

insula, to acute in-scanner tastes of varying concentrations of
sucrose among lean and overweight adults [92]. Given that the
amygdala and insula are key regions involved in integrating
flavor nutrient signals, these findings are consistent with those
of rodent literature suggesting that chronic NNS use may un-
couple the association between sweet taste and post-ingestive
consequences of predicted calories. In addition, Green and
colleagues showed that among individuals who were non-
habitual diet soda drinkers, patterns of activation in the
orbitofrontal cortex (OFC), a region implicated in processing
of reward, differed in response to acute tastes of saccharin
compared with sucrose; in contrast, among the habitual con-
sumers of diet sodas, neural activation patterns did not differ
between either the sucrose or saccharin condition [93].
Furthermore, habitual diet soda drinkers exhibited greater ac-
tivation in the OFC, lentiform nucleus, dopaminergic mid-
brain, and right amygdala in response to both sucrose and
saccharin, compared with non-diet soda drinkers [93].
Together, these findings support that chronic NNS consump-
tion may compromise the efficacy of brain regions related to
appetite and reward to process sweet taste.
Neuroimaging studies that have assessed brain responses to
NNS have largely been focused on lean and healthy cohorts
[78,79,86,87,90–94]. Studies that examine potential obesity
related differences in neural responses to NNS are warranted.
In addition, many of the neuroimaging studies that examine
brain responses to NNS have been limited to same-sex cohorts
[78,79,86,87,90,91,94]. Given that sex differences regard-
ing sweet taste perception have been previously reported in
rodents [95], future investigators should include both males
and females. Finally, to the best of our knowledge, there have
been no studies to date that examine the effects of NNS on
brain regulation of appetite and reward in children.
Conclusion
While NNS seem to elicit differential brain responses in ap-
petite and reward regions, compared with caloric sweeteners,
findings are equivocal as to whether these divergent brain
responses are predictive of subsequent metabolic conse-
quences. Gaps in the knowledge include how NNS affect both
glucose metabolism and the neural regulation of eating behav-
ior in particularly vulnerable populations such as pregnant and
lactating women, children, obese individuals, and persons
with metabolic disease. A key goal of future research should
investigate how both chronic and acute intake of NNS influ-
ence the neural and peripheral responses of these populations.
In addition, exposure to NNS during development and
throughout the lifespan may also influence sweet taste prefer-
ences; given that there is an abundance of sweet taste receptors
in the brain, it would be of interest to examine how individual
variation in sweet taste preference affects the neural
processing of NNS. Considering both the increasing preva-
lence of dietary NNS intake and the rising rates of obesity
and chronic disease, additional studies in humans are critical
to determine how NNS consumption impacts neuroendocrine
systems across the lifespan.
Funding Information This work was supported by the National Institutes
of Health (NIH) National Institute of Diabetes and Digestive and Kidney
Diseases R01DK102794 (PI: K.A.P).
Compliance with Ethical Standards
Conflict of Interest The authors have nothing to disclose.
Human and Animal Rights and Informed Consent All cited studies by
the authors were approved by the institutional review boards of their
respective institutions.
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