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com
ScienceDirect
Targeting gastrointestinal nutrient sensing mechanisms
to treat obesity
Mariana Norton and Kevin G Murphy
Gut hormones have important roles in the regulation of appetite
and glucose homeostasis. Understanding how macronutrient
sensing in the gastrointestinal tract modulates gut hormone
release may reveal novel pharmacological or dietary
approaches to metabolic disease. In this short review we
discuss the mechanisms by which the gut senses
macronutrients and the products of macronutrient digestion,
and their putative utility in treating obesity and related
conditions.
Address
Section of Endocrinology and Investigative Medicine, Department of
Medicine, Imperial College London, W12 0NN, UK
Corresponding author: Murphy, Kevin G (k.g.murphy@imperial.ac.uk)
Current Opinion in Pharmacology 2017, 37:16–23
This review comes from a themed issue on Endocrine and metabolic
diseases
Edited by Gavin Bewick
http://dx.doi.org/10.1016/j.coph.2017.07.005
1471-4892/ã 2017 Elsevier Ltd. All rights reserved.
Introduction
Obesity is associated to comorbidities including cancer
and diabetes [1]. The most effective therapy is gastric
bypass but it is expensive and invasive. Some of the
benefits of gastric bypass are attributed to changes in
patients’ gut hormone profiles [2]. Gut hormones,
secreted by enteroendocine cells (EECs), are crucial in
appetite regulation. They respond to a variety of stimuli,
such as nutrients in the lumen, which are detected by a
wide range of sensors [3!]. These sensors may be useful
anti-obesity targets capable of modulating endogenous
gut hormone secretion to promote weight loss. This
review will focus on extracellular nutrient sensors
expressed in the gut, their role in gut hormone secretion
and their potential use as anti-obesity targets (Figure 1).
Macronutrients are classified as carbohydrates, fats or
proteins. Upon ingestion, these macronutrients are con-
verted by endogenous and bacterial enzymes to metab-
olites that are detected by sensors in the gut.
Current Opinion in Pharmacology 2017, 37:16–23
Carbohydrate
Glucose, a common carbohydrate and break-down prod-
uct of larger carbohydrates, potently stimulates the
release of the incretin and appetite-regulating hormones
gastric-inhibitory peptide (GIP) and glucagon-like pep-
tide 1 (GLP-1) when administered orally but not intrave-
nously [4!,5,6]. In the small intestine, this effect is pri-
marily mediated by the sodium-dependent glucose co-
transporter SGLT-1, which is expressed in both K-cells
and L-cells; GIP and GLP-1 expressing EECs, respec-
tively [5]. The entry of sodium, coupled to glucose,
depolarizes the cell membrane, opening voltage gated
calcium channels and stimulating hormone exocytosis
[4!,7!]. Knockout of SGLT-1 in mice abolishes peak
glucose-induced GIP and GLP-1 secretion [8,9], but at
later time points, circulating levels of GLP-1 and the
anorectic gut hormone peptide YY (PYY) are increased in
both SGLT-1"/" and antagonist treated mice [9], sug-
gesting alternative glucose sensing mechanisms in the
distal gut. Specifically inhibiting intestinal SGLT-1 in
mice also resulted in a trend for increased GLP-1 follow-
ing a glucose challenge, but importantly highlighted
potential gastrointestinal side effects consistent with
the malabsorption observed in knockout mice and
humans with SGLT-1 inactivating mutations [8,10].
In humans, SGLT-1 inhibition resulted in decreased
postprandial GIP and increased postprandial GLP-1
levels [11]. Longer term human studies have used
antagonists such as LX4211 that also target SGLT-2.
Inhibiting SGLT-1/2 in diabetic patients improved gly-
cemic control and resulted in a trend for decreased
weight and increased GLP-1 and PYY levels [12].
Decreased weight gain, regardless of increased food
intake was observed in animal models [13]. As an adjunct
therapy to insulin in diabetic patients, LX4211 improved
glycemic control, increased post-prandial PYY levels and
promoted weight loss [14]. Some FDA approved SGLT-
2 inhibitors also lead to weight loss [15]. Whether the gut
hormone effects resulting from SGLT-1 antagonism
contribute to this needs further investigation. Overall,
SGLT-1 partial antagonism, to minimise malabsorption
side effects, may be a better anti-obesity strategy than
SGLT-1 agonism.
Glucose transporter 2 (GLUT-2) may also mediate glu-
cose-induced gut hormone secretion. GLUT-2 inhibition
and knockout in mice reduced glucose-stimulated GLP-1
secretion by #11% and 55% respectively [4!,16]. Intesti-
nal specific GLUT-2 knockout did not alter basal GLP-1
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 Targeting nutrient sensing mechanisms to treat obesity Norton and Murphy 17

Figure 1

GPRC6A
Orexigenic
Amino Acids T1R1/T1R3

B0AT1 Ghrelin
Protein
CaSR
Peptides and P/D1-cell
Oligopeptides GPR93

PEPT-1 Anorectic

FFAR1 CCK
LCFA
FFAR4
I-cell
Fat (TG)
MAG GPR119

GIP
SGLT-1
K-cell
Glucose GLUT-2

TIR2/TIR3
PYY
GLUT5 GLP-1
Carbohydrate Fructose

FFAR2 L-cell
SCFA
FFAR3
Current Opinion in Pharmacology

Simplified overview of gastrointestinal nutrient sensors of the gut. Macronutrients are broken-down by endogenous and bacterial enzymes in
the gut, producing metabolites which can be detected by G-protein coupled receptors and transporters. This leads to the modulation of the
secretion of appetite-regulating hormones by enteroendocrine cells. This schematic does not include intracellular nutrient sensors. Abbreviations:
long chain fatty acids (LCFA), 2-monoacylglycerols (MAG), short chain fatty acids (SCFA), G protein-coupled receptor family C group 6 member A
(GPRC6A), amino acid sensing heterodimer taste receptor type 1 member 1/taste receptor type 1 member 3 (T1R1/T1R3), neutral amino acid
transporter (B0AT1), calcium sensing receptor (CaSR), G protein-coupled receptor 93 (GPR93), peptide transporter 1 (PEPT-1), free fatty acid
receptor 1 (FFAR1), free fatty acid receptor (FFAR 4), G protein-coupled receptor 119 (GPR119), sodium-dependent glucose co-transporter 1
(SGLT-1), glucose transporter 2 (GLUT-2), sweet taste receptor taste receptor type 1 member 3/taste receptor type 1 member 3 (T1R2/T1R3),
glucose transporter 5 (GLUT-5), free fatty acid receptor 2 (FFAR 2), free fatty acid receptor 3 (FFAR 3), cholecystokinin (CCK), gastric inhibitory
polypeptide (GIP), glucagon-like peptide 1 (GLP-1), peptide YY (PYY).

levels but resulted in lower L-cell density, compensated
for with an 80% increase in GLP-1 content per cell [17!],
suggesting the long-term effects of targeting GLUT-2
may differ from the acute effects. Additionally, human
mutations in GLUT-2 result in Fanconi-Bickel syn-
drome, suggesting it may not be a useful target in the
treatment of obesity [18].
The essential role of SGLT-1 and the contributory role of
GLUT-2 in GLP-1 secretion is in agreement with math-
ematical spatial models and transporter knockout models,
but the effect of GLUT-2 knockout on glucose-induced
GIP secretion is less clear [8,16,19]. Overall, SGLT-1
appears more important than GLUT-2 in peak glucose-
induced gut hormone secretion.
The clinical utility of targeting the heterodimer sweet
taste receptor T1R2/T1R3 may also be limited. Expres-
sion of its subunits is low in K-cells and L-cells, and
studies in perfused rat intestine required toxic levels of
sweeteners to stimulate GLP-1 release [20]. In humans,
sweeteners which activate the receptor failed to increase
gut hormone release [21]. Additionally, lactisole, a T1R2/
T1R3 antagonist, failed to suppress the secretion of
incretins in response to glucose in one study [22] but
not in another [23].
ATP-sensitive potassium channels (KATP) on EECs have
also been suggested as potential sensors due to their role
in b-cell glucose sensing. In rat perfused intestine, KATP
inhibition increases GLP-1 release [4!]. However,

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18 Endocrine and metabolic diseases
sulfonylurea treatment, which leads to KATP channel
closure, failed to affect gut hormone secretion in humans
during an oral glucose tolerance test [24]. In addition,
individuals with KATP channel mutations have neonatal
diabetes, but normal baseline and glucose-stimulated
GLP-1 levels, questioning its importance in mediating
gut hormone release [25].
There is also evidence of fructose sensing in the gut [26]
and short chain fatty acids, products of carbohydrate
fermentation in the colon, [27] influencing gut hormone
release and appetite.
Fat
Fatty acid products of fat digestion can act intracellularly
to alter metabolic processes [28]. However, there is cur-
rently much interest in the gut-based cell surface receptor
systems which detect lipids. Triglycerides from dietary
fat are metabolised by pancreatic lipase into long chain
fatty acids, which are detected by fatty acid receptors 1
(FFAR1) and 4 (FFAR4), and 2-monoacylglycerol,
detected by G-protein coupled receptor 119 (GPR119).
These receptors are expressed in EECs and are thought
to modulate the release of GLP-1, PYY, GIP and chole-
cystokinin (CCK), which is anorectic, and perhaps
ghrelin, which is orexigenic, in response to dietary fat
[29–31]. They thus may also have potential as anti-obesity
targets.
FFAR1"/" mice have blunted CCK, GIP and perhaps
GLP-1 responses to fat ingestion, FFAR1 is therefore
important in mediating the gut hormone response to
dietary fat but is not essential, and likely functions
alongside other sensors [29,32,33]. In humans, FFAR1
is expressed more than FFAR4 and GPR119 in the small
intestine [32,34].
Known endogenous ligands of FFAR1 signal via Gaq. In
vivo FFAR1 is thought to synergistically interact with Gas
coupled receptors such as GPR119, the bile acid receptor
TGR5 and the GIP receptor to potentiate GLP-1 (but not
GIP) release. This can be recapitulated in vitro using
second generation FFAR1 agonists that signal via both
Gaq and Gas [30,35]. Second generation agonists may
therefore be more effective at promoting weight loss than
Gaq coupled first generation agonists such as TAK-875,
which failed to show any clinically significant effects on
body weight in clinical trials stopped due to liver toxicity
concerns [36]. Gut hormone release is likely driven by
basolaterally expressed FFAR1 in EECs, thus fatty acid
absorption is an important step in lipid sensing; an impor-
tant consideration for the design of drugs aimed at
exploiting FFAR1 [37!].
FFAR4 is one of the most highly expressed nutrient
receptors in the large intestine [38!]. Like FFAR1, its
expression in the small intestine increases in response to a
Current Opinion in Pharmacology 2017, 37:16–23
high fat diet (HFD) in DIO but not DIO-resistant rats
[39], and in humans, expression is positively correlated
with BMI [34].
FFAR4 agonists inhibit ghrelin secretion in vitro; an
effect lost following FFAR4 knock-down [40]. In vivo,
FFAR4"/" mice have raised fasting plasma ghrelin levels
but are still responsive to triglyceride’s inhibitory effect
on ghrelin secretion. FFAR4 may therefore provide a
baseline inhibitory tone on ghrelin secretion, but other
systems may mediate triglyceride-induced ghrelin sup-
pression [31]. FFAR4"/" mice also have blunted CCK
and GIP responses, but a normal GLP-1 response to orally
gavaged oil [29,41]. In humans, an FFAR4 loss-of-func-
tion mutation is associated with increased obesity risk
[42].
Overall, FFAR4 may be a possible target to modulate gut
hormones. FFAR4 internalisation is observed in response
to agonist administration in vitro, but the system appears
to re-sensitise quickly [43]. Additionally, though mice
with FFAR4 agonist supplemented food did not show
changes in basal GLP-1 levels or body weight
[29,41,44,45], colonic administration of an alternative
agonist in mice did increase plasma GLP-1 levels [46],
suggesting the region of the gastrointestinal tract targeted
is important.
GPR119, a constitutively active receptor, is expressed in
K-cells and L-cells [47,48]. In humans, GPR119 duodenal
expression is inversely correlated to BMI [34], though
intraduodenal administration of lipids increases duodenal
expression [49].
GPR119 agonists stimulate GLP-1 and GIP release. The
receptor is also thought to act in synergy with FFARs to
potentiate GLP-1 secretion [47,48]. The proportion of L-
cells responsive to GPR119 agonists varies along the
length of the gut, suggesting GPR119 may be expressed
in a specific L-cell subpopulation [50]. In accord with this,
GPR119 agonists-stimulated GLP-1 release is blunted in
ileal and colonic cultures, but not in proximal gut cultures,
from mice lacking GPR119 specifically in L-cells. In vivo,
L-cell specific knockout of GPR119 reduced the GLP-1
response to lipid gastric gavage [50] and global knockout
blunted GLP-1 and GIP responses to oral triglycerides
[48].
The incretin effects of GPR119 agonism have made
GPR119 a popular therapeutic target [51]. However, thus
far, these agonists have failed to translate to the clinic.
The agonist JNJ-38431055 increased GLP-1 and GIP
secretion after a meal challenge, but the resulting glucose
lowering effect was insufficient to be clinically useful, and
there was no effect on appetite [52]. Another agonist,
GDK263, increased PYY levels by fivefold but did not
affect food intake or hunger [53]. Several other clinical
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 Targeting nutrient sensing mechanisms to treat obesity Norton and Murphy 19
candidates have also been discontinued [54], questioning
the potential of GPR119 as an anti-obesity drug target.
Protein
Protein, the most satiating macronutrient, stimulates the
release of various anorectic hormones including: PYY
[55,56], CCK [57,58], GLP-1 [56,59–61] and GIP [57],
which are thought to be important in protein’s satiating
effect. Therefore protein metabolite nutrient sensors are
potential anti-obesity targets.
Three well characterised promiscuous L-amino acid sens-
ing receptors: G protein-coupled receptor family C group
6 member A (GPRC6A), umami taste receptor T1R1/
T1R3 and the calcium sensing receptor (CaSR); a more
recently identified amino acid receptor: GPR142; and the
peptide receptor GPR93 are all present in the gut and
appear to sense the products of protein digestion.
GPRC6A is activated by basic amino acids which trigger
GLP-1 secretion in vitro in the GLUTag L-cell line, but
not in primary cultures of the mouse small intestine
[62,63]. Data from GPRC6A"/" mice suggest it is not
necessary for the appetite-reducing effects of high protein
diets or L-arginine, or for L-arginine-induced or L-Orni-
thine-induced GLP-1 secretion [64,65!,66]. Additionally,
in the majority of humans, particularly Europeans and
Asians, the receptor tends to be retained intracellularly,
putting into question its physiological role [67].
GPRC6A is closely related to the CaSR, making it possi-
ble to target both receptors with one agent. The CaSR is
allosterically modulated by aromatic amino acids and
oligopeptides. CaSR activation has been associated with
the secretion of various anorectic hormones in vitro,
including CCK and GLP-1 [68,69,70,71!!]. CaSR antag-
onism decreased GLP-1, GIP and PYY secretion from
small intestinal loops [72]. However, variable effects of
CaSR activation on ghrelin secretion have been reported
[73]. In vivo oral administration of a CaSR agonist
decreased food intake in mice [74], but at high concen-
trations caused emesis in mink, highlighting a potential
side effect of targeting this receptor [75].
The CaSR undergoes agonist-driven insertional signal-
ling, making it highly resistant to functional desensitisa-
tion [76]. This, alongside its ability to stimulate the
secretion of a variety of anorectic hormones, make it
an interesting anti-obesity pharmacological target. How-
ever, it is widely expressed, crucial in calcium homeosta-
sis and has multiple roles in the gastrointestinal tract
which could lead to several side effects if targeted
pharmacologically. In addition, mice with a gain-of-func-
tion mutation showed no difference in food intake or
body weight, but did have impaired glucose tolerance
and hypocalcaemia [77].
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The umami taste receptor T1R1/T1R3 in humans is
particularly sensitivity to L-glutamate, whereas the rodent
receptor responds to a wider range of amino acids [78,79].
Amino acids can stimulate CCK release via T1R1/T1R3
in rodent in vitro models [79]. In pigs, signalling compo-
nents of T1Rs are up-regulated in response to HPDs [80].
Whether the human receptor is also able to mediate gut
hormone secretion is unknown. Additionally, there is
redundancy in the system; taste cells from T1R1"/" or
T1R3"/" mice partially responded to L-amino acids,
which may reflect the detection of L-amino acids by
metabotropic glutamate receptors [81–83], and similar
redundancy is possible in the gut.
GPR142 is particularly activated by the essential aro-
matic amino acids L-phenylalanine and L-tryptophan.
The concentrations of luminal amino acids following
protein digestion are within the range of receptor activa-
tion [84!!]. GPR142"/" mice have a similar food intake
and body weight to control mice but the effect of agonists
on food intake and body weight remain to be explored
[85!!]. There is evidence that GPR142 activation can
modulate gut hormone release. In mice it is expressed in
gastrin-releasing G-cells and in K-cells [31,85!!,86]. L-
tryptophan simulates GIP and insulin secretion, and
improves glucose tolerance in rodents via GPR142
[85!!,87]. Additionally, oral administration of a
GPR142 agonist increased plasma GLP-1 in control mice
but not GPR142"/" mice [85!!]. The importance of
GPR142 in energy and glucose homeostasis thus requires
further investigation.
GPR93 is expressed more than other amino acid or fatty
acid nutrient sensor in the small intestine [38!]. It is found
on EECs including L-cells and G-cells [38!,88,89]. Over-
expression in STC-1 cells increases the transcription and
release of CCK in response to protein hydrolysate [90]
and in vivo its expression may be responsive to changes in
diet [89]. However, in primary cell culture, receptor
knockout does not impair peptone-induced GLP-1 secre-
tion [70].
Some amino acid and peptide transporters can act as
nutrient sensors that stimulate gut hormone release,
including peptide transporter 1 (PEPT-1) and the
sodium-dependent transporter of neutral amino acids,
B0AT1, which is enriched in L-cells [91,92].
PEPT-1 is a proton coupled di-peptide and tri-peptide
transporter expressed on the intestinal brush border.
Peptide transport through PEPT1 can lead to membrane
depolarisation, opening of calcium channels and subse-
quent secretion of GLP-1 in vitro [70,93]. It may also
indirectly mediate the secretion of gut hormones such as
CCK [94]. Expression and activity of the transporter is
influenced by dietary protein content [95] and may influ-
ence food intake in response to a HPD [96].
Current Opinion in Pharmacology 2017, 37:16–23
20 Endocrine and metabolic diseases
B0AT1"/" animals fed a HFD have lower abdominal
white adipose tissue and weight gain, increased basal
levels of GIP and GLP-1, and improved glycaemic con-
trol. This phenotype may reflect the reduced absorption
of protein digest products. These animals are also slightly
hyperphagic, perhaps in an attempt to meet their amino
acid requirements [97]. B0AT1 human mutations result in
Hartnup disorder, suggesting it is perhaps a less than
optimal anti-obesity therapy target [98].
Conclusion
The weight loss observed in gastric bypass patients and
patients treated with incretin mimetics suggest gut hor-
mone signalling is a viable anti-obesity target. Evidence
suggests that exploiting signals from multiple gut hor-
mones concurrently would cause greater appetite sup-
pression, and perhaps fewer side effects [99,100]. Target-
ing nutrient sensors to stimulate the endogenous
production of multiple gut hormones thus seems a prom-
ising avenue. However, there are a number of challenges
to overcome, including understanding where in the gut
such nutrients are acting, how they or mimetics can be
delivered to these regions, administration regimens that
avoid desensitisation of the system, and the potential for
side effects. Further work is required to better understand
these nutrient sensing systems to enable their effective
exploitation for the prevention or treatment of obesity.
Funding sources
M.N. is funded by the Imperial College Ghatei Student-
ship. The Section of Endocrinology and Investigative
Medicine is funded by grants from the Medical Research
Council, Biotechnology and Biological Sciences Research
Council, National Institute for Health Research, an Inte-
grative Mammalian Biology (IMB) Capacity Building
Award, an FP7-HEALTH-2009-241592 EuroCHIP grant
and is supported by the NIHR Biomedical Research
Centre Funding Scheme. The views expressed are those
of the authors and not necessarily those of the NHS, the
NIHR or the Department of Health.
Conflict of interest statement
Nothing declared.
Acknowledgements
A special thank you to David Leonard for his drawing of the gut.
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