Nrgastro.2012.185

REVIEWS
Ghrelin, the proglucagon-derived peptides
and peptide YY in nutrient homeostasis
Charlotte X. Dong and Patricia L. Brubaker
Abstract | Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2
diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting
occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic
islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the
gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This
Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during
nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric
orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide
(GLP)‑1, GLP‑2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological
actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in
the clinic for the treatment of obesity and type 2 diabetes mellitus.
Dong, C. X. & Brubaker, P Nat. Rev. Gastroenterol. Hepatol. 9, 705–715 (2012); published online 2 October 2012;
. L.
doi:10.1038/nrgastro.2012.185

Introduction
A complex interplay of metabolic, hormonal and neural
factors is required to maintain nutrient homeostasis
under a wide variety of environmental conditions includ
ing, most notably, the daily cycle of feeding and fasting.
Although pancreatic islets, the liver, muscle, adipocytes
and the central nervous system (CNS) are all key players
in this network, the gastrointestinal tract is the first tissue
affected by nutrient ingestion. As dysregulation of nutri
ent homeostasis might be linked to the current epidemics
of obesity and type 2 diabetes mellitus, this Review
focuses on several of the hormones released by the
gastrointestinal tract prior to or during nutrient ingestion
that have key roles in maintaining energy balance.
Many gastrointestinal hormones have now been iden
tified,1 making the gut the largest endocrine organ of the
body; most of these hormones are produced by entero
endocrine cells scattered throughout the gastrointestinal
epithelium. 2 These cells were originally classified as
being either ‘open’ or ‘closed’ to the intestinal lumen on
the basis of the presence or absence of microvilli on the
luminal surface.3 Some enteroendocrine cells are also
directly innervated and/or extend long ‘axonal-like’ pro
cesses into the lamina propria, both of which probably
permit direct interactions with the nervous system.4,5
These findings are consistent with the expression of
multiple entero ndocrine hormone receptors by the
e
Competing interests
C. X. Dong declares no competing interests. P Brubaker
. L.
declares associations with the following companies: Eli Lilly;
Merck, Sharp & Dome; NPS Pharmaceuticals. See the article
online for full details of the relationships.

vagus nerve.6 Open-type enteroendocrine cells seem to
‘sense’ luminal nutrients through multiple mechanisms,
including both classic transporters and membranebound nutrient receptors, through which intracellular
signalling pathways are activated.7 Collectively, these
findings indicate the existence of a highly inter-related
network between luminal nutrients, gut hormones and
the nervous system.
Two enteroendocrine cells have been selected for this
Review on the basis of the demonstrated importance
of their constituent hormones to whole body energy
homeo tasis, as well as on the basis of their actual or
s
potential use in the treatment of the prevalent syndromes
of nutrient dysregulation, obesity and type 2 diabetes
mellitus. These two cells are the proximal X/A-like cell,
which releases ghrelin, and the distal L cell, which pro
duces the proglucagon- erived peptides, glucagon-like
d
peptide (GLP)‑1, GLP‑2 and oxynto odulin, as well as
m
peptide YY (PYY). Of note, although all of these peptides
are also synthesized in the brain, the focus of this Review
is on the gastro ntestinal tract as the major source of
i
these hormones in the peripheral circulation. Finally, the
focus of this Review on these specific peptides does not
discount the key contributions of other gut hormones
to nutrient homeostasis, including glucose-dependent
insulino ropic peptide (GIP) and cholecystokinin.8,9
t
Indeed, develop ental, functional and compensatory
m
relationships between ghrelin, GLP‑1, GLP‑2, PYY, GIP
and cholecystokinin have been reported,8,10,11 indicat
ing that the gastrointestinal hormones function in a
highly integrated fashion to optimize nutrient digestion,
absorption and assimilation.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY
© 2012 Macmillan Publishers Limited. All rights reserved

Department of
Physiology, Medical
Sciences Building,
University of Toronto,
1 King’s College Circle,
Toronto, ON M5S 1A8,
Canada (C. X. Dong,
P. L. Brubaker).
Correspondence to:
P Brubaker
. L.
p.brubaker@utoronto.ca

VOLUME 9 | DECEMBER 2012 | 705

REVIEWS
Key points
■■ Enteroendocrine cells in the gastrointestinal tract produce various hormones
that have essential roles in the maintenance of nutrient homeostasis in both
the fasting and fed states
■■ Ghrelin is an orexigenic peptide released by the proximal X/A-like cells prior to
nutrient ingestion; the enteroendocrine L cells release glucagon-like peptide
(GLP)‑1, GLP‑2, oxyntomodulin and peptide YY (PYY) in response to nutrient
ingestion
■■ GLP‑1 is a key incretin hormone, which also inhibits glucagon release, gastric
emptying and appetite; agents that increase GLP‑1 action are used to treat
type 2 diabetes mellitus
■■ GLP‑2 regulates nutrient absorption by the gastrointestinal tract through
enhancement of intestinal growth, nutrient digestion and transport, as well as
blood flow
■■ The physiologic role of oxyntomodulin remains to be established, but
exogenous administration suppresses food intake; PYY3–36NH2 has an important
role as an anorexigenic gut hormone
■■ Surgically induced alterations in the levels of ghrelin and/or GLP‑1,
oxyntomodulin and PYY improve glycaemic control and induce weight loss;
pharmacological manipulation of these gut hormones might prove beneficial

The X/A-like cell
Ghrelin was first discovered in 1999 as a growthhormone-releasing peptide.12 The following character
istics make ghrelin unique amongst the gut hormones:
first, it is located primarily in the proximal gut; second,
it is produced by both closed-type and open-type entero
endocrine cells; third, it is acylated; fourth, levels are
increased in the fasting state; and fifth, it is orexigenic.
As a consequence, the regulation of ghrelin synthesis,
secretion and biological activities differs markedly from
that of GLP‑1, GLP‑2, oxyntomodulin and PYY.
The rat X/A-like cell (known as the P/D 1 cell in
humans) was identified as the ghrelin-producing cell in
2000, having originally been named ‘X’ for its unknown
hormone product and ‘A-like’ for the morphologic simi
larity of its secretory granules with those of the pancre
atic A cell.13,14 X/A-like cells represent ~20% of the total
number of endocrine cells of the gastric corpus mucosa
in rats, with profoundly reduced cell numbers along the
aboral axis.15 Interestingly, the proximal X/A-like cells
are almost exclusively closed-type enteroendocrine cells,
whereas >60% of the distal X/A-like cells (that is, ileal,
cecal and colonic) are open type.15 Although the func
tional importance of these different cell types remains
unclear, their morphologic characteristics suggest that
these cells might be differentially regulated, such that the
distal, but not the proximal, cells might be responsive to
the presence of nutrients in the intestinal lumen.
Synthesized by post-translational processing of
proghrelin through the actions of prohormone con
vertase (PC) 1/3,16 ghrelin is modified on Ser3 through
covalent linkage to a medium-chain (C8–C10) fatty
acid by ghrelin O‑acyltransferase (GOAT).17 This acyla
tion is required for the activity of ghrelin on the growth
hormone secretagogue receptor, now also known as
the ghrelin receptor (GRLN‑R),12 and is a unique posttranslational modification amongst all of the known
peptide hormones. Hence, GOAT levels determine the
proportion of bioactive ghrelin that is released by the
X/A-like cell.
706 | DECEMBER 2012 | VOLUME 9

Circulating levels of ghrelin increase before a meal in
both rodents and humans, and are suppressed by nutri
ent ingestion (Figure 1).18,19 Given the closed nature of
the proximal X/A-like cell, it has proven difficult to elu
cidate the exact mechanisms regulating ghrelin release in
response to fasting and nutrient ingestion. Nonetheless,
in vivo studies have implicated both sympathetic and
parasympathetic neurons as stimulatory effectors of
the X/A-like cell, as well as hyperglycaemia, insulin and
somato tatin from gastric D cells as inhibitory regulators
s
of ghrelin release.20–24 Studies on primary rodent gastric
X/A-like cell cultures have confirmed the stimulatory
effects of epinephrine and norepinephrine on ghrelin
release.25,26 Furthermore, 1 mM glucose (comparable
to hypo lycaemia) enhanced ghrelin release, whereas
g
5 mM ‘normoglycaemic’ glucose had no effect and 10 mM
glucose inhibited ghrelin release; inhibitory effects of
insulin were also observed but only in the setting of low
or normal glucose levels.25,26 These findings are consistent
with the demonstration that these cells express glucosesensing machinery, including transporters, hexokinases
and the KATP channel, as well as a functional insulin recep
tor/phosphatidylinositol 3 (PI3)-kinase/Akt signalling
pathway.25,26 Hence, the available data suggest that ghrelin
release before a meal is coupled to activation of the sym
pathetic nervous system. Conversely, the prandial suppres
sion of ghrelin secretion is probably mediated, at least in
part, by increasing levels of glucose and/or insulin. Finally,
given the original identification of ghrelin-producing cells
as ‘A-like’ on the basis of their morphological characteris
tics,13,14 it is interesting that the regulation of ghrelin secre
tion by X/A-like cells bears a striking resemblance to that
of pancreatic glucagon by the A cell, which is also stimu
lated by the sympathetic nervous system and inhibited by
high levels of both glucose and insulin.27,28 The finding of
a lineage relationship between pancreatic islet ghrelin and
A cells further suggests that the gastric X/A-like and islet
A cells might also be related,29 although transgenic expres
sion studies have not identified any such link to date.29–31
Nonetheless, these findings suggest that, under both
fasting and fed conditions, ghrelin and glucagon secretion
are coordinated to maintain nutrient homeostasis.
The orexigenic action of ghrelin and the require
ment for the GRLN‑R in nutrient homeostasis has been
demonstrated in rodents and humans using a wide variety
of gain-of-function and loss-of-function approaches, and
is mediated not only by increased food intake, but also
via decreased energy expenditure.32–36 As ghrelin crosses
the blood–brain barrier, related in part to its acylation
status,37 the orexigenic effects of this gut hormone are
thought to be mediated through direct effects on neurons
in the central feeding centre, including those expressing
the orexins.32,38 However, the GRLN‑R is also expressed
by the vagus nerve and, although controversial, one study
has demonstrated that both truncal vagotomy and vagal
afferent ablation can prevent the orexigenic actions of
peripherally administered ghrelin on food intake.39
Studies have also demonstrated that ghrelin has a
role in glucose homeostasis through expression of the
GRLN‑R in pancreatic islets, the liver and, to a much

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REVIEWS
lesser extent, muscle. 40 Consistent with these find
ings, ghrelin has been shown to both inhibit glucose-
stimulated insulin secretion and decrease insulin
sensitivity in normal mice, with improved glucose toler
ance found in knockout animals.34,36 Administration of a
GOAT inhibitor also enhances glucose tolerance in mice,
in a ghrelin- ependent manner.35 However, the glycae
d
mic actions of ghrelin might also be mediated through
its effects as a growth hormone secretagogue, as GOAT
knockout mice subjected to severe caloric restriction
experience lethal hypoglycaemia, even in the setting of
profoundly reduced insulin levels, and ghrelin replace
ment prevents the mortality through increased growth
hormone levels.41 Together, these findings suggest the
existence of a metabolic negative feedback loop that
regulates circulating ghrelin levels, probably through
modulation of blood glucose levels.
Given the important role of ghrelin in stimulat
ing appetite, it is not surprising that ghrelin levels are
decreased in obese individuals, consistent with negative
feedback regulation under conditions of positive energy
balance. 42–44 However, concentrations of circulating
ghrelin are reduced even further by insulin resistance
that is associated with either obesity or type 2 diabe
tes mellitus.43,45 These in vivo data are in keeping with
reports that ghrelin release by primary X/A-like cells
is inhibited by physiological concentrations of insulin
in the setting of low glucose levels,25,26 but not with the
finding that insulin resistance in these cells prevents
insulin-induced suppression of ghrelin.26 Furthermore,
the suppression of endogenous ghrelin levels in all
of these conditions raises the question as to whether
antagonism of the ghrelin system will provide additional
benefit to body weight regulation in any of these condi
tions. Collectively, therefore, it remains to be established
whether manipulation of ghrelin signalling will be of
clinical benefit in conditions characterized by obesity.
No strong link has been found between body weight
dysregulation and polymorphisms in the ghrelin–
GRLN‑R axis.46 However, increased ghrelin levels have
been reported in individuals with anorexia, which sug
gests a role for ghrelin resistance in this condition.47 A
number of clinical trials have now examined the effects
of ghrelin administration in a variety of conditions char
acterized by reduced food intake due to cachexia; to date,
results from these trials have been generally positive.48
Conversely, ghrelin receptor antagonists have been pro
posed for use in obesity,49 with a reduction in body weight
associated with decreased food intake demonstrated in
diet-induced obese mice; enhanced glycaemic control
during an intraperitoneal glucose tolerance test was
also noted in these animals.32 Similar findings have been
reported for a GOAT inhibitor.35 However, results from
clinical trials using either approach are still pending.

The L cell
In contrast to ghrelin, peptides synthesized by the intes
tinal L cell have the following characteristics: first, they
are produced predominantly in the distal small intestine
(that is, the ileum) and colon; second, they are found

Norepinephrine

Glucose

Insulin

IR

β1R

GLUT1/4/5

PI3K

cAMP

Glucokinase or
hexokinase

AKT

??

Low
concentrations
of glucose

High
concentrations
of glucose

PKA
Ghrelin

Figure 1 | The X/A-like cell. Under fasting conditions (for
example, low levels of insulin and glucose), the X/A-like cell
is stimulated by the sympathetic nervous system through
release of norepinephrine and activation of the β1R, which is
known to be coupled to cAMP and PKA signalling. Low
concentrations of glucose also directly stimulate ghrelin
release, at least in vitro. Under fed conditions (for example,
high levels of insulin and glucose), insulin inhibits ghrelin
release through the canonical PI3K/Akt pathway, whereas
glucose inhibits secretion through a pathway that might
involve glucose transporters and glucokinase or hexokinase.
Abbreviations: β1R, β1 adrenergic receptor; GLUT1/4/5,
glucose transporter 1, 4 or 5; IR, insulin receptor; PI3K,
phosphatidylinositol‑3 kinase‑1; PKA, protein kinase A.

only in open-type L cells; third, their levels are increased
by feeding; and fourth, they are anorexigenic.
GLP‑1, GLP‑2 and oxyntomodulin are synthesized by
PC1/3-mediated cleavage of proglucagon, and are cosecreted by the L cell.50–52 Although glicentin and two
intervening peptides are also liberated from proglucagon
in the L cell, no physiological actions have been delin
eated for these hormones and we do not discuss them
further in this Review. The highest density of L cells is
in the distal gut, but they are also localized in the upper
gastro ntestinal tract of rats and humans, although
i
in markedly lower numbers than in the distal gut.53,54
Interestingly, findings have indicated that ~20% percent
of proximal L cells co-express GIP, and 40% express
cholecystokinin.11,55 By contrast, GIP and cholecysto
kinin expression by distal L cells is fairly low, but ~45%
of the ileal and ~70% of the colonic L cells co-express
PYY, the functions of which are described below. 11,55
Furthermore, a study has indicated that the phenotype
of the colonic L cell is altered by abnormal carbohydrate
flux to this tissue, such that the cell increases its capacity
to respond to the presence of these luminal nutrients.56
Compared with proximal L cells, colonic L cells might

NATURE REVIEWS | GASTROENTEROLOGY HEPATOLOGY


REVIEWS

Insulin

Acetylcholine

Leptin

IR

M1R

LR

PI3K

MEK

AKT

ERK1/2

STAT3

GLP1/2
Oxyntomodulin
PYY

Ca2+

PKCζ

PKA/PKC

GPRs

Fatty acids
Oleoylethanoloamide
2-Oleoylglycerol

∆ψ

FATP4

Oleic acid

SGLT1

Glucose Na+

Figure 2 | The L cell. In the fed state, secretion by the L cell
is rapidly stimulated by the vagus, through release of
acetylcholine and activation of M1R. After passage down the
gastrointestinal tract, luminal nutrients then enhance
secretion through a variety of pathways: GPRs for long and
short-chain fatty acids, oleoylethanoloamide and
2‑oleoylglycerol (leading to activation of PKA or PKC); FATP4
for oleic acid (leading to PKCζ signalling); and SGLT1 for
sodium and glucose (resulting in depolarization (Ψ)-induced
calcium signalling). Insulin and leptin also enhance secretion
by the intestinal L cell in a positive-feedback fashion, through
canonical signalling pathways. Abbreviations: ERK1/2,
extracellular signal-regulated kinase 1/2; FATP4, fatty acid
transport protein 4; GLP‑1/2, glucagon-like peptide 1 or 2;
GPRs, G protein-coupled receptors; IR, insulin receptor; LR;
leptin receptor isoform b; M1R, the M1 muscarinic receptor;
MEK, MAPK/ERK kinase; PI3K, phosphatidylinositol‑3
kinase‑1; PKA, protein kinase A; PKC, protein kinase C; PYY,
peptide YY; SGLT1, sodium-glucose transporter 1; STAT3,
signal transducer activator of transcription 3.

also respond preferentially to short-chain fatty acids,57
which is consistent with the high density of gut bacteria
in this organ. The physiological importance of the differ
ences between the proximal and distal L cell populations,
as well as their developmental aetiology, clearly requires
further examination.
Hormone secretion by the L cell is stimulated by nutri
ent ingestion; plasma levels of these hormones exhibit an
early rise followed by a prolonged plateau phase.58 Studies

in rodents have demonstrated that the early L cell response
is mediated indirectly by proximal activation of the vagus
nerve, leading to muscarinic receptor signalling in the
distal L cell; some evidence exists for a similar pathway
in humans (Figure 2).4,59,60 By contrast, the prolonged
secretory phase is triggered by nutrients in the gut lumen
that act directly on ileal and/or colonic L cells through
a variety of mechanisms, including the following: sig
nalling coupled through transporters (for example, for
glucose: sodium–glucose transporter‑1 and, to a lesser
extent, KATP channels, leading to Na+ and K+-induced
depolarization, respectively; and for oleic acid: fatty acid
transport protein 4 and atypical protein kinase C‑ζ);7,61–65
or G‑protein-coupled receptor signalling (for example, for
short-chain fatty acids: GRP40 and GRP43; for long-chain
fatty acids: GPR40 and GPR120; for oleoylethanol mide
a
and 2‑oleoylglycerol: GPR119; and for glucose: sweet taste
receptors). The bile acid receptor, TGR5, is also expressed
by the distal L cell.56,57,66–70 Thus, luminal nutrient compo
sition has a key role in the stimulation of L cell secretion,
with diets enriched in oleic acid, for example, increasing
hormone release to a greater extent than diets high in
saturated fatty acids.71,72 Although L cell secretion is also
known to be modulated by a number of hormones and
neuropeptides (for example, cholecysto inin, gastrink
releasing peptide, GIP, insulin, leptin and somatostatin),73
the physiological role of many of these factors and how
their actions are coupled to nutrient ingestion remain to
be fully elucidated. Finally, just as the X/A-like cell shares
many regulatory features with the pancreatic A cell, so too
is hormone secretion by the L cell similar to that of islet
β cells, particularly with respect to the pathways regulating
glucose and fatty acid responses.74 Not only is hormone
secretion by the gut and pancreatic islets thereby coor
dinated in the fed state, but many of these pathways are
currently under investigation as coordinated L and β‑cell
secretagogues, as discussed in more detail below.
Both insulin and leptin also serve as GLP‑1 secreta
gogues, with the effects of insulin seeming to form
a positive feedback loop between the L cell and islet
β cell.75,76 The concomitant findings that conditions of
leptin and insulin resistance impair the L cell response to
oral glucose are consistent with reports of reduced GLP‑1
levels in individuals with obesity and insulin resistance
and/or type 2 diabetes mellitus, respectively,77–79 and indi
cate that, like the X/A-like cell, the L cell is dysregulated
by perturbations in nutrient homeostasis.
Once released into the circulation, GLP‑1 and GLP‑2
are cleaved by dipeptidylpeptidase 4 (DPP‑4), render
ing short bioactive half-lives of ~1–2 min and ~7 min,
respectively. 53,80,81 Oxyntomodulin has intermediate
susceptibility to degradation by DPP‑4, at least in vitro,
and a DPP‑4-resistant analogue has been reported to
demon trate enhanced bioactivity compared with the
s
native peptide in vivo.82,83 In the case of both GLP‑1 and
GLP‑2, the cleavage product serves as a partial agonist or
antagonist at the respective receptor,84,85 although trun
cated GLP‑1 also seems to mediate some of the cardio
protective actions of GLP‑1 through a yet-to-be-identified
receptor.86 Finally, PYY is also degraded by DPP‑4,87,88


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with the half-lives of both PYY1–36NH2 and PYY3–36NH2 being
~13 min,89 but, in contrast to the inactivation of GLP‑1,
GLP‑2 and oxynto odulin, DPP‑4-mediated cleavage of
m
PYY is actually required for its biological activity at the
Y2 receptor.90 Thus, the truncated peptide, PYY3–36NH2,
mediates the effects of PYY as a satiety factor.87
Together, therefore, GLP‑1, GLP‑2, oxyntomodulin
and PYY are all released by the intestinal L cell. However,
these L cell hormones have distinct profiles of biological
actions, which ultimately integrate at the level of whole
body nutrient homeostasis.

GLP‑1
As a result of the widespread distribution of the GLP‑1
receptor, in both peripheral tissues and the CNS,91–93 cir
culating GLP‑1 exerts a diverse array of effects on nutrient
homeostasis. The major biological actions of GLP‑1 are
antidiabetic, and are most notably exerted through the
pancreatic β cell. Hence, GLP‑1 is an incretin that enhances
glucose-dependent insulin secretion, as well as stimulat
ing insulin biosynthesis and, in rodents, promoting β‑cell
proliferation while inhibiting apoptosis.94,95 GLP‑1 also
inhibits release of glucagon by pancreatic α cells, delays
nutrient absorption through inhibition of gastric emptying
and intestinal motility, and enhances insulin sensitivity at
the level of both the liver and peripheral tissues—although
the majority of its effects on glycaemia seem to be medi
ated through changes in islet hormone secretion.96 The
beneficial effects of circulating endogenous and exogenous
GLP‑1 or its analogues on regulation of glucose have also
been confirmed in studies using both antagonist and
receptor knockout approaches.97,98 However, peripherally
administered GLP‑1 and its analogues also have anorexi
genic actions, inducing satiety and inhibiting food intake
in normal and obese rodents and humans, as well as in
patients with type 2 diabetes mellitus.99–102
As a consequence of the reported biological actions
of GLP‑1, several long-acting, DPP‑4-resistant GLP‑1based drugs have now been licensed for clinical use in the
treatment of type 2 diabetes mellitus, the major effects
of which are a reduction in haemoglobin A1c (HbA1c, a
glycated haemoglobin) levels in association with weight
loss.103 Of note, although GLP‑1R agonists do induce
weight loss in overweight and obese individuals with
and without type 2 diabetes mellitus, the overall effect
is fairly modest, averaging 2.9 kg.104 However, a GLP‑1–
glucagon co-agonist that takes advantage of the inhibi
tory effects of GLP‑1 on food intake and the stimulatory
effects of glucagon on energy expenditure, while at the
same time balancing the hypoglycaemic and hyper
glycaemic effects of the two peptides, respectively, indi
cates that novel approaches to the use of GLP‑1 could
optimize its use in obesity. 105 Conversely, although
DPP‑4 inhibitors are used clinically to increase circulat
ing levels of endo enous GLP‑1, as well as of the other
g
major incretin, GIP, in patients with type 2 diabetes mel
litus,103 the use of these agents is associated with reduced
levels of HbA1c but not weight loss, the latter possibly
owing to concomitantly reduced production of bioactive
PYY3–36NH2, as discussed above. An alternative approach

to the use of GLP‑1 in the treatment of patients with
type 2 diabetes mellitus and/or obesity is enhancement
of endogenous GLP‑1 secretion by activation of novel
L cell secretory pathways and, in particular, those medi
ating the responses to fatty acids, including GPR40 and
GPR119.74,106 Such agents would have the advantage of
concomitantly increasing the release of all of the L cell
hormones, of which oxynto odulin and PYY3–36NH2 are
m
also anorexigenic (discussed in more detail below).
Although GLP‑1 is released into the circulation as a
hormone, its short half-life suggests that at least some of its
physiological actions might be mediated indirectly, prob
ably through the GLP‑1R expressed on afferent neurons.
Hence, despite the well-established direct effects of GLP‑1
on β cells in vitro,107,108 the in vivo actions of GLP‑1 to
stimulate insulin release have been reported to require
afferent neurons.92 Indeed, GLP‑1 increases vagal afferent
firing in rats.109 However, in direct comparative studies,
the requirement for sensory afferents in the actions of
GLP‑1 on both insulin release and food intake in mice
was observed at low, but not high, doses of GLP‑1.110,111
Whether some of the anorexigenic actions of GLP‑1 are
also mediated via suppression of gastric emptying remains
unclear.112 Nonetheless, these findings collectively suggest
that the physiological effects of endogenously secreted
GLP‑1, which includes the actions of GLP‑1 in patients
treated with DPP‑4 inhibitors, are mediated indirectly by
local effects of GLP‑1 on its receptor expressed by gastro
intestinal and/or vagal afferent neurons.113 By contrast, the
pharmacologic actions of GLP‑1 and long-acting GLP‑1R
agonists seem to be exerted, at least in part, through direct
effects on the GLP‑1R in β cells and the brain.
Genetic studies have demonstrated that poly
morphisms in the voltage-gated K + channel gene,
KCNQ1, are associated with reduced secretion of GLP‑1,
whereas variants in the genes for the GLP‑1R, the β‑cell
transcription factor, TCF7L2, and the neuroendocrine
transmembrane protein, Wolfram syndrome 1, lead to
reduced GLP‑1-stimulated insulin release.114–117 Hence,
inter ndividual differences in GLP‑1 release or func
i
tion might be linked to alterations in the effectiveness of
DPP‑4 inhibitors and GLP‑1R agonists, respectively, in
patients with type 2 diabetes mellitus, a notion that has
yet to be rigorously assessed.

GLP‑2
In contrast to GLP‑1, the actions of GLP‑2 are more
restricted owing to the highly concentrated expression of
the GLP‑2R in the gastrointestinal tract; these receptors
are expressed in only a few other tissues, including the
vagus nerve and brain.118,119 GLP‑2 is, therefore, known
foremost for its effects in the gastrointestinal tract. Both
GLP‑2 and its degradation-resistant analogues increase
small and large intestinal weight, crypt-villus height
and mucosal surface area through stimulation of crypt
cell proliferation and inhibition of epithelial cell apop
tosis.120–122 GLP‑2 also enhances nutrient absorption
through various actions, including increasing expression
of digestive enzymes and nutrient transporters, as well as
stimulating intestinal blood flow.120–122 Of note, although



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GLP‑2 also inhibits gastric emptying, these effects are
minor compared with the actions of GLP‑1 on gastric
emptying.123 Furthermore, in a wide variety of animal
models of intestinal damage and insufficiency, GLP‑2
exerts protective effects on the gastrointestinal epithelium
by reducing inflammation and increasing barrier func
tion, as well as by preventing and repairing damage.124–127
However, in contrast to the profound pharmacological
actions of GLP‑2, the role of the endogenous hormone
seems to be more limited, with only a small or no reduc
tion in bowel size noted upon administration of a GLP‑2R
antagonist and in GLP‑2R null mice.128,129 Nonetheless,
endogenous GLP‑2 is required for the intestinal adaptive
responses to nutrient ingestion after a prolonged fast, as
well as for protection from chemically induced enteri
tis.85,130 Importantly, the majority of the major findings
on GLP‑2 in rodent models have also been confirmed in
humans, most notably in patients with intestinal insuffi
ciency owing to short bowel syndrome or damage associ
ated with Crohn’s disease.131,132 Clinical trials are ongoing,
and a long-acting analogue of GLP‑2 has been approved in
Europe for use in patients with short bowel syndrome.133
Despite extensive characterization of the effects of
GLP‑2, the mechanistic basis of the action of GLP‑2 is only
poorly understood. The GLP‑2R is not localized to the
major site of action of GLP‑2 (that is, intestinal epithelial
cells) but rather it is localized to the intestinal subepithelial
myofibroblasts, enteric nervous system and diffuse entero
endocrine cells;122 the actions of GLP‑2 must therefore be
exerted indirectly by the release of paracrine factors from
these cells. Downstream players that have been identified
to date include: insulin-like growth factor (IGF)‑1 and
IGF‑2, and the ErbB network for crypt cell proliferation in
the small and large intestine;130,134–136 keratinocyte growth
factor, for large bowel growth;137 vasoactive intestinal poly
peptide, for anti-inflammatory actions in the small and
large intestine;138 and endothelial nitric oxide synthase, for
intestinal blood flow.139 Finally, and again in contrast to
the actions of GLP‑1, the known effects of GLP‑2 do not
seem to be mediated through afferent pathways, as activa
tion of this receptor is not linked to any change in vagal
firing, and centrally administered but not peripherally
administered GLP‑2 inhibits food intake.109,140,141

Oxyntomodulin
Although oxyntomodulin was originally named for its
inhibitory effects on gastric acid secretion,142 these actions
are relatively weak compared with those exerted by other
gut peptides, such as somatostatin.143 Hence, the biologi
cal role of oxyntomodulin remained somewhat uncer
tain until ~10 years ago, when it was reported to inhibit
food intake in both rats and humans when administered
exogenously.144,145 Indeed, a number of studies have now
demonstrated that repeated peripheral administration
of either oxyntomodulin or its long-acting analogues
induces weight loss in obese rats, mice and humans, with
this effect being mediated through both suppression of
food intake and increased energy expenditure.146–148
Interestingly, early studies on oxyntomodulin and
gastric acid secretion suggested the existence of a receptor

for this hormone through which glucagon might also
act, although with less potency.142 Although no specific
oxyntomodulin receptor has been identified to date, this
hormone has been established to be an agonist for both
the GLP‑1R and the glucagon receptor. Hence, oxynto
modulin has EC50s (half maximal effective concentra
tions) for the GLP‑1R and glucagon receptor that are
approximately 100-fold and 10-fold greater than those
of GLP‑1 and glucagon, respectively.144,149,150 Consistent
with these findings, the actions of oxyntomodulin on the
gastric glands are now known to be mediated through
GLP‑1R, as are the effects of peripheral oxyntomodulin
to suppress food intake.151,152 However, the stimulatory
effect of oxyntomodulin on energy expenditure might
also be dependent upon the glucagon receptor, as this
is also a well-established effect of glucagon.153,154 Hence,
not only DPP‑4-resistant analogues of oxyntomodulin,
but also dual GLP‑1R/glucagon receptor oxyntomodulin
analogues have been developed as possible thera eutic
p
agents for the treatment of obesity. 83,148,155 Notably,
oxyntomodulin also improves glycaemic control, through
GLP‑1R-dependent increase of glucose-stimulated insulin
secretion.156 Although this effect might be expected to be
counter-balanced by oxyntomodulin-induced activation
of the glucagon receptor, the available data suggest that
the anti-hyperglycaemic effects of oxyntomodulin prevail
in the setting of dual receptor activation.153 Furthermore,
the mechanism of action of oxyntomodulin also implies
that polymorphisms in either the GLP-1R, the glucagon
receptor and/or their signalling pathways might influence
the effectiveness of these drugs.115–117,157
Finally, the cellular pathway(s) by which oxynto
modulin inhibits food intake are thought to include
both the CNS and the vagus nerve. Peripheral admin
istration of oxynto odulin activates a variety of central
m
nuclei involved in feeding, including the arcuate nucleus
that abuts areas of the hypothalamus characterized by
a leaky blood–brain barrier.150,152 Oxyntomodulin also
stimulates release of the anorexigenic neuropeptide,
α‑melanocyte-stimulating hormone, from hypothalamic
explants in vitro, which is consistent with possible direct
effects on central feeding centers.152 However, activation
of the nucleus of the solitary tract by peripheral oxynto
modulin is also in keeping with a role for vagal sensing
of this hormone.150 Although studies of oxyntomodulin
actions on food intake following vagal disruption have
yet to be conducted, the inhibitory actions of oxynto
modulin on pancreatic exocrine secretion are abrogated
in vagotomised rats, which indicates that signalling can
occur through this peripheral neural pathway.158

PYY
Which prohormone convertase cleaves proPYY to
PYY1–36NH2 is not known, although it is presumed to be
PC1/3 owing to the known actions of this enzyme on pro
glucagon in the intestinal L cell.50 PYY1–36NH2 was first iden
tified as a gut peptide with tyrosine (‘Y’) at its N‑terminal
and C‑terminal ends, and was initially characterized as
an inhibitor of both pancreatic exocrine secretion and
intestinal motility.159,160 However, although PYY1–36NH2


REVIEWS
binds to multiple receptors of the neuropeptide Y recep
tor (YR) family, its cleavage by DPP‑4 in the circula
tion converts it to a Y2-receptor-selective agonist.87,90
Thus, compared with both full-length PYY 1–36NH2
and neuropeptide Y, which stimulate food intake through
the Y1R and possibly the Y5R, the Y2R-selectivity of
PYY3–36NH2 and its agonists enables suppression of food
intake through inhibition of neuropeptide Y release in the
arcuate nucleus, while Y2R specific antagonists prevent
the anorexigenic actions of PYY3–36NH2.161–164 Consistent
with these findings, initial studies in mice have suggested
that the actions of PYY3–36NH2 are not mediated by periph
eral sensory afferent nerves such as the vagus.111 However,
in the rat, the Y2R is expressed by the vagus nerve, and
peripherally administered PYY3–36NH2 stimulates gastric
vagal afferent firing, while vagotomy prevents the anorexi
genic actions of PYY3–36NH2.165 Thus, the mechanism of
action of PYY3–36NH2 might exhibit species- pecific dif
s
ferences. Alternatively, as the Y2R expressed by rat vagal
afferent neurons is regulated by cholecystokinin in a nutri
ent-dependent manner,166 experimental differences could
also account for these apparent discrepancies.
Although great interest was generated by the first
reports of the anorexigenic actions of PYY3–36NH2 in
rodents as well as normal-weight and obese humans,163,167
these findings have been the subject of some controversy
in the literature, with both confirmatory and negative
findings reported.111,168,169 The reason for these discrepant
findings remains elusive. Nonetheless, both a rare PYY
mutation and Y2R variants have been linked to altera
tions in body weight in humans.170–172 Hence, long-acting
PYY3–36NH2 analogues, as well as Y2R agonists, are cur
rently under development for the treatment of obesity,
and many clinical trials are ongoing.

Combined effects
Although the L cell hormones are co-secreted, few studies
have examined the combined effects of simultaneous
increased levels of these hormones. With respect to feed
back suppression of food intake, additive and/or syner
gistic effects of PYY3–36NH2 with oxyntomodulin, as well
as of PYY3–36NH2 with GLP‑1 or its analogues have been
reported.111,173–175 Furthermore, PYY3–36NH2 and GLP‑1 also
have additive effects to delay gastric emptying.176 Finally,
GLP‑1 and GLP‑2 do not demonstrate additive effects
to suppress food intake,177 but do exert opposing effects
on glucagon release, with the inhibitory effect of GLP‑1
predominating.178 No studies to date have examined the
physiological consequences of increasing the levels of all
four of these hormones, or of their effects when given in
combination with all of the other gut hormones released
by nutrient intake. Such investigations will clearly be nec
essary to fully understand the integrated contribution of
the L cell to nutrient homeostasis, particularly if L cell
secretagogues are to be used for the treatment of type 2
diabetes mellitus and/or obesity, as discussed above.

Clinical relevance
Two successful, surgical treatments for obesity—Rouxen‑Y gastric bypass (RYGB) and sleeve gastrectomy—also

improve or reverse the symptoms of type 2 diabetes mel
litus. RYGB markedly reduces the size of the stomach
and diverts ingested nutrients and pancreato-biliary flow
directly to the distal small intestine, whereas sleeve gas
trectomy introduces gastric restriction only.179 Despite
the differences between these surgical interventions,
the results of clinical trials indicate that both proce
dures result in equivalent improvements in glycaemic
control and identical weight loss 1 year after surgery.180,181
Remarkably, the reductions in glucose levels occur
rapidly after surgery, often prior to the changes in body
weight.182 The success of RYGB for both resolution of
type 2 diabetes mellitus and weight loss has largely been
attributed to an increase in the release of peptides from
the L cells, with the effects to reduce ghrelin release being
controversial.181,183–187 The concomitant diversion of bile
flow to the distal small intestine might also contribute to
the increase in L cell secretion following RYGB through
activation of the L cell bile acid receptor, TGR5.69 Indeed,
a study has demonstrated that enhanced release of GLP‑1
following gastric bypass in obese rats is responsible for
the weight-loss-independent improvement in glucose
tolerance associated with this procedure.188 By contrast,
sleeve gastrectomy has been reported to cause greater
decreases in ghrelin levels and increased cholecystokinin
release than found with RYGB, in addition to increasing
L cell secretion.181 Thus, although differing somewhat in
their mechanisms of action, RYGB and sleeve gastrec
tomy are unique approaches that manipulate the physio
logical actions of the gut hormones to regulate nutrient
homeostasis through their combined effects on gut
nutrient handling, glucose tolerance and food intake.

Conclusion
This Review has focused on the hormones produced
by the enteroendocrine X/A-like cell (ghrelin) and the
L cell (GLP‑1, GLP‑2, oxyntomodulin and PYY). These
peptides have key roles in the integration of food intake
with metabolism, as well as providing feedback signals to
the brain to induce satiety during feeding. However, it is
recognized that the gastrointestinal tract releases many
other hormones that also have important roles in nutri
ent homeostasis including, most notably, GIP and chol
ecystokinin. Elucidation of the combined actions of all of
these hormones will be essential to develop a comprehen
sive understanding of the integrative role that the gastro
intestinal tract has in maintaining nutrient homeostasis
during fasting and in response to feeding.

Review criteria
PubMed was searched for full-length articles using the
keywords “ghrelin”, “GLP‑1”, “GLP‑2”, “oxyntomodulin”,
“enteroglucagon” and “PYY”, alone and in combination
with key author names and/or the keywords “secretion”,
“food intake”, “obesity”, “insulin resistance”, “type 2
diabetes” and/or “review”; review articles were used to
further search for original papers. All years were included
in the search. Articles published in languages other than
English were excluded from the analysis.



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Acknowledgements
C. X. Dong is supported by a graduate studentship
from the Banting and Best Diabetes Centre, University
of Toronto, Canada. P Brubaker is supported by the
. L.
Canada Research Chairs program. Studies on GLP‑1
and GLP‑2 in the Brubaker laboratory are supported
by operating grants from the Canadian Diabetes
Association (#2374) and the Canadian Institutes of
Health Research (#MOP‑9940), respectively.
Author contributions
Both authors contributed equally to all aspects of the
manuscript.


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