Review

Special Issue: Neuroendocrine control of appetite

Glucagon-like peptide 1 and appetite

Megan J. Dailey and Timothy H. Moran
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Glucagon-like peptide 1 (GLP-1) and GLP-1 analogs have

received much recent attention due to the success of
GLP-1 mimetics in treating type II diabetes mellitus
(T2DM), but these compounds may also have the potential to treat obesity. The satiety effect of GLP-1 may
involve both within-meal enteroenteric reflexes, and
across-meal central signaling mechanisms, that mediate
changes in appetite and promote satiety. Here, we
review data supporting the role of both peripheral and
central GLP-1 signaling in the control of gastrointestinal
motility and food intake. Understanding the mechanisms underlying the appetite-suppressive effects of
GLP-1 may help in developing targeted treatments for
obesity.
Introduction
GLP-1 has been the focus of much research because of the
success of GLP-1 mimetics in treating T2DM, acting as
incretins (see Glossary) in the pancreas. It is becoming
clear that GLP-1 may also have potential for the treatment
of obesity. GLP-1 and its synthetic analogs, exendin 4 (Ex
4) and liraglutide, are potent inhibitors of food intake in
both animal models and human subjects. Thus, understanding the mechanisms underlying the appetite suppressive effects of GLP-1 may help in developing targeted
treatments for obesity.
GLP-1 biology and physiological properties
GLP-1 is derived from the gene encoding proglucagon,
which in the gastrointestinal tract and brain is post-translationally modified and cleaved into the biologically active
forms, GLP-1 (736) amide and GLP-1 (737) [1]. The
major circulating bioactive species in humans is the truncated form GLP-1 (736) amide [2]. The hormone has been
identified as playing a prominent role in glucose homeostasis, gastrointestinal motility, and appetite, and also
plays additional roles beyond ingestive behaviors [35].
GLP-1 is secreted from mucosal endocrine L cells of the
intestine in response to intraluminal nutrients, but nonnutrient-driven increases in GLP-1 also have been
reported such as cephalic [6] and meal anticipatory
increases [7]. With regard to nutrients, there are two peaks
in GLP-1 secretion that are seen in response to a meal in
humans [8]. The first peak appears within 15 min after
meal initiation, and even before nutrients can access the L
cells lower in the intestine. This rapid rise in GLP-1 levels
appears to involve a neuroendocrine loop where nutrients
Corresponding author: Dailey, M.J. (mdailey5@jhmi.edi).
Keywords: GLP-1; appetite; gastrointestinal motility; food intake.

in the stomach or proximal intestine stimulate the release

of hormones, such as gastric inhibitory peptide [9] and
gastrin-releasing peptide [10], that act through vagal pathways to stimulate L cells to secrete GLP-1 [11] (Figure 1e).
The enteric nervous system may contribute to this early
GLP-1 rise after a meal [11] (Figure 1b). The second peak
occurs later, is larger, and is thought to derive from direct
nutrient contact with intestinal L cells. Thus, nutrients
within the gastrointestinal tract have the ability to stimulate GLP-1 directly and indirectly through hormonal and
neural mechanisms.
GLP-1 is also expressed by neurons within the nucleus of
the solitary tract of the brainstem (NTS) and is released from
terminals across a variety of brain areas, including hypothalamic nuclei and hippocampal and cortical sites [12].
Central GLP-1 appears to be an important link in the
downstream mediation of anorexia produced by a number
of factors. Stimulation of the endogenous caudal brainstem
Glossary
Colonic transit: the time it takes a substance to enter the colon and move
completely through the colon to be excreted.
Dipeptidyl peptidase IV (DPP-IV): an enzyme that degrades incretins such as
GLP-1 and thus plays a major role in glucose metabolism. A new class of oral
hypoglycemics (DPP-IV inhibitors) act by inhibiting the action of this enzyme,
thereby prolonging incretin effect in vivo.
Exenatide: a GLP-1-like agonist used for the treatment of T2DM. It belongs to
the group of incretin mimetics. Exenatide enhances glucose-dependent insulin
secretion by pancreatic b cells, suppresses glucagon secretion, and slows
gastric emptying.
Exendin-4 (Ex-4): a hormone found in the saliva of the venomous lizard Gila
monster. Ex-4, similar to GLP-1, regulates glucose metabolism and insulin
secretion.
Evoked activity: brain activity that is the result of a task, sensory input, or
motor output. It is the opposite of spontaneous brain activity that takes place in
the absence of any explicit task.
Glucagon-like peptide-1 (GLP-1): a gut hormone secreted from intestinal L cell
and that is generated by selective cleavage of proglucagon. The biologically
active forms of GLP-1 are GLP-1-(737) and GLP-1-(736) amide.
Glucagon-like peptide 1 receptor (GLP1R): G protein-coupled receptor that
binds specifically GLP1. GLP1R is expressed in pancreatic b cells and in the
brain where it is involved in the control of appetite. Activated GLP1R stimulates
adenylyl cyclase resulting in increased insulin synthesis and release. Therefore, GLP1R has been suggested as a potential target for the treatment of
diabetes.
Ileal brake: the primary inhibitory feedback mechanism to control transit of a
meal through the gastrointestinal tract. It helps optimize nutrient digestion and
absorption.
Incretins: a group of gastrointestinal hormones that increase insulin release
from pancreatic b cells after eating, even before blood glucose levels rise. They
also inhibit glucagon release from pancreatic a cells. Incretins slow the rate of
absorption of nutrients into the bloodstream by reducing gastric emptying, and
may directly reduce food intake.
Liraglutide: a long-acting GLP-1-like agonist and anti-diabetic medication.
Peristalsis: a radially symmetrical contraction and relaxation of muscles, which
propagates in a wave down the muscular tube, in an anterograde fashion. In
humans, peristalsis in the contraction of smooth muscles propels contents
through the digestive tract.
Secretagogue: a substance that causes another substance to be secreted.

1043-2760/$ see front matter 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2012.11.008 Trends in Endocrinology and Metabolism, February 2013, Vol. 24, No. 2

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Review

Trends in Endocrinology and Metabolism February 2013, Vol. 24, No. 2

(a)

(b)

(c)

(d)

(e)

GLP-1
GLP-1

GLP-1

GLP-1

-IV

Mucosae

DPP

To lymph
To hepac
portal vein

Ach
Secretomotor neuron
Sensory
neurons

GRP+
neuron
Ach
Eector neuron

Interneuron
Eector neuron

Vagal primary aerent bers

Muscularis mucosae
Submucosal nerve plexus

Circular muscle layer

Myenteric nerve plexus

Longitudinal muscle layer

Submucosae

Muscularis
externa

Parasympathec
bers
TRENDS in Endocrinology & Metabolism

Figure 1. GLP-1 action in the gut. (a) GLP-1 released from the L cells diffuses into the lamina propria and enters the lymph or capillaries. DPP-IV is expressed in the
capillaries and can immediately begin to degrade GLP-1 even before it reaches the hepatic portal vein. GLP-1 released from the L cell can mediate changes in the
submucosal (b) and myenteric nerves (c). (d) GLP-1 can have a direct effect on vagal primary afferents. (e) Luminal nutrients in the proximal GI tract may stimulate distal
GLP-1 secretion through an enteroendocrine loop that involves vagal and enteric neural connections. Hormones released from the stomach or proximal intestine stimulate
vagal pathways that synapse onto GRP neurons in the myenteric plexus to cause downstream stimulation of GLP-1 fom the L cell in the mucosal epithelium. Ach,
acetylcholine; DPP-IV, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; GRP, gastrin-releasing peptide.

GLP-1 activity has been implicated in mediating the anorexic effect of lipopolysacharide (LPS [13,14]), lithium chloride
(LiCl [14,15]), cholecystokinin (CCK [14]), leptin [16], and
oxytocin [17]. Many of these factors administered to rodents
at doses that decrease food intake are found to increase c-fos
expression in GLP-1 neurons [14], and the anorexic effects
are attenuated or eliminated by central injection of a GLP-1
receptor (GLP-1R) antagonist [13,15,17]. The central GLP-1
pathway involved in reducing appetite may involve some of
the same neural circuits known to be involved in ingestive
behaviors because GLP-1 fibers are found within these
brain sites [12] and GLP-1 actively binds to receptors in
these same areas [18,19]. However, there appears to be a
mismatch between the density of GLP-1 nerve fibers and
GLP-1 receptors. There are few GLP-1 nerve fibers present
in some brain nuclei where GLP-1 binding is high [12], a
finding that suggests a role for peripheral GLP-1 in central
GLP-1 receptor activation.
The GLP-1 receptor
The actions of GLP-1 are mediated by the activation of a
GLP-1 receptor (GLP-1R). GLP-1R is a G protein-coupled
receptor that is expressed throughout the periphery (i.e.,
enteric nerves, vagal nerves, pancreas, stomach, small and
large intestine, and adipose tissue [2022]) and brain (i.e.,
caudal brainstem and hypothalamic, hippocampal, and
86

cortical nuclei [12,23]). It is still not completely clear if

peripheral GLP-1 acts locally to alter gastrointestinal
motility and appetite, or if GLP-1 can directly activate
brain GLP-1R to modulate these functions/behaviors. Endogenous GLP-1 released from the L cells diffuses into the
lamina propria and enters the lymph or capillaries [24]
(Figure 1a). Once GLP-1 enters the capillaries, it is rapidly
degraded by dipeptidyl peptidase IV (DPP-IV), an enzyme
expressed on the capillary walls [25] and throughout the
body [26,27]. It has been estimated that only 25% of the
absorbed GLP-1 reaches the liver through the hepatic
portal vein [26]. It is possible, nevertheless, that GLP-1
could act on GLP-1R on vagal afferents in the lamina
propria, or on enteric nerves in the intestinal wall, before
entering the capillaries [22,28] (Figure 1bd). It also may
be possible that greater and longer increases in GLP-1
could saturate the available DPP-IV and allow more GLP-1
to enter into general circulation. This idea is supported by
an accumulation of evidence showing that mRNA expression or blood levels of DPP-IV are altered under a variety of
conditions and, thus, could be a mechanism by which
greater GLP-1R stimulation could occur throughout the
body [2931]. If GLP-1 survives degradation by DPP-IV, it
is possible that it could activate central GLP-1R, because
circulating GLP-1 appears to pass the bloodbrain barrier
by simple diffusion to circumventricular organs [32] and

Review
elsewhere [33]. As mentioned above, peripheral GLP-1
activation of central receptors appears likely because
few GLP-1 nerve fibers are present in feeding-related brain
nuclei, such as the arcuate nucleus [12], where GLP-1
binding is high [18,19]. It has also been suggested that
there are regional differences in DPP-IV present in rat
cerebral capillaries that could account for more precise
control of brain access of peripherally derived GLP-1 [33].
GLP-1 and gastrointestinal motor functions
One mechanism by which GLP-1 can alter appetite is
through changes in gastrointestinal function. GLP-1
decreases gastric emptying and intestinal motility
[34,35] and contributes to the ileal break [36], an inhibitory
feedback mechanism that functions to optimize nutrient
digestion and absorption. GLP-1 appears to affect gastrointestinal motor functions through both peripheral and
central nervous system mechanisms. Vagus-mediated
pathways have been shown to participate in the attenuation of gastric motility and emptying induced by GLP-1 in
non-human animal models [37,38] and in intestinal motility in humans [34]. Interactions with brain GLP-1R may
also contribute to these changes because intracerebroventricular (icv) injection of GLP-1 inhibits gastric emptying
through non-cholinergic and non-adrenergic pathways in
rats [37]. A third and more direct route of GLP-1-mediated
changes in motor function can occur through GLP-1R
activation in enteric neurons in the gastrointestinal wall.
GLP-1R immunoreactivity is present on myenteric neurons and on a few submucosal neurons of the duodenum
and proximal colon in mice [28]. In mouse intestinal
explants, the hormone was found to inhibit intestinal
motility through direct interaction and activation of
GLP-1R in enteric neurons [28]. More specifically, GLP-1
appears to inhibit evoked activity (provided by electrical
field stimulation on parallel sides of intestinal segments
from mice) in the circular muscle of the intestine by
modulating parasympathetic cholinergic input presynaptically [28]. GLP-1 administered intra-arterially in an ex
vivo canine preparation also inhibits evoked activity of the
circular muscle, and this response is blocked by a GLP-1
receptor antagonist, exendin-9 (Ex 9) [39]. Conversely,
GLP-1 does not affect spontaneous circular muscle activity
or evoked or spontaneous activity in the longitudinal muscle [28,40]. Taken together, these results suggest that
GLP-1 may modulate neural input to the circular, but
not the longitudinal, muscle layer and are consistent with
the notion that circular-muscle layer contraction is dominant in peristalsis. These results also show that GLP-1
may only inhibit evoked, but not spontaneous, neural
action on motility. This finding may provide insight into
the mechanisms underlying the ability of GLP-1 to inhibit
gastrointestinal function in normal, but not vagotomized,
patients [41]. Much of the neural stimulation of the gut
wall is provided by the parasympathetic fibers of the vagus
nerve, and severing this connection would block electrical
stimulation of the circular muscle of the intestine. Because
the role of GLP-1 appears to be to modulate cholinergic
stimulation of the circular muscle, an attenuated response
to GLP-1 in vagotomized human patients would be
expected.

Trends in Endocrinology and Metabolism February 2013, Vol. 24, No. 2

In contrast to the inhibitory effect of GLP-1 in the

stomach and small intestine, GLP-1 increases colonic transit, and this effect may be mediated through a central mode
of action [42,43]. Indeed, icv, but not intraperitoneal (ip),
injections of GLP-1 dose-dependently accelerate colonic
transit [44]. The central GLP-1 effect on colonic transit
was attenuated by methods that blocked the parasympathetic nervous system, such as vagotomy, use of the competitive antagonist for the muscarinic acetylcholine
receptor atropine, or the ganglionic blocker hexamethonium, but not by sympathetic nervous system blockade (i.e.,
guanethidine) [44]. Cholinergic stimulation enhances colonic motor activity and transit in humans [45]; thus, GLP1 may act within the dorsal motor nucleus of the vagus to
mediate changes in the parasympathetic innervation to
alter motor contractions in the colon.
GLP-1 and satiety
Peripheral action of GLP-1 in reducing food intake
GLP-1 decreases food intake after peripheral (ip) [46],
intravenous (iv) [4749], or central (icv) administration
[50,51], but the relative roles of peripheral and central
GLP-1R in the actions of endogenous intestinal GLP-1
remain to be clarified. The story is complicated by the fact
that many of the studies investigating the action of GLP-1
use ip or iv administration of the GLP-1 synthetic analogs
Ex 4 or liraglutide, which escape the degradation of DPPIV and are able to cross the bloodbrain barrier [47,52].
Thus, the effectiveness of these GLP-1R agonists may
depend in part on an enhanced ability to access additional
GLP-1R, compared with endogenously released or exogenously administered GLP-1. There is some evidence, however, to support a peripheral action of GLP-1 in reducing
food intake. For example, central administration of the
GLP-1R antagonist Ex 9 is not able to block the decreases
in food intake produced after peripheral administration of
GLP-1, but is able to block decreases in food intake after
central injection of GLP-1 [53]. Ex 9 administered peripherally is also able to block decreases in food intake after a
nutrient preload and a peripheral GLP-1 injection [53].
These data suggest that the satiety actions of intestinally
derived GLP-1 are through peripheral receptors.
It is not clear where in the periphery GLP-1 may be
acting to decrease appetite. The rapid degradation of GLP1 that occurs soon after release into the capillaries of the
intestinal wall supports the notion that GLP-1 may act
locally on enteric or vagal neurons. The results from studies using varying routes of administration of GLP-1 do not
clearly support this idea, though. The decreases in food
intake after ip GLP-1 in rats [54] or Ex-4 in mice [55] are
attenuated by complete sub-diaphragmatic vagotomy or by
capsaicin administration (a procedure that lesions sensory
nerves), respectively. When GLP-1 is infused in rats at the
onset of the first spontaneous dark-phase meal (a model
that may mimic the initial meal-induced secretion of GLP1 from the intestine), decreases in food intake occurred
after hepatic portal vein (HPV), vena cava (vc), and ip
infusions of GLP-1 [56]. Sub-diaphragmatic vagal deafferentation attenuates the decrease in food intake after
ip GLP-1 infusion, but not after HPV GLP-1 infusions [56].
Moreover, the effect of iv infusion of GLP-1 to reduce
87

Review
sucrose intake was not abolished by capsaicin treatment or
vagotomy [57]. Thus, the satiating effect of ip, but not of
HPV or iv GLP-1, requires vagal afferent signaling. The
different findings with different routes of administration
suggest that in each case GLP-1 could be binding to
different GLP-1R populations, even though each can produce a decrease in food intake after administration. It is
possible that only ip, and not HPV, vc, or iv, infusion of
GLP-1 may be able to access the GLP-1R on enteric or
vagal nerves of intestinal origin that are normally and
immediately accessible to endogenous GLP-1 released
from intestinal L cells. HPV, vc, and iv infusions of
GLP-1 could mimic endogenous circulating GLP-1 if
enough GLP-1 is able to escape degradation by DPP-IV
in the capillaries of the intestine and enter the HPV and
systemic circulation, at each step encountering more
DPP-IV. Thus, precisely where in the periphery GLP-1
acts to inhibit feeding behavior remains unresolved. A
study to investigate whether local administration of Ex
9 in the intestinal wall increases food intake would prove
useful in defining the role of local GLP-1R.
Central action of GLP-1 in reducing food intake
Central mechanisms are certainly important in mediating
the satiety actions of both peripheral and central GLP-1.
Even if peripheral GLP-1 acts locally on enteric or vagal
neurons, the downstream neural or hormonal responses
must activate many brain circuits to affect food intake. For
example, lesions of the projections from the brainstem to
the hypothalamus reduce the appetite suppression mediated by peripheral GLP-1 in rats [54]. Even though peripheral and central GLP-1 utilize brain mechanisms to inhibit
feeding, some differing neural substrates appear to be
involved. Both peripheral and central injections of GLP1 induce c-fos in the paraventricular nucleus of hypothalamus (PVN), but only central and not peripheral GLP-1
injection induces c-fos in the Arc [58], suggesting differential mechanisms underlying the ability of central versus
peripheral GLP-1 in decreasing appetite.
Central injections of GLP-1 inhibit food intake [50,51],
and this central effect does not require the presence of food
in the stomach or an inhibition of gastric emptying [59].
The caudal brainstem appears to be sufficient to mediate
GLP-1-induced decreases in food intake. Ip or 4th ventricular Ex-4 are still able to decrease intake in chronic
supracollicular decerebrate rats [60]. Only 4th ventricular
injection of Ex-9, and not forebrain injection with aqueduct
occlusion, blocked the decreases in food intake induced by
LPS administration [13]. Moreover, 4th ventricular injection of Ex-9 prior to 4th ventricular leptin administration
attenuates the inhibitory effect of leptin. Coadministration
of Ex-4 and leptin into the 4th ventricle suppresses food
intake in an additive manner [16]. Within the brainstem,
leptin receptors are exclusively expressed within the medial NTS, and the medial NTS has been suggested as the
main site of action for GLP-1 [16,61]. This would mean that
the central endogenous GLP-1 produced exclusively in the
NTS might act on GLP-1R within the same nuclei. Such a
local feedback loop may play defined roles in satiety, but
this is only part of an integrated process that also involves
forebrain processing.
88

Trends in Endocrinology and Metabolism February 2013, Vol. 24, No. 2

Endogenous brainstem GLP-1 and feeding control

A role of endogenous brainstem GLP-1 in overall feeding
control is supported by data showing that knockdown of the
proglucagon gene in the NTS using RNA interference
results in hyperphagia and weight gain [62]. NTS GLP-1
neurons project widely throughout the brain and, thus, this
food-intake and body-weight response could be mediated
by multiple neural circuits. Sandoval et al. [63] have
demonstrated that GLP-1 administration into the Arc
affected glucose metabolism and insulin release, whereas
PVN GLP-1 reduced food intake. Many others, though,
have provided evidence that the Arc does play a role in
GLP-1 mediated anorexic effects. This discrepancy may
result from differences in the methods for manipulating
GLP-1 signaling in the Arc, and whether GLP-1 targets
both orexigenic and anorexigenic neurons or can differentiate between the two.
Arc orexigenic and anorexigenic neurons are known to
respond to many ingestive signals, including GLP-1. Receptors for GLP-1 are present on the orexigenic neuropeptide Y/
agouti-related peptide (NPY/AgRP) neurons, and the anorexigenic proopiomelanocortin (POMC) neurons, and icv
injections of GLP-1 induce c-fos immunoreactivity within
the Arc [64]. Seo et al. [65] found that icv injection of GLP-1
at doses that decrease fasting induces feeding, attenuates
fasting-induced increases in NPY and AgRP mRNA levels,
and decreases POMC and CART mRNA levels. In the Arc,
fasting-induced increases in AMP-activated kinase a2
(AMPKa2) mRNA levels and the phosphorylation of
AMPKa and acetyl-CoA carboxylase (ACC) are also attenuated by icv GLP-1 [65]. These data suggest that NTS-GLP-1
projections to the Arc could mediate satiety by affecting both
orexigenic and anorexigenic signaling. Further data, however, have suggested that GLP-1 actions are mediated
through the anorexigenic component and not the orexigenic.
Icv injections of GLP-1 in fasted or ad libitum fed rats did not
alter Arc NPY expression levels [50]. Ex-4 administration
also failed to alter hypothalamic NPY gene expression [66].
In addition, responses to central GLP-1 remain after NPY/
AgRP neurons are destroyed by lesions induced by saporin, a
ribosome-inactivating toxin, conjugated to NPY (NPYSAP)
[67]. Although GLP-1 may not directly decrease Arc NPY
mRNA levels to induce satiety, GLP-1R signaling may still
affect NPY signaling. If GLP-1R is blocked by icv administration of Ex-9 before to icv injection of NPY, there is a
significant increase in food intake beyond that with NPY
alone [50]. Along these lines, the contribution of POMC
neurons in producing anorexia under a variety of stimuli
has been well documented and involves POMC projections
to other brain sites expressing melanocortin receptors.
POMC neurons project to the NTS [68], where GLP-1-producing cells are located, and may be a component of a
forebrainbrainstem circuit in which a variety of signals
interact with GLP-1 signaling. Arc POMC cells also project
to melanocortin receptor-expressing cells within the PVN
[68], suggesting a circuit where GLP-1 may indirectly affect
PVN-mediated decreases in food intake.
There are direct, reciprocal neural connections between
the PVN and NTS which allow an additional integration
of anorexic signals with GLP-1 signaling [68]. GLP-1producing neurons of the NTS have strong projections to

Review
GLP-1R-expressing cell bodies in the PVN [14], and central
GLP-1 activates oxytocin (OT) and corticotrophin releasing
hormone (CRH) neurons within the PVN [64]. OT neurons
express GLP-1R, and the anorexigenic effect of OT is
eliminated in rats injected in the 3rd ventricle with
GLP-1R antagonist, but an OT antagonist does not block
the anorexigenic effect of GLP-1 [17]. This suggests that
NTS GLP-1-producing cells may act through OT GLP1R-positive cells to alter OT cell signaling or OT release.
GLP-1 also activates the hypothamicpituitaryadrenal
(HPA) axis through CRH neurons [69], and GLP-1-positive
nerve terminals densely innervate CRH neurons [70].
Thus, GLP-1-mediated decreases in food intake may be
at least partially mediated by activation of the stress axis.
CRH neuronal activity is essential for LPS-induced
decreases in food intake and may utilize this additional
hypothalamicbrainstem circuit to activate NTS GLP-1
neurons [71]. Thus, the satiety effects of GLP-1 may be
mediated by both hypothalamic Arc and PVH connections
to the brainstem.
GLP-1 neurons in the NTS also project directly to the
ventral tegmental area (VTA) [72] and nucleus accumbens
[37] core and shell [72,73], nuclei involved with food reward
that have also been demonstrated to express GLP-1R.
GLP-1 or Ex-4 injected into the VTA or NAc core decrease
food intake of rats on chow, high-fat diet, or sucrose solution [72,73]. Dissimilar effects of GLP-1 are found in the
NAc core versus the shell. Ex-4 injected into the NAc shell
was also able to decrease high-fat food intake, but Ex-4 and
GLP-1 at this site had no effect on intake of chow or sucrose
solution [72,73]. In each case where there was a decrease in
food intake with agonist administration, a GLP-1 antagonist was able to induce an increase in chow, high-fat diet, or
sucrose solution intake. These data suggest a role for
endogenous GLP-1R in the VTA and NAc in mediating
satiety, and that this effect may be due to modifying
reward signaling.
GLP-1 and conditioned taste aversion
A concern about the specificity of the feeding-inhibitory
actions of GLP-1 has arisen due to the idea that the
decreases in food intake after treatment with GLP-1, or
a synthetic analog, are attributable to visceral illness or
feelings of nausea [74]. GLP-1 is able to induce a conditioned taste aversion (CTA) under a variety of conditions,
but the satiety and CTA effects appear to be nuclei-specific
[74]. Lateral and 4th ventricle injections of GLP-1 in rats
decreased food intake similarly, but only lateral ventricle
GLP-1 injections produced CTA [75]. Furthermore, direct
injections of GLP-1 into the PVN decrease food intake
without a CTA [76]. By contrast, the typical CTA response
after LiCl administration is attenuated by bilateral injections of a GLP-1R antagonist into the central nucleus of the
amygdala [29,75]. These data suggest that the illness
response to GLP-1 may be dependent on discrete receptors
outside the brainstem or PVN.
GLP-1 and control of meal size
A final issue is whether endogenously released GLP-1
works as a within-meal or across-meal stimulus for reducing food intake. The decreases in food intake that are

Trends in Endocrinology and Metabolism February 2013, Vol. 24, No. 2

typically elicited by GLP-1 (or Ex-4) are attributed to

decreases in meal size, not meal number [48,53,56,77].
Ruttimann [56] and others have shown that GLP-1 works
within a meal if administered during a first meal, and
decreases meal size of that first meal without affecting
intermeal interval or total food intake. In line with these
results, Ex-4 decreased meal size over a 6 h daily feeding
period in non-human primates [77]. Chelikani et al. [48]
reported that 3 h intrajugular infusions of GLP-1 reduced
meal frequency in addition to meal size, but the reduction
in meal size came before meal frequency. However, they
further demonstrated that feeding remained reduced following the termination of the GLP-1 infusion, suggesting
lasting effects on subsequent meals. Thus, investigations
into the role of endogenous GLP-1 in the control of meal
size have produced mixed results. This may relate to the
timing of antagonist administration relative to the initiation of food intake.
The release and effects of GLP-1 may involve withinmeal enteroenteric reflexes and across-meal central signaling to mediate changes in appetite. The timing and
levels of GLP-1 may signal the type of nutrients, the
amount of food, and/or timing of ingestion, and the body
may receive this information based on which central or
peripheral receptors are activated. Additional knowledge
on the modes and mechanisms of action of GLP-1-induced
reductions in food intake may contribute to the development of obesity treatments targeting GLP-1 signaling.
Concluding remarks
We have concentrated on reviewing the actions of endogenous GLP-1 on appetite in an attempt to understand its
normal physiological role. Certainly the GLP-1 analogs
that escape degradation by DPP-IV are effective at decreasing appetite, but the high incidence of side effects
reported in patients taking these analogs raises concerns
about their utility for treating obesity. The GLP-1 analogs
appear to activate additional mechanisms that are not
utilized by endogenous GLP-1. GLP-1 and the synthetic
analogs share a similar mode and binding affinity to the
human GLP-1R, thus it seems likely that the side effects
are caused by greater GLP-1R stimulation from the longlasting GLP-1 analogs [78]. Understanding which GLP-1R
populations are stimulated under endogenous GLP-1-induced decreases in appetite may help in designing effective
obesity drugs without the negative side effects.
Acknowledgments
The drawing is courtesy of Alexander A. Moghadam.

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