Physiology & Behavior 92 (2007) 256 – 262
Review
Appetite signaling: From gut peptides and enteric nerves to brain
Erik Näslund a , Per M. Hellström b,⁎
a
b
Karolinska Institutet, Division of Surgery, Danderyd Hospital, S-182 88 Stockholm, Sweden
Karolinska Institutet, Department of Gastroenterology and Hepatology, Karolinska University Hospital, S-171 76 Stockholm, Sweden
Abstract
The signaling systems underlying eating behavior control are complex. The current review focuses on gastrointestinal (GI) signaling systems as
physiological key functions for metabolic control. Many of the peptides that are involved in the regulation of food intake in the brain are also
found in the enteric nervous system and enteroendocrine cells of the mucosa of the GI tract. The only identified hunger-driving signal from the GI
tract is ghrelin, which is mainly found in the mucosa of the stomach. Neuropeptides in the brain that influence food intake, of which neuropeptide
Y, agouti gene-related peptide and orexins are stimulatory, while melanocortins and α-melanocortin stimulating hormone are inhibitory, are
influenced by peptide signaling from the gut. These effects may take place directly through action of gut peptide in the brain or through nervous
signaling from the periphery to the brain. The criteria for considering a gut hormone or neurotransmitter in a satiety signal seem to be fulfilled for
cholecystokinin, glucagon-like peptide-1 and peptide YY(3-36). Other endogenous gut signals do not fulfill these criteria as they do not increase
food intake in knock-out animals or in response to receptor antagonism, or display an inconsistent temporal profile with satiety and termination of
the meal. Satiety signals from the GI tract act through the arcuate nucleus of the hypothalamus and the solitary tract nucleus of the brain stem,
where neuronal networks directly linked to hypothalamic centers for food intake and eating behavior are activated. We have primarily focused on
GI effects of various gut peptides involved in the regulation of food intake, using motor activity as a biomarker for the understanding of gut
peptide effects promoting satiety.
© 2007 Elsevier Inc. All rights reserved.
Keywords: Gastric emptying; Gastrointestinal; Hunger; Satiety; Peptides; Food intake
Contents
1.
2.
Introduction . . . . . . . . . . . . . . .
Gastrointestinal signaling . . . . . . . .
2.1. Hunger signal and meal initiation
2.2. Satiety signals . . . . . . . . . .
3. Signaling in obesity . . . . . . . . . . .
3.1. Central nervous system. . . . . .
3.2. Enteric nervous system . . . . . .
4. Discussion . . . . . . . . . . . . . . . .
5. Concluding remarks . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author. Tel.: +46 8 51773877; fax: +46 8 51771100.
E-mail address: [email protected] (P.M. Hellström).
0031-9384/$ - see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.physbeh.2007.05.017
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E. Näslund, P.M. Hellström / Physiology & Behavior 92 (2007) 256–262
1. Introduction
Energy balance is a metabolic state that exists when total
body expenditure equals dietary energy intake. Normally,
energy balance is very well regulated both in the short- and
long-term. However, in some individuals there is an imbalance
between energy intake and energy expenditure resulting in
weight gain and, ultimately, obesity. Early research on obesity
concentrated almost exclusively on hypothalamic control of
food intake, where the maximum daily intake of food was
determined by some limiting factor in addition to hypothalamic
mechanisms [1]. Today it is recognized that short-term control
of food intake involves not only the central nervous system
(CNS), but also the adrenals, pancreas as well as gastrointestinal
(GI) tract. Furthermore, adipose tissue has been found to play an
important role in the long-term regulation of food intake by
producing several endocrine and paracrine mediators, including
leptin, adiponectin, resistin and tumour necrosis factor-α, which
are known to influence food intake. Our understanding of
factors regulating food intake has increased greatly during the
last decade, partly as a result of the discovery of leptin [2]. That
the study not only demonstrated that our fat stores can signal
energy reserves to the CNS, but also spawned an increased
interest in the field of appetite regulation. The resulting research
has improved our knowledge of the signals underlying energy
balance. The aim of this review is to further broaden the view of
peripheral regulation of food intake by describing the influence
of different gut peptides on appetite.
2. Gastrointestinal signaling
Many GI peptide hormones are connected to different foodrelated gastric and intestinal signals [3]. Distention of the
stomach activates gastric stretch receptors and mechanoreceptors that transmit satiety signals to the brain [4]. The stomach
also serves as a food reservoir, which ultimately delimits eating.
257
However, this does not happen physiologically and a meal is
usually terminated long before such stretch sensors are
activated. This points in favor of some, yet undefined, metabolic
signal contributing in the cessation of a meal. Even though the
specific relationships between such gastric signals and release
of GI peptides in relation to hunger and satiety have not been
clearly identified, recent research on gut peptide hormones has
shed some light on the importance of the GI tract in regulation
of food intake (Fig. 1).
2.1. Hunger signal and meal initiation
Today the only GI peptide hormone with confirmed orexigenic
properties is ghrelin [5]. Ghrelin, is a ligand for the growth
hormone secretagogue receptor, and is produced mainly in the
stomach (Fig. 1). When administered both centrally and
peripherally it stimulates appetite and increases food intake in
animals [6] and man [7]. Plasma ghrelin peaks before a regular
meal, then decreases to progressively increase to another peak just
before the next meal suggesting that ghrelin may be a meal
initiator [8]. Ghrelin also seems to play a role in long-term regulation of energy balance as chronic administration of ghrelin in
rodents results in hyperphagia and weight gain independent of
growth hormone [6]. The effects of ghrelin on eating behavior are
mediated via the arcuate nucleus and the solitary tract nucleus to
merge in the hypothalamus. There is also data suggesting that
ghrelin partly exerts its effect through vagal afferent loops [9].
There, ghrelin opposes the actions of leptin through disinhibition
of second line neuropeptides such as neuropeptide Y (NPY) and
agouti gene-related peptide (AgRP) [10]. Circulating levels of
ghrelin are lower in obese than in normal-weight individuals [11],
and negatively correlated with body mass index [12]. The increase
in ghrelin during starvation boosts eating behavior and the low
levels of ghrelin in obesity may be a secondary response to overeating [11]. Indeed, ghrelin is negatively correlated with percentage body fat, fasting insulin, and fasting leptin, all of which
Fig. 1. Afferent gastrointestinal signals controlling food intake. CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; PYY(3-36), peptide YY(3-36); NPY,
neuropeptide Y; AgRP, Agouti gene-related peptide; α-MSH, α-melanocyte stimulating hormone; POMC, pro-opiomelanocortin; NTS, nucleus tractus solitarius;
ARC, arcuate nucleus.
258
E. Näslund, P.M. Hellström / Physiology & Behavior 92 (2007) 256–262
are elevated in obesity [11,12], indicating a regulatory role for
ghrelin and the upper GI tract in control of food intake.
Like many of the peptides involved in the regulation of food
intake ghrelin also influences GI motility. In rats, intravenous
ghrelin increases fasting motility [13] and increases the rate of
gastric emptying [14]. There are ghrelin receptors in the gut,
which most likely mediate these effects of ghrelin on gut
function [15]. These data, in addition to those demonstrating
inhibitory effects of many gut peptides involved in satiety
responses demonstrate a link between motor function in the gut
and appetite regulation.
2.2. Satiety signals
Amongst the GI peptide hormones several are known to be
anorexigenic, mainly cholecystokinin (CCK), glucagon-like
peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)), which
all are recognized as physiologic regulators of food intake
(Fig. 1). CCK is the most studied gut peptide regulating control
of food intake, and research on CCK has been widely reviewed
[16]. After food intake, CCK is released into the circulation
from endocrine I-cells of the duodenum and the jejunum [17].
Studies in several species, including humans have shown that
CCK inhibits food intake [18,19], although a concurrent gastric
preload is necessary to achieve a normal satiety effect with CCK
in both obese and lean subjects [20]. Peripherally administered
CCK also acts on CCK1 (previously CCKA) receptors in the
gastric antrum, known to be involved in the CCK-mediated
inhibition of gastric emptying [21]. Hence, CCK1 receptors are
found in the abdominal part of the vagus nerve [22] and vagotomy
eradicates the satiating effect of this peptide in rats. A relationship
between decreased plasma levels of CCK, increased hunger and
decreased fullness has also been reported in man [23], speaking in
favor of CCK as a true physiological mediator of satiety.
GLP-1 and glucagon-like peptide-2 (GLP-2) are produced and
secreted from endocrine L-cells in the mucosa of the ileum and
colon. After a meal, both peptides are released in equimolar
amounts to the blood stream [24,25]. GLP-1 is a major contributor
to the ileal brake mechanism of the upper GI tract, thereby
modulating gastric emptying and acid secretion [26]. GLP-1 also
exerts dual actions in regulation of blood glucose concentrations
through its concurrent insulinotropic and glucagonostatic actions
[27]. Since GLP-1 slows gastric emptying of both liquid and solid
meals [26,28], the metabolic requirements for insulin after food
intake are reduced [29]. Accumulating evidence indicates that
GLP-1 exerts its effects on GI functions through the vagus nerve
both in animals and man [29–33].
After a meal GLP-1 also brings dual actions on feeding
behavior and satiety into play: intracerebroventricular (ICV)
injections of GLP-1 in rats inhibit food and water intake [34–
36] and induce c-fos expression in the paraventricular nucleus
of the hypothalamus [36]. ICV administration of the GLP-1
receptor antagonist exendin(9-39)amide also results in increased food intake in satiated, but not in fasted, rats [36]. With
continuous ICV infusion exendin(9-39)amide rats not only
increase their food intake, but also their body weight [37].
However, no effects were seen with intraperitoneal injections,
suggesting central mechanisms to be involved in the satiety
action of GLP-1. Furthermore, GLP-1 release in obese subjects
has been found to be lower in obese than lean subjects [38–40].
In humans, studies invariably report decreased food intake with
ratings of reduced hunger and increased fullness following
infusion of GLP-1, including studies in normal weight, diabetic
and obese participants [41–48].
In contrast to GLP-1, the role of GLP-2 in the regulation of
food intake is unclear. GLP-2 is primarily known to exert
trophic effects on the intestinal mucosa [49], which may lead to
advances in the treatment of short bowel syndrome [50].
However, gastric emptying studies including ratings of satiety
have failed to verify any effect of GLP-2 in appetite control in
man [51], and peripheral administration of GLP-2 did not
influence appetite and ad libitum food intake [52].
A third peptide from the pre-proglucagon gene has recently
been implicated in regulating food intake in obese subjects.
Oxyntomodulin (OXM), which is released from intestinal Lcells in response to food ingestion has been shown to reduce
food intake. Subcutaneous injections of OXM over 4 weeks
significantly reduced food intake and resulted in an additional
0.45 kg per week weight loss compared to a control group [53].
The truncated form of PYY, PYY(3-36), is released after a
meal from the GI tract and induces satiety [54]. The effect of
PYY(3-36) has been suggested to have a longer duration of
action than other GI satiety peptides. Animal studies show that
PYY(3-36) exerts its effect as a Y2-receptor agonist, thereby
suppressing NPY-induced hunger in the arcuate nucleus of the
hypothalamus. In analogy to GLP-1, PYY concentrations in
plasma after a meal have recently been shown to be lower in obese
than lean subjects [55], which should reinforce the argument for
PYY(3-36) as a mediator of satiety. However, as pointed out
above, this property seems not to be specific but rather a common
feature of the obese (cf. GLP-1); due to weak signaling from the
gut inhibitory mechanisms on food intake. PYY(3-36) has also
been shown to decrease food intake in rodents [54]; however,
there is an ongoing debate regarding this, as other independent
researchers have been unable to reproduce these results [56]. In
analogy with other GI peptides involved in regulating food intake
PYY also inhibits fasting small bowel motility [57] and gastric
emptying [58] and there are suggestions that the anorectic effects
of PYY(3-36) may be the result of nausea (Thelin, Näslund and
Hellström, unpublished).
Very recently a second peptide has been isolated from the
proghrelin gene. This peptide of 23 amino acids binds to the
orphan G protein-coupled receptor GPR39 and has been named
obestatin. Obestatin has been reported to suppress food intake,
jejunal contractions in vitro and gastric emptying in vivo in mice
[59]. However, as judged from work by our group and others the
role of obestatin as a regulator of motility and appetite can be
questioned. Further work is needed to characterize obestatin in
detail, as well as its effects and relationship to ghrelin.
3. Signaling in obesity
Obese subjects in general have a larger than normal gastric
capacity [60,61] (Fig. 2). The volume not only seems to be
E. Näslund, P.M. Hellström / Physiology & Behavior 92 (2007) 256–262
259
PYY(3-36) may mediate satiety sensations by acting directly
on Y2 receptors in the arcuate nucleus of the hypothalamus [55].
The effect of PYY(3-36) on gastrointestinal motility is largely
unknown and it would be of interest to see whether PYY(3-36)
affects the gastric emptying profile in lean as well as in obese
subjects as a possible peripheral mechanism of action.
3.1. Central nervous system
Fig. 2. The relationship between intragastric pressure in obese (n = 16) and
normal-weight subjects (n = 11) given as mean values. Volume range and
intragastric pressure causing satiety indicated for normal and obese. After
Granström and Backman [60].
important for satiety signaling but also intragastric pressure
[60]. Delayed gastric emptying, due to gastric distension, is
generally associated with greater satiety, but also diminished
intestinal satiety signaling to the brain. Thus, gastric emptying
may be delayed and the secretion of CCK reduced and hence
satiety blunted. This, in turn may contribute to the development
of obesity [62].
Further evidence for the importance of gastric capacity is the
notion that dieting reduces capacity [63] and surgical reduction
of the stomach reduces meal-size and induces weight loss [64].
Delayed gastric emptying due to gastric distension is generally
associated with greater satiety, but also diminishes intestinal
satiety signaling to the brain, such as intestinal release of CCK
[65] which satiating effect might be reduced leading to obesity.
As mentioned previously, plasma levels of both GLP-1 and
PYY are attenuated in the obese after a meal [38–40]. These
attenuated plasma levels of GLP-1 and PYY may result in weak
GLP-1 and PYY cues in the obese, which may promote an earlier
onset of the next meal and thus contribute to the development of
obesity. In favor for this supposition, we have demonstrated that
treatment with prandial subcutaneous injections of GLP-1 over a
five-day period in obese subjects resulted in decreased gastric
emptying along with a modest weight loss [66].
The arcuate nucleus in the hypothalamus seems to be
dominant for the inflow of peripheral signals mediating information on metabolic storage and needs, while the nucleus
tractus solitarius in the brain stem is the main entry port for
signals from the GI tract (Fig. 1).
There are two different populations of cells in the arcuate
nucleus, which control food intake in opposite ways. One of
these cell populations contains NPY, which is the most powerful stimulator of feeding behavior known so far [67]. The
other cell population contains pro-opiomelanocortin (POMC)
which is split into α-melanocyte stimulating hormone (α-MSH)
that inhibits eating by acting on melanocortin receptors [68].
There is an inhibitory cross-talk between the two neuropeptide
systems, with NPY neurons promoting not only hunger sensations, but also inhibiting satiety feelings by inhibition of the
feeding-suppressive α-MSH system [69,70]. Peptide hormone
receptors are located on both these two cell populations, which
are regulated by leptin and insulin, which inhibit NPYcontaining neurons and stimulate POMC-containing neurons.
Interestingly, PYY(3-36) is considered the natural ligand for
presynaptic Y2 receptors, thus inhibiting NPY release in the
brain [54].
In the lateral hypothalamus, brain cells targeted by NPY- and
POMC-immunoreactive neurons regularly contain the two
orexigenic peptides, orexin A (OXA) and orexin B [71]. In
contrast, GLP-1 is found in the solitary tract and in the dorsal
and ventral medullary reticular nucleus, which corresponds to
brain stem regions that collect vagal input from the gut [72].
GLP-1-immunoreactive nerve fibers are also found in the
paraventricular nucleus of the hypothalamus, projecting further to hunger centers in the lateral hypothalamus and periventricular areas [72–74].
Fig. 3. Immunohistochemical illustrations of orexin A immunoreactive nerve fibers surrounding neurons in a myenteric plexus from the small intestine of a rat (arrow, A)
and projecting in a villus from human small bowel (arrow, B).
260
E. Näslund, P.M. Hellström / Physiology & Behavior 92 (2007) 256–262
3.2. Enteric nervous system
Many of the peptides found in enteroendocrine cells of the
mucosa of the GI tract and in central centers regulating food
intake are also found in the enteric nervous system (ENS) and
vagal afferent nerve fibers. An example of this is that neurons in
the GI submucosal and myenteric plexuses, and endocrine cells
in the intestinal mucosa and pancreatic islets display OXA as
well as orexin receptor immunoreactivity [75,76] (Fig. 3). OXA
inhibits GI motility and modulates both insulin and glucagon
release in the rat, [77,78].
Plasma concentrations of OXA are increased during fasting
[79], and orexin-positive neurons in the gut, like those in the
hypothalamus, are activated by fasting, indicating a functional
response not only in the brain, but also in the GI tract [75]. It is
possible, that vagal or sympathetic afferent fibers may be
activated in the ENS relaying information to the CNS regarding
peripheral metabolic tone. In line with this, orexin receptors are
found on vagal afferent neurons in both rat and man, and may be
of importance for an OXA-dependent inhibition of vagal satiety
responses to CCK [80]. Intravenous administration of OXA to
man does not influence appetite ratings, however plasma concentrations of leptin decrease during a 180-min infusion of
OXA in man suggesting a gut-fat mass cross-talk which may
influence long-term energy balance (unpublished data).
The peripheral and central vagus systems sense mechanical
distension and chemical stimulation by different nutrients. These
signals do not only affect the sensory nerve fibers directly, but are
also released in the form of hormones to the blood stream, as is the
case with CCK and GLP-1. The endocrine effects of these
peptides are likely to be mediated through the vagus nerve. In the
vagus, the satiating effects of CCK are mediated by the CCK1
receptor [81,82], while the effects of GLP-1 are mediated through
its distinct receptor. Impulses from these receptors in the GI tract
are further conveyed to the brain stem and specifically to the
nucleus tractus solitarius thus relaying signals from the GI tract. In
general terms, the brain stem is activated by CCK and GLP-1
through the afferent vagus nerve as nutrients releasing these
hormones are delivered to the intestines.
4. Discussion
Our review emphasizes the peripheral signaling systems of the
GI tract that underlie the intestinal control of ingestion and
development of obesity. As it seems today the short-term control
of ingestion is primarily controlled by signaling pathways
emanating from the GI tract, being relayed through the nucleus
tractus solitarius in the brain stem with further branching to higher
centers of the CNS. This implies regulatory brain centers of
hunger and satiety in the hypothalamus such as the arcuate
nucleus, as well as other higher brain centers of reward, such as
the ventral tegmental area. The long-term control of ingestion,
however, is more complicated as it seems that the primary signaling emanates from peripheral tissues, mainly adipose tissue,
which is to be considered as an endocrine organ releasing leptin
and among others, adiponectin and resistin, to the bloodstream in
order to achieve a balanced basal metabolic performance.
The initial discovery of CCK actions in the 70s, as well as
later findings with GLP-1 and PYY(3-36) during the last decade
is an important step in our understanding of endocrine control of
satiety. Research with GLP-1 and PYY today suggests the
importance of gastric and intestinal signaling to the brain in the
regulation of hunger, satiety and eating behavior. Treatment
with GLP-1 in over-weight subjects reduced their appetite and
daily intake leading to weight control [43,44,66]. Furthermore,
infusion of PYY(3-36) decreased appetite and reduced daily
food intake [54] in normal, as well as obese subjects [55]. This
is in contrast to other satiety-stimulating peptide hormones
such as CCK, where the latency period to the next meal was
shortened and therefore the daily intake was unchanged. In spite
of this, CCK may be beneficial in a therapeutic setting if combined with other physiological signals since its CCK1 receptor
is of major importance for satiety sensations. However, just to
indicate how complex these mechanisms are a recent publication indicated that the combination of GLP-1 and CCK did not
result in an increased satiety response in human subjects [83].
After food intake a whole array of peptides are released and the
most effective combination needs to be elucidated in future
studies. Recent studies of e.g., ghrelin have increased our understanding of the endocrine control of hunger and it is hoped
that future research on the interactions between GI peptides and
of the ENS and the CNS in the control of eating behavior will
increase our understanding of the development of obesity as
well. Future research needs to focus on interactions between GI
peptides, the ENS and CNS in the control of eating behavior and
development of obesity.
5. Concluding remarks
Regulation of food intake seems to involve dual mechanisms.
The short-term control of hunger and satiety ultimately leading to
meal taking is primarily governed by gut-derived signaling to the
brain, and of which ghrelin is stimulatory, whereas GLP-1 and
PYY are inhibitory. The long-term control is of metabolic origin
where the endocrine action of adipose tissue comes into focus,
with peptide hormones such as leptin, are released in the periphery
to act on centers in the brain regulating appetite and metabolic
control.
Acknowledgements
The present article was supported by the Swedish Research
Council and Karolinska Institutet.
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