GASTROENTEROLOGY 2005;128:175–191
SPECIAL REPORTS AND REVIEWS
Gastrointestinal Hormones and Food Intake
APRIL D. STRADER and STEPHEN C. WOODS
University of Cincinnati Medical Center, Genome Research Institute, Cincinnati, Ohio
Despite dramatic fluctuations in calorie intake, animals
maintain a very stable body weight. The reason is that
energy intake and expenditure are precisely matched.
Long-term regulation of energy balance is dependent on
the coordination and interpretation of signals such as
those given by insulin and leptin indicating sufficient
long-term energy stores as well as short-term, mealrelated signals such as those given by cholecystokinin
(CCK). Within the last 30 years, our knowledge of shortterm signals has increased dramatically. Throughout the
cephalo-caudal axis of the gastrointestinal system, discrete enteroendocrine cells respond to both mechanical
and chemical stimulation. Meal-associated hormone release is dependent on the concentration and composition of the nutrients ingested. Released signals are
transmitted neurally through vagal afferents or humorally as circulating ligands for specific receptor populations in the periphery and central nervous system. These
signals are interpreted by the CNS and manifested as a
behavioral modification of feeding. This review will
present past and recent literature in support of gut
hormones and their roles as mediators of satiety. Evidence from pharmacologic and physiologic studies involving both humans and rodents will be presented,
along with a short section outlining the knowledge
gained through the use of murine knockout models.
Last, the contribution of satiety hormones as likely mediators of the effectiveness seen following obesity surgery will be reviewed. Although traditionally thought of
as short-term, meal-related signals, enhanced, chronic
hormone secretion and signaling resulting from gut reconstruction as seen with gastric bypass surgery most
likely contributes to the superior efficacy of surgery as a
treatment for obesity.
he central nervous system (CNS) receives information from the periphery relevant to an individual’s
energy balance through metabolic, neural, and endocrine
signals. The CNS in turn is able to integrate accurately
and interpret these signals and subsequently direct information to controllers of energy intake and expenditure, including sending signals to numerous organs in
the periphery, with the net outcome of these processes
T
enabling the individual to maintain energy homeostasis
over long periods of time. The long-term regulation of
energy homeostasis and maintenance of a stable body
weight are achieved through effective integration of signals indicating body fat stores, such as those given by
insulin and leptin, with signals indicating immediately
available energy as well as with signals indicating what
is available from recently ingested food in the gastrointestinal tract.1-3 These short-term, meal-related signals,
such as those given by cholecystokinin (CCK), are effective in maintaining appropriate meal size such that the
daily regulation of energy intake is well coordinated with
energy usage and long-term body weight.4,5
Gastrointestinal Signals
Contributing to Energy
Homeostasis
Dozens of hormonal and paracrine signals are
known to be secreted from endocrine cells lining the
gastrointestinal (GI) tract in response to the physicochemical properties of ingested food passing along the
lumen. The term “hormone” was coined by Bayliss and
Starling in 1902 when they isolated secretin from duodenal mucosa and observed that it stimulated pancreatic
exocrine secretion.6 Two additional gastrointestinal hormones (gastrin7 and CCK8) were subsequently discovered
and characterized, but it was not until the 1970s that
significant progress in gastrointestinal endocrinology occurred, with over 40 novel hormones being discovered.
Over the ensuing years came the important finding that
many GI hormones are also expressed in the central
nervous system (CNS)9 and that many of these are important signals that relay metabolic information between
the GI tract and the brain.5,10-13
Gastrointestinal signals that influence the brain to
stop an ongoing meal are collectively called satiety sigAbbreviations used in this paper: GLP-1, glucagon-like peptide-1;
PYY, peptide tyrosine-tyrosine.
© 2005 by the American Gastroenterological Association
0016-5085/05/$30.00
doi:10.1053/j.gastro.2004.10.043
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STRADER AND WOODS
Figure 1. The mucous membrane covering the small intestine is
organized into villi. The villi are composed of a capillary network
surrounding a central lymphatic vessel (lacteal). Lining the villi are
enterocytes that are covered with a thin layer of microvilli, which
serves to increase surface area and maximize absorptive contact with
nutrients. Enterocyctes secrete a variety of substances that aid in the
digestion of nutrients such as enzymes and hormones (eg, CCK).
nals because, when they are administered exogenously,
animals behave as if they are sated, ie, they eat smaller
meals and engage in behaviors that normally occur when
meals end.14-16 Humans given the same compounds also
eat smaller meals and report that they are more
sated.15,17-20 Although most GI-generated signals that
influence meal size cause less food to be eaten, consistent
with the term satiety signals, an exception has recently
been discovered. Ghrelin is a peptide hormone made in
the stomach, and, as discussed below, its administration
causes more food to be eaten during meals.21,22
Satiety signals are released from specialized enteroendocrine cells that are interspersed among the gastric and
intestinal cells lining the lumen of the GI tract (Figure 1).23
These enteroendocrine cells have finger-like extensions that
project into the lumen and that contain chemoreceptors
sensitive to nutrients and other constituents of the chyme or
partially digested food as it progresses through the GI
tract.24-27 Several different types of enteroendocrine cells
have been identified and are categorized by the peptide
signals that they synthesize and secrete, and Table 1 lists
some of the important gastrointestinal-derived peptides involved in the control of food intake. Different enteroendocrine cells are sensitive to different classes of nutrients (eg,
carbohydrates, fats, or proteins).27-32 The secretions of the
enteroendocrine cells are mainly peptides, and they either
enter the bloodstream and act as hormones or diffuse
through the extracellular fluid to act in a paracrine fashion
on nearby cells.24,33,34 The hormonal actions of these peptides are relatively well-known and involve actions at the
liver,35 gallbladder,36 and pancreas37 as well as other organs38 (Figure 2). These are the actions that enable the
proper mix of digestive enzymes to be added to the chyme
to ensure optimal digestion. The paracrine actions of these
GASTROENTEROLOGY Vol. 128, No. 1
same peptides comprise an area of intense investigation,33,34,39 and one model is depicted in Figure 2.
Afferent neurons innervate the gut, and some endings of their neurites are interspersed among the enteroendocrine cells.33,40 These nerve endings are
thought to contain receptors for some of the peptide
signals secreted in response to specific nutrients in the
lumen. As an example, CCK secreted from intestinal I
cells interacts with CCK-1 receptors (formerly called
CCK-A receptors) on endings of sensory fibers of the
vagus nerve, eliciting increased activity in the form of
action potentials.13,41 The activated vagus in turn
stimulates cells in the brainstem, eliciting reflexes
that control GI function and sending signals to other
brain areas that cause the individual to stop eating.12,13,42 Hence, satiety elicited by CCK and other
GI peptides can be considered a neuroendocrine reflex.
We consider it a reflex in part because CCK-mediated
satiety exists in animals in which the hindbrain has
been surgically disconnected from the forebrain.43
These chronically decerebrate animals, as they are
called, do not initiate meals but will swallow liquid
food that is slowly infused into their mouth and in
this way consume normal-sized meals.44,45 These same
animals eat (swallow) smaller meals when CCK is
administered systemically, indicating that all components of the satiety reflex are contained within the
hindbrain and peripheral nerves to the GI tract.43
Afferent fibers of the vagus nerve also express mechanoreceptors (stretch receptors) that are located on
branches penetrating the musculature lining the GI
tract.46,47 These receptors are sensitive to stomach and
intestinal volume and lumenal pressure, and increased
pressure or volume in the stomach can result in the
termination of a meal.48,49 This is presumably another
important aspect of the satiety response. An intriguing
recent observation is that the same vagal fibers have some
Table 1. Gastrointestinal Hormones That Affect Satiety
Peptide
Cell type
Effect on
food intake
CCK
Amylin
GLP-1
PYY (3-36)
APO-AIV
Enterostatin
Bombesin/GRP
Oxyntomodulin
Gastric leptin
Ghrelin
I
P
L
L
Villus epithelia
Exocrine pancreas
Stomach
L
Chief
X/A-like
2
2
2
2
2
2
2
2
2
1
NOTE. To date, the newly discovered hormone ghrelin is the only GI
hormone known to increase food intake.
January 2005
GASTROINTESTINAL HORMONES AND FOOD INTAKE
177
signals is transmitted through direct contact with the
central nervous system by circulating signals and also
through stimulation of vagal afferents as recently reviewed.51 Accurate reception of these signals followed by
the appropriate behavioral output by the central nervous
system is vital to the maintenance of sufficient energy
stores.4 The purpose of this review is to present current
and vital information pertinent to the control of food
intake for many of the established gastrointestinal signals. The role of structural manipulation of the gut
during bariatric surgery will also be covered with an
emphasis on the gastrointestinal hormone changes that
result from these procedures.
Cholecystokinin
Figure 2. Endocrine and paracrine action of intestinal hormones.
Satiety signals released from the GI tract following ingestion can
modulate feeding behavior in either an endocrine or paracrine manner. As an example, CCK and GLP-1 can be released directly into the
bloodstream, allowing them to circulate to distant sites of action
(endocrine) to relay information regarding nutritional status. These
peptides can also interact locally with specific receptors located on
vagal afferent axons passing to the brain (paracrine). Reprinted with
permission from Havel.276
branches that express mechanoreceptors and are sensitive
to volume and other branches that are located near
enteroendocrine cells and could be sensitive to locally
released GI peptides.47 This suggests that the same nerve
fibers could be sensitive to both lumenal volume and
lumenal contents. Support for this hypothesis is the
observation that the same individual vagal fibers that
respond to stretch by increasing their firing rate also
increase their firing rate in response to CCK.50 This
implies that different modes of sensory information are
integrated within individual fibers innervating the GI
tract. Information from the periphery generated by these
CCK is the most studied satiety signal and is
secreted primarily in 2 forms, CCK-33 and CCK-8, from
the I cells within the duodenal and jejunal mucosa.52
CCK is also synthesized within the central nervous system, primarily in the form of CCK-8.53 The 2 receptors
that mediate the effects of CCK are termed CCK-1 and
CCK-2, previously named CCK-A and CCK-B, respectively.13,54-56 The CCK-1 or A (for alimentary) receptor is
primarily localized to the gastrointestinal system,
whereas the CCK-2 or B (for brain) receptor is found
within the CNS.57 CCK release from the intestine occurs
in response to nutrient stimulation. Specifically, CCK is
stimulated by fat and protein in the chyme, although the
precise stimulants are species specific.58,59
Following its release, CCK elicits multiple effects on
the gastrointestinal system, including the regulation of
gut motility, contraction of the gallbladder, pancreatic
enzyme secretion, gastric emptying, and gastric acid
secretion.60,61 Most of these are thought to be due to
endocrine actions of circulating CCK that has entered the
bloodstream. Over 30 years ago, Gibbs et al first demonstrated that exogenous administration of either purified CCK or synthetic CCK-8 into the peritoneal cavity
(ip) of rats reduced meal size.62 The response is dose
dependent, with larger doses causing a greater reduction
of food intake, and they observed that the CCK must be
administered near the start of a meal to be effective. If
CCK is administered more than 15 minutes before animals begin eating, it has no effect on meal size. The same
group also observed that exogenous CCK elicited the
same sequence of behaviors that noninjected rats display
when they terminate meals.14 Centrally administered
CCK also causes animals to consume smaller meals.63,64
The finding that exogenous CCK reduces meal size in
rats has been replicated in many labs and extended to
numerous species, including nonhuman primates and
humans.19,20,65-70
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STRADER AND WOODS
The observation that the administration of exogenous
CCK reduces meal size, although consistent with the
hypothesis that CCK is a natural satiety factor, is insufficient in and of itself to draw conclusions. Stronger
evidence would be the demonstration that endogenous
CCK, acting during normal meals, acts to limit caloric
intake. Consistent with this, the administration of specific CCK-1 antagonists increases meal size in experimental animals and humans.71-74
Behavioral experiments indicate that CCK is truly a
short-term, meal-reducing signal. This is illustrated by
the fact that repeated or long-term chronic75 or intermittent76 administration of CCK to rats has no effect on
weight loss. When the size of every meal is reduced by
CCK, animals compensate by increasing meal frequency.76,77 Although the effects of exogenous CCK are brief,
acting within the time of an ongoing meal, CCK also
appears to interact with long-term signals of energy
balance such as leptin and insulin.78 The anorectic effects
of CCK can be augmented by the coadministration of
subthreshold concentrations of leptin.79-82 Analogously,
administering low doses of insulin directly into the brain
also increases the satiating effect of CCK.83,84 Because
leptin and insulin are important signals indicating the
level of body fat to the brain,1,3,4,85 the implication is
that body fat is regulated, at least in part, by changes in
the sensitivity to meal-generated satiety signals such as
those given by CCK. That is, if an individual loses body
weight, the consequently reduced leptin and insulin
signals in the brain would render the individual less
sensitive to CCK, and there would be a tendency to eat
larger meals; the opposite would occur if an individual
were to gain body weight. When individuals are chronically obese, however, they are characterized with insulin
and leptin resistance; hence, rats with hypothalamic obesity have hyperinsulinemia but a normal sensitivity to
CCK’s satiating action,86 and fatty Zucker rats with
genetic obesity have slightly reduced sensitivity to
CCK.87 Although these forms of obesity are characterized
with a blunted response to adiposity hormones, others
are characterized by an absent response to CCK. Rats
with a spontaneous mutation of the CCK-1 receptor
(called OLETF rats88) eat slightly enlarged meals and
gradually develop mild obesity over their lifetime.89,90
As discussed above, CCK is thought to interact with
CCK-1 receptors on vagal sensory fibers, with the signal
being relayed to the brainstem. Consistent with this,
CCK’s anorectic effects can be eliminated by subdiaphragmatic vagotomy or selective damage to vagal afferent nerves.91,92 Likewise, lesions of the brainstem area
that receives vagal sensory afferents attenuate CCK-elicited anorexia.93 Within the brain, recent data suggest
GASTROENTEROLOGY Vol. 128, No. 1
that melanocortin-4 receptors (MC4) mediate CCK’s action.94
The Bombesin Family of Peptides
Exogenous administration of bombesin reduces
meal size in animals and humans.18,95,96 Bombesin itself
is an amphibian peptide, but gastrin releasing peptide
(GRP) and neuromedin B (NMB) are mammalian analogs that reduce food intake when administered systemically to animals.97,98 Both GRP and NMB and their
respective receptors are synthesized in the mammalian
brain,99,100 and central administration of either peptide
reduces food intake in rats.101 Consistent with the possibility that endogenous GRP and NMB reduce food
intake, mice deficient for the GRP receptor do not
suppress their food intake when administered either
GRP or NMB, eat significantly large meals, and develop
late-onset obesity.102
Most satiety factors such as CCK are thought to act by
reducing the size of an ongoing meal. Hence, if they are
administered between meals, they have no behavioral
effects such as prolonging the time until the individual
initiates a meal.62,103 Members of the bombesin family of
peptides appear to be an interesting exception in that,
when they are administered to animals between meals,
they increase the amount of time until the subsequent
meal begins.104-108
Amylin
Amylin, a peptide hormone secreted by pancreatic
B cells in tandem with insulin secretion during meals,
inhibits gastric emptying and gastric acid secretion.109
Amylin causes a dose-dependent reduction of meal size
when administered systemically110-112 or directly into the
brain.113 In contrast to the effects of several other satiety
peptides that reduce food intake by sending a signal to
the brain via the vagus nerves, amylin appears to stimulate neurons in the area postrema of the brain directly.114-116 As is the case with CCK, the ability of
amylin to reduce meal size is augmented in the presence
of elevated adiposity signals such as those given by
insulin.117
Glucagon-Like Peptide-1
Glucagon-like peptide-1 (GLP-1) is derived from
posttranslational modification of the larger precursor
molecule proglucagon.118 Proglucagon is synthesized
within the enteroendocrine L cells in the intestines,
primarily the ileum and colon.118 The release of GLP-1 is
elicited by both nutrient and neurohumoral stimulation
from proximal regions of the small intestine, and a major
action of GLP-1 is as an incretin, helping stimulate
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insulin secretion during a meal.119-122 GLP-1 is secreted
as GLP-1 (7-37) and GLP-1 (7-36).123 However, within
a very short time (⬃2 minutes), most plasma GLP-1 is
degraded by the enzyme dipeptidyl-peptidase IV (DPPIV), yielding the inactive analogs GLP-1 (9-36) and
GLP-1 (9-37).123 The GLP-1 receptor (GLP-1r) is found
in the periphery (gut and endocrine pancreas) and is
widespread throughout the central nervous system.124
The release of GLP-1 from the distal gut results from
both direct and indirect mechanisms (for review see
Brubaker and Anini125). Although GLP-1 is rapidly secreted from the ileum during a meal, the process does
not rely on actual nutrient contact with the endocrine
L cells.126 Rather, the mechanism is thought to result
from neural or humoral signals arising from the proximal
intestine. Because GLP-1 inhibits gastrointestinal motility, reduces gastrointestinal secretions, and attenuates
gastric emptying, it has been implicated as a major
component of the “ileal brake,” an inhibitory feedback
mechanism that regulates transit of nutrients through
the course of the gastrointestinal tract.127,128
GLP-1 also reduces food intake in animals and
humans.129-135 The anorectic actions of GLP-1 are
probably mediated through both peripheral and central mechanisms, and a population of neurons that
synthesize GLP-1 is located in the brainstem and
projects to hypothalamic and brainstem areas important in the control of energy homeostasis.136,137 In
rats, central administration of GLP-1 dose dependently reduces food intake,134,135,138-140 an effect that
is reversed by coadministration of the GLP-1 receptor
antagonist exendin (9-39).130 Centrally administered
GLP-1 reduces food intake through at least 2 mechanisms. GLP-1 receptors in the hypothalamus are
thought to reduce intake by acting through the normal controls of caloric homeostasis.141-144 GLP-1 receptors in the amygdala, on the other hand, are
thought to reduce food intake by eliciting symptoms
of malaise141 and are presumably responsible for the conditioned taste aversions caused by GLP-1.134,141,145,146 It has
recently been found that the receptors that trigger the
satiety action of GLP-1 are located in the hypothalamus,
whereas those that mediate malaise are in the amygdala.141
Kinzig et al observed that GLP-1 mediates both the endocrine and the behavioral responses to stress in rats,147 implying that the GLP-1 signal has complex actions, only
some of which are directly relevant to the control of caloric
homeostasis.
Peripherally administered GLP-1 elicits satiety in
healthy,133 obese,148 and diabetic humans.149,150 Because
the half-life of active GLP-1 is less than 2 minutes, any
direct effects are likely transient, and the reduction of
GASTROINTESTINAL HORMONES AND FOOD INTAKE
179
food intake is most likely a result of GLP-1’s inhibitory
effects on gastrointestinal transit and reduced gastric
emptying.151 However, peripherally administered GLP-1
does cross the blood-brain barrier,152 such that its role
and relative contribution within the CNS on food intake
are not conclusive.
Because it both reduces food intake and stimulates insulin secretion, GLP-1 is a logical candidate as a therapeutic
agent in the treatment of obesity and type-2 diabetes.153,154
However, as discussed above, a major problem in the potential use of GLP-1 as a treatment is its rapid degradation
by DPP-IV. Hence, treatment strategies based on GLP-1
will likely use compounds that are not so rapidly destroyed,
such as exendin-4, a 39-amino acid peptide originally isolated from the venom of the Gila monster salivary gland
that shares 53% homology with GLP-1 (7-36).155,156 Exendin-4 is potent agonist for the GLP-1 receptor and has a
significantly greater half-life (⬃30 minutes) than endogenous GLP-1.157 In animals and humans, exendin-4 has been
demonstrated to reduce gastric emptying,158 lower fasting
plasma glucose,158,159 and reduce food intake,158,160,161 supporting its potential use as a possible treatment for obesity
and diabetes. An alternative strategy may be to utilize
compounds that compromise DPP-IV, thus prolonging the
half-life of endogenous GLP-1.
Glicentin, GLP-2, Oxyntomodulin, and
Glucagon
Other peptides derived from proglucagon’s posttranslational processing include glicentin, GLP-2, and
oxyntomodulin as well as glucagon itself.118 Glicentin is
involved in the inhibition of gastric acid secretion.162 It
was recently reported by Dakin et al that, in the rat,
neither intracerebroventricular injection nor direct application of glicentin to the hypothalamic paraventricular
nucleus (PVN) reduced food intake.163 In contrast, that
same group observed that oxyntomodulin does reduce
food intake in the same paradigm.163 Although a specific
receptor for oxyntomodulin has yet to be identified, it
has been suggested that oxyntomodulin exerts its anorectic effects through the GLP-1r. This is supported by
the finding that subthreshold doses of the GLP-1r antagonist, exendin (9-39), block both GLP-1 and oxyntomodulin-induced reductions in food intake.163 Longterm treatment with oxyntomodulin results in
attenuated weight gain and a persistent decrease in food
intake in rats.164 A more recent report by Dakin et al
indicates that intravenous oxyntomodulin reduces caloric
intake during a buffet meal and decreases hunger ratings
in humans.165
GLP-2 is best known for its beneficial role in intestinal
adaptation and has become the focus of research on
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STRADER AND WOODS
short-bowel syndrome.166-168 GLP-2 and GLP-1 are
highly similar in structure and are secreted in parallel
from perfused ileal preparations.169 Therefore, a role for
GLP-2 in the regulation of feeding seems logical. However, the participation of GLP-2 receptor in the regulation of food intake is controversial. Intracranial administration of GLP-2 reduces food intake in rats, but the
effect can be blocked with a specific GLP-1 receptor
antagonist.170 More recent studies in humans using both
physiologic171 and pharmacologic172 doses of GLP-2
given intravenously had no effect.
Glucagon is the most widely studied peptide hormone
cleaved from preproglucagon.118 It is secreted from both
the endocrine pancreatic A cells and the distal intestine,
and its best known action is to increase glucose secretion
from the liver. Glucagon reduces meal size when administered systemically173,174 but not centrally,175 the signal
being detected in the liver and relayed to the brain.176 A
role for glucagon in the normal control of meal size was
demonstrated by the observation that blocking the action
of endogenous glucagon increases food intake.177,178 An
authoritative review of proglucagon-derived peptides as
potential candidates for the treatment of obesity has
recently been made.153
Peptide Tyrosine-Tyrosine
Peptide tyrosine-tyrosine (PYY) is a member of the
pancreatic polypeptide family that also includes pancreatic
polypeptide (PP) and neuropeptide-Y (NPY). Like proglucagon-derived peptides, PYY is synthesized and secreted by
L cells in the distal ileum and colon.179 In fact, most L cells
that secrete GLP-1 also secrete PYY.180 PYY is secreted as
PYY (1-36) and is degraded to PYY (3-36) by DPPIV.181,182 Receptors that mediate the effects of PYY belong
to the NPY receptor family and include Y1, Y2, Y4, and
Y5.183 PYY (1-36) is an agonist for the Y1 and Y2 receptor181 and is a potent orexigen.184 Once PYY (3-36) is
formed, it displays highly selective agonist activity for the
Y2 receptor and has been reported to reduce food intake.185
The secretion of PYY from the gut is proportional to the
caloric density of the ingested nutrients,186 with lipids and
carbohydrates being the primary nutrients in the stimulation of PYY release.179,187
Like GLP-1, PYY has been implicated as a major
component of the ileal brake.31,188 Its secretion can be
stimulated by the presence of nutrients, particularly lipids, within the ileum itself189 or else prior to direct
nutrient contact because of neurohumoral signals originating from the proximal gut.190 Pharmacologic experiments have yielded conflicting results regarding PYY as
a satiety signal. Several reports indicate that PYY is an
orexigenic peptide,184,191-195 with feeding stimulatory
GASTROENTEROLOGY Vol. 128, No. 1
properties superior to those of neuropeptide-Y (for review see Hagan191). This is particularly the case when
PYY is administered directly into the cerebral ventricles.191 In contrast, it was recently reported that peripheral administration of PYY (3-36) reduces food intake in
rodents, nonhuman primates, and humans.185,196,197 The
modest decrease of food intake has been replicated in
monkeys but not in rats.198-200
It has been hypothesized that PYY influences food
intake through its interaction with Y2 receptors in the
hypothalamic arcuate nucleus. The arcuate nucleus is a
major conduit for feeding-related signals.1,3,4,201 The
model is that circulating PYY gains access to the brain
as it freely crosses the blood-brain barrier.202 The Y2
receptor is the most likely mediator of the food intakereducing properties of PYY because peripherally injected
PYY (3-36) is ineffective in reducing food intake in the
Y2-deficient mouse.203
Gastric Leptin
Leptin was first described as a gene product from
adipose tissue, which plays an important role in the
central regulation of food intake and energy balance.204
Extra-adipose sites have now been identified that synthesize and secrete leptin, including the placenta,205 skeletal
muscle,206 and the stomach.207,208 The production of
leptin within the stomach is localized to the fundic
glands, specifically the P cells and pepsinogen-secreting
chief cells. The presence of leptin within both of these
cell types suggests that gastric leptin possesses both
exocrine and endocrine functions,208,209 and it has been
estimated that up to 25% of circulating leptin actually
derives from the stomach.210
Studies in humans and animals indicate that gastric
leptin is regulated by energy state. During fasting, gastric leptin synthesis is reduced, and a brief period of
refeeding is capable of emptying all the leptin stores
within the stomach of the rat.207,208,211 Leptin synthesis
is also regulated by other gut peptides, including CCK,
secretin, and pentagastrin.78,210 CCK-1 receptors are colocalized with leptin in the gastric mucosal cells, and
CCK administration increases leptin synthesis and release from gastric chief cells.78 Insulin increases gastric
leptin secretion into the lumen of the stomach in humans. This effect appears to be vagally mediated because
vagotomy abolishes the response.212 Pentagastrininduced leptin secretion, on the other hand, is not influenced by vagotomy.212 The ability of circulating leptin
to reduce food intake and body weight is well-known,
and several reviews exist.1,3,4,213,214 The physiologic effects of gastric-derived leptin are presumably comparable
with those of adipocyte-derived leptin and mediate the
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central regulation of energy homeostasis via receptors in
the arcuate nucleus and elsewhere in the brain.214
Apolipoprotien A-IV
Apolipoprotein A-IV (apo A-IV) is a large peptide
synthesized by intestinal cells during the packaging of
digested lipids into chylomicrons that subsequently enter the blood via the lymphatic system.215 Apo A-IV is
also synthesized in the arcuate nucleus.216 Systemic or
central administration of apo A-IV reduces food intake
and body weight of rats,217 and administration of apo
A-IV antibodies has the opposite effect.218 Because both
intestinal and hypothalamic apo A-IV are regulated by
absorption of lipid but not carbohydrate,219 this peptide
may be an important link between short- and long-term
regulators of body fat (see review by Tso et al215). A
second digestion-related peptide, enterostatin, is also
closely tied to lipid digestion. When ingested fat enters
the intestine, the exocrine pancreas secretes lipase and
colipase to aid in the digestive process; enterostatin is a
cleavage by-product of the formation of colipase from
pro-colipase. Administration of exogenous enterostatin
either systemically220,221 or directly into the brain222
reduces food intake, and, when rats are given a choice of
foods to eat, the reduction is specific for fats; that is,
enterostatin does not decrease the intake of carbohydrates
or proteins.223 Therefore, 2 peptides that are secreted
from the gut during the digestion and absorption of
lipids, apo A-IV and enterostatin, act as signals that
decrease food intake, and at least one of them selectively
reduces the intake of fat. Macronutrient specificity has
not been assessed with apo A-IV.
Ghrelin
Although not a gastrointestinal satiety hormone,
ghrelin must be included in any discussion of gut hormones that influence food intake. Ghrelin is synthesized
and secreted from the fundic region of the stomach and
has been identified as the endogenous ligand for the
growth hormone secretagogue receptor. Fasting increases
plasma levels of ghrelin,224 and exogenous ghrelin exhibits potent orexigenic properties when administered peripherally or centrally.22,225,226 Ghrelin has also been
linked to the anticipatory aspects of meal ingestion because levels peak shortly before scheduled meals in humans and rats224 and fall shortly after meals end, and
high plasma ghrelin has been linked to the hyperphagia
and obesity of individuals with the Prader Willi syndrome.227
An intriguing question concerns why there is such a
large imbalance in the gastrointestinal peptides that
influence food intake, ie, whereas numerous peptides
GASTROINTESTINAL HORMONES AND FOOD INTAKE
181
secreted from the stomach and intestines decrease food
intake, only one, ghrelin, increases it. One possibility
relates to the phenomenon of satiety. Meals are generally
stopped long before any physical limit of the stomach is
reached. This is easily demonstrated when food is diluted
with noncaloric bulk and animals increase the volume of
food consumed to attain the same caloric load.228,229 It
has therefore been argued that a major function of satiety
signals is to prevent the consumption of too many calories at one time, lest too great an increase of postprandial
blood glucose and other nutrients occurs.230,231 That is,
as the gastrointestinal tract detects the various macronutrients consumed as a meal is being eaten, the secretions
that it makes to coordinate the digestive process also
reflect the quantity of nutrients that will soon be entering the blood and thereby constitute a behavioral brake
to the eating process. This is presumably complementary
to the ileal brake that slows gastric emptying and consequently also limits the rate at which absorbed nutrients
enter the blood.
Relationship Between
Gastrointestinal and Brain Signals
That Influence Food Intake
An important principle is that many of the peptides that are made in the gastrointestinal system and
influence food intake are also synthesized in the brain.
This includes CCK, GLP-1, apolipoprotein A-IV, gastrin-releasing peptide, neuromedin B, PYY, and ghrelin.
Apparent exceptions are the pancreatic hormones insulin,
glucagon, and amylin and the adipose tissue/stomach
hormone leptin. The fact that so many peripheral signals
are also synthesized locally in the brain raises the question of whether and how the same signals secreted from
different places in the body interact. A simple generalization is that, if a peptide reduces (or increases) food
intake when administered systemically, it probably has
the same action when administered centrally. With regard to changes of food intake, this is true of CCK,63,64
GLP-1,134,135,138-140 apolipoprotein A-IV,217 gastrinreleasing peptide,101 neuromedin B,101 and ghrelin.22
PYY is a possible exception in that it reportedly decreases food intake when administered systemically185
but increases it when administered directly into the
brain.184,191-195 Another confounding observation is that
peptide signals that are not synthesized in the brain
nonetheless have the same effect on food intake when
administered directly into the brain. This is true of
leptin232,233 as well as the pancreatic hormones insulin175,234 and amylin113 but not glucagon.175 Because
specific receptors for each of these hormones exist on
182
STRADER AND WOODS
neurons in the brain,85 the implication is that molecules
in the circulation are able to circumvent the blood-brain
barrier. This could occur by any of several means, including selective transport systems through capillary
endothelial cells as has been described for insulin and
leptin, interaction with neuronal receptors in brain areas
with a relaxed or absent blood-brain barrier as has been
described for amylin, or by being sufficiently small or
lipophilic to penetrate the barrier in small amounts (see
reviews in Banks235 and Woods et al236).
There are other complexities of the peripheral-central
dichotomy. GLP-1 is synthesized in the ileum as well as
in the brainstem, and it reduces food intake when administered either systemically or centrally. However,
when administered directly into the brain, the reduction
of food intake occurs for different reasons in different
specific areas. Kinzig et al141 found that the anorexia
caused by GLP-1 in the amygdala is secondary to a
sensation of visceral illness, whereas the anorexia elicited
by GLP-1 in the hypothalamus appears to mimic what
occurs in natural satiety.
Knockout Mice and Natural
Mutations
Because the gastrointestinal signals that govern
food intake are components of a complex integrated and
redundant control system, it is not surprising that
knockout models often provide inconclusive information
as to a peptide’s contribution to the regulation of feeding.237 To use CCK as an example and as discussed
above, considerable evidence implicates CCK as an
acutely acting satiety signal. Consistent with this, genetically engineered mice lacking CCK-1 receptors are
insensitive to the anorexic action of CCK, and they have
a normal body weight.238 This is consistent with the
observation that, when rats are administered exogenous
CCK prior to every meal, they do not lose weight despite
receiving 20 or more injections of CCK each day.76 In
contrast to what is observed in mice lacking CCK-1
receptors and as discussed above, OLETF rats lacking a
functional CCK-1 receptor develop obesity over their
lifetime.89,90 Hence, either there are fundamental species
differences in the impact of CCK on body weight or there
are subtle differences between the natural and the engineered animal lacking functional CCK-1 receptors.
As another example, despite the apparent role of
GLP-1 in the control of food intake and glucose homeostasis as discussed above, GLP-1 receptor knockout
mice have normal body weight, implying that GLP-1
signaling is not essential for the long-term control of
energy homeostasis. These mice do, however, develop
GASTROENTEROLOGY Vol. 128, No. 1
diabetes, thus emphasizing the critical importance for
GLP-1 in the maintenance of pancreatic function.239-241
Analogously, ghrelin-deficient mice have no obvious behavioral or metabolic phenotype and are indistinguishable from wild-type littermates.242 Glucagon inhibitory
peptide (GIP) is secreted from intestinal K cells within
the duodenal mucosa. Although exogenous GIP administration does not alter food intake,243 GIP is an incretin
that, like GLP-1, is important in glucose homeostasis.244
Interestingly, the generation of GIP receptor knockout
mice revealed previously unidentified roles for GIP as an
important regulator of energy balance. GIP knockout
mice are resistant to diet-induced obesity and, when
crossed with ob/ob or leptin-deficient mice, cause a reduction in body weight.245 GIPr-deficient mice also have
increased energy expenditure when exposed to diets high
in fat.245 Given that GIP receptors are found on the
adipocyte, these findings are consistent with a role for
GIP in the regulation of body fat stores. Last, some
phenotypes of other GI peptide knockout mice are quite
consistent with the peptides’ described physiologic role,
such as the GRP receptor-deficient mice (as mentioned
above). These mice eat large meals, become obese, and do
not reduce their food intake when given GRP or
NMB.102
Effect of Obesity Surgery on Gut
Hormones
Surgery is the most effective treatment for morbid
obesity, with the most successful surgeries involving a
substantial restructuring of the stomach and/or the small
intestines. The contemporarily most commonly performed surgery, the Roux-en-Y gastric bypass, involves
both restrictive and malabsorptive features. In this procedure, the stomach volume is minimized to hold
ⱕ50 mL while the small intestines are attached proximal
to the pylorus, allowing for rapid delivery of stomach
contents to the small intestine (Figure 3B). Additionally,
a considerable segment of small intestine is bypassed,
resulting in a much shorter gastrointestinal tract. Developed by Mason and Ito in 1967,246 the Roux-en-Y has
proven to be effective in reducing body weight and is
associated with relatively few complications compared
with jejunoileal bypass ( JIB) procedure, which involved
bypassing nearly 90% of the small intestine (Figure
3A)247 and caused severe malabsorption.
Although the obvious contribution of restriction and
malabsorption was recognized when various bariatric
surgeries were being developed, not so obvious were the
resulting changes in endocrine signals arising within the
gastrointestinal tract. Changes in these signals have re-
January 2005
GASTROINTESTINAL HORMONES AND FOOD INTAKE
183
could be solely a consequence of weight loss following
surgery, improvements in fasting glucose have been documented within days following surgery, with many patients becoming medication free within weeks (for review
see Rubino and Gagner254). It is reasonable to speculate
that the increased secretion of incretins such as GLP-1
and GIP following surgery are at least partly responsible
for these improvements.
One surgical model that supports the hypothesis that
increased intestinal hormones alone may act as mediators
of weight loss and reduced food intake is ileal transposition. First designed in 1981 to isolate the effects of
distal gut stimulation in the absence of malabsorption
and restriction, ileal transposition has only been systematically investigated in the laboratory rat.255 This procedure involves the transposition of an isolated segment
(10-20 cm) of distal ileum-jejunum carrying full vasculature and innervation to the duodeno-jejunal region.255
The results of ileal transposition surgery are that rats eat
less and lose weight255-258 following the procedure and
have significant increases in the secretion and synthesis of
distal gut hormones such as PYY and GLP-1.259 These
findings are consistent with the hypothesis that augmented levels of intestinal hormones independently regulate body weight and food intake.
Figure 3. Restrictive and malabsorptive bariatric surgeries. The
mechanisms underlying bariatric surgeries range from being primarily
malabsorptive, such as occurs with the (A) jejunoileal bypass, to
completely restrictive as in (D) vertical banded gastroplasty. Surgeries
including the (B) Roux-en-Y gastric bypass and (C) biliopancreative
diversion use a combination of restrictive and malabsorptive components.
cently become recognized as likely contributors to the
weight loss following surgery.248 The hypothesis is that
enhanced or premature nutrient stimulation of distal
segments of the intestines causes increased secretion of
intestinal peptides that function as satiety signals and
that this may be sufficient to induce weight loss, independent of any malabsorption or restriction. Several
studies have documented changes in gastrointestinal hormones following bariatric surgery (Table 2). Twenty
years following jejunoileal bypass, patients had significantly enhanced CCK, enteroglucagon, and peptide YY
levels.249 Gastric bypass250 and biliopancreatic diversion251 also resulted in increased plasma enteroglucagon.
These findings therefore support a role for gut hormones
as potentially important mediators in the hypophagia
and weight-reducing effects of bariatric surgery. Furthermore, patients who were presurgically type 2 diabetic
often have rapid improvements in glucose homeostasis252
(for review see Greenway et al253). Although this effect
Table 2. Effects of Bariatric Surgery on Gastrointestinal
Intestinal Hormones
Surgery
Hormone
Change
Reference no.
Gastric bypass
(Roux-en-Y)
Ghrelin
Ghrelin
Ghrelin
Ghrelin
Ghrelin
Ghrelin
Ghrelin
Enteroglucagon
Enteroglucagon
GLP-1
CCK
Ghrelin
Ghrelin
PYY
2
1
2
no change
2
2
1
1
1
1 (ns)
no change
2
2
1
263
264
265
266
267
268
269
250
270
271
250
265
266
272
Enteroglucagon
Enteroglucagon
Enteroglucagon
Ghrelin
CCK
CCK
PYY
Enteroglucagon
GLP-1
1
1
1
2 (initial only)
1 (cell No.)
1
1
1
1
251
273
274
252
275
249
249
274
249
Gastric
banding
Verticalbanded
Gastroplasty
Biliopancreatic
diversion/
duodenal
switch
Jejunoileal
bypass
184
STRADER AND WOODS
Effects of Bariatric Surgery on
Plasma Ghrelin
The initial report by Cummings et al263 that,
following gastric bypass, circulating ghrelin is drastically
diminished has led to intense investigation into a possible role of ghrelin in the effects of obesity surgery. In
contrast to what occurs after gastric bypass, plasma
ghrelin normally increases following nonsurgical weight
loss260 and is proportional to lean body mass. Hence, a
reduction of ghrelin, and a consequent reduced stimulant
for food intake, might well contribute to the weight loss
of gastric bypass surgery. Initially, it was proposed that
the exclusion of the fundus region of the stomach, the
site that produces the majority of circulating ghrelin,
was the mechanism through which gastric bypass resulted in lower ghrelin levels. However, numerous follow-up studies have either contradicted such findings or
reported no change in ghrelin following surgery
(Table 2). Normally, ghrelin levels rise prior to or in
preparation for a meal and decline immediately postprandially.224 To examine the contribution of the stomach in
this response, Williams et al examined whether distension of the stomach and/or nutrient stimulation were
required for the prandial changes in plasma ghrelin.261
Only when the infused calories (glucose) were allowed to
pass through the pylorus into the foregut did ghrelin
levels change, indicating that postgastric feedback is
necessary for changes in ghrelin to occur postprandially.
No changes in ghrelin were seen when glucose was held
in the stomach by use of a pyloric cuff.261 Furthermore,
infusion of nutrients directly into the foregut is just as
effective in suppressing ghrelin as is nutrient administration into the stomach.262 These findings argue against
the hypothesis that exclusion of the stomach lumen from
ingested nutrients is the cause of reduced ghrelin following gastric bypass surgery. More investigation is required
to determine the mechanisms underlying changes in
ghrelin secretion following gastric bypass surgery.
Summary
We have reviewed what is known of the gastrointestinal and related peptide signals that influence food
intake, including what is known of their mechanism of
action. Several generalities can be made. The first is that
the majority of these signals act to reduce the intake of
further calories, effectively categorizing them as satiety
signals. The lone exception is ghrelin, and its endogenous function is not yet well established. The second
point is that there are many different satiety signals and
that these are released as chyme or other stimuli that
interact with all levels of the gastrointestinal tract from
GASTROENTEROLOGY Vol. 128, No. 1
the stomach to the ileum. Different signals are released
in response to different nutrients that have been ingested. Another generalization is that the information
carried in satiety signals reaches the brain posteriorly,
either being conveyed in the vagus nerve or entering the
hindbrain directly. This is in contrast to adiposity signals
such as insulin and leptin that enter the brain at the level
of the hypothalamus. For the most part, satiety signals
work by stopping meals once they have begun as opposed
to delaying the onset of eating. A final point is that one
reason certain types of intestinal bypass surgery is successful at reducing food intake and causing weight loss
may be related to enhanced secretion of satiety signals.
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Received July 1, 2003. Accepted April 30, 2004.
Address requests for reprints to: Stephen C. Woods, PhD, University
of Cincinnati Medical Center, Genome Research Institute, Building 43,
Third Floor ML 0506, 2170 E. Galbraith Road, Cincinnati, Ohio 45237.
e-mail: [email protected]; fax: (513) 558-8990.