read the article and answer the questions.It has to be a complete answer to receive full credit.

Review series

Gastrointestinal regulation of food intake
David E. Cummings and Joost Overduin
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington,
Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.

Despite substantial fluctuations in daily food intake, animals maintain a remarkably stable body weight, because
overall caloric ingestion and expenditure are exquisitely matched over long periods of time, through the process of
energy homeostasis. The brain receives hormonal, neural, and metabolic signals pertaining to body-energy status
and, in response to these inputs, coordinates adaptive alterations of energy intake and expenditure. To regulate food
consumption, the brain must modulate appetite, and the core of appetite regulation lies in the gut-brain axis. This
Review summarizes current knowledge regarding the neuroendocrine regulation of food intake by the gastrointestinal system, focusing on gastric distention, intestinal and pancreatic satiation peptides, and the orexigenic gastric
hormone ghrelin. We highlight mechanisms governing nutrient sensing and peptide secretion by enteroendocrine
cells, including novel taste-like pathways. The increasingly nuanced understanding of the mechanisms mediating
gut-peptide regulation and action provides promising targets for new strategies to combat obesity and diabetes.
Principles of satiation
“Satiation” refers to processes that promote meal termination,
thereby limiting meal size (1, 2). “Satiety” refers to postprandial
events that affect the interval to the next meal, thereby regulating meal frequency, which is also influenced by learned habits (3).
Satiation results from a coordinated series of neural and humoral
signals that emanate from the gut in response to mechanical and
chemical properties of ingested food. Although the relevant signals are commonly dubbed “satiety signals,” this term is usually a
misnomer, because most of them promote termination of ongoing
meals and do not delay subsequent meal initiation or affect intake
if delivered between meals (4).
A primary function of the gut is to achieve efficient nutrient
digestion and absorption; many satiation signals optimize these
processes by influencing gastrointestinal (GI) motility and secretion. Their additional capacity to limit meal size enhances this
control by restricting the rate at which nutrients reach the gut (5).
Meals are typically stopped long before gastric capacity is reached,
and when food is diluted with noncaloric bulking agents, the volume ingested increases to maintain constant caloric intake (6).
Therefore, animals can consume much larger meals than they
typically do. A major function of satiation is to prevent overconsumption during individual meals, thereby averting deleterious
consequences from incomplete digestion as well as excessive disturbances in circulating levels of glucose and other nutrients (7).
Satiation signals arise from multiple sites in the GI system,
including the stomach, proximal small intestine, distal small intestine, colon, and pancreas, each of which is discussed below (Figure 1 and Table 1). Ingested food evokes satiation by two primary
effects on the GI tract — gastric distention and release of peptides
from enteroendocrine cells. The hindbrain is the principal central
site receiving input from short-acting satiation signals, which are
transmitted both neurally (for example, by vagal afferents projecting to the nucleus of the solitary tract) and hormonally (for
Nonstandard abbreviations used: AGRP, agouti-related protein; AP, area postrema;
APO AIV, apolipoprotein A-IV; CCK, cholecystokinin; CCK1R, CCK receptor 1; DPP4,
dipeptidyl peptidase-4; FA, fatty acid; GI, gastrointestinal; GLP, glucagon-like peptide;
GLP1R, GLP1 receptor; MCH, melanin-concentrating hormone; NPY, neuropeptide
Y; PP, pancreatic polypeptide; PYY, peptide YY.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J. Clin. Invest. 117:13–23 (2007). doi:10.1172/JCI30227.


example, by gut peptides acting directly on the area postrema [AP],
which lies outside the blood-brain barrier). Although the perception of fullness clearly involves higher forebrain centers, conscious
awareness of GI feedback signals is not required for satiation. Even
animals whose hindbrain is surgically disconnected from the forebrain exhibit satiation and respond to GI satiation peptides (8, 9).
Therefore, gut-hindbrain communication is sufficient for satiation, although this normally interacts with higher cognitive centers to regulate feeding.
Pathways relaying short-acting satiation signals from the gut
to the hindbrain also interact at several levels with long-acting
adiposity hormones involved in body-weight regulation, such as
leptin and insulin. Through multifaceted mechanisms, adiposity
hormones function as gain-setters to modulate the sensitivity of
vagal and hindbrain responses to GI satiation signals. Adiposity
hormones thereby regulate short-term food intake to achieve longterm energy balance (10, 11).
Here we provide an overview of the regulation of feeding by
gastric, intestinal, and pancreatic signals. We discuss interactions
among these signals and between short-acting GI factors and
long-acting adiposity hormones. We also highlight new insights
regarding mechanisms by which enteroendocrine cells sense
and respond to nutrients. The increasingly sophisticated understanding of these topics should help guide development of novel?
antiobesity therapeutics.
Gastric satiation signals
Densely innervated by sensory vagal and splanchnic nerves (12),
the stomach is optimized to monitor ingestion. Long-standing evidence demonstrates that animals overeat with voluminous meals
if food is drained from their stomach as they eat (13). This observation, however, does not specifically implicate the stomach as a
source of satiation signals, because the exodus of ingesta through
a gastric cannula also precludes meal-related signals that would
normally arise from postgastric sites.
Evidence that the stomach itself contributes to satiation derives
from experiments involving cuffs that can reversibly close the pylorus (the exit from the stomach) and prevent passage of food downstream. Studies using this model demonstrate that major gastric
distention alone is sufficient to terminate ingestion, but the amount
of food required for this exceeds that eaten in a typical meal (2, 14).

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Figure 1
Principal sites of synthesis of GI peptides implicated in the regulation of food intake. Depicted are
the main locations of production for each peptide,
although many of these molecules are detectable in
smaller quantities at other sites in the GI system. In
addition, most of them are also synthesized within
the brain, including CCK, APO AIV, GLP1, oxyntomodulin, PYY, enterostatin, ghrelin, gastrin-releasing
peptide (GRP), neuromedin B (NMB), and possibly
PP. GI peptides that regulate appetite and do not
seem to be produced within the brain include leptin,
insulin, glucagon, and amylin.

However, normal postprandial gastric distention does contribute
to satiation when acting in concert with pregastric and postgastric
stimuli (2, 14). Oral and gastric stimuli happen concurrently during
eating, and up to 40% of a meal empties into the intestine before
meal termination (15). Therefore, pregastric, gastric, and intestinal
satiation signals commence almost simultaneously, and they function in unison, augmenting each other’s satiating effects (14).
Gastric satiation signals arise primarily from mechanical distention, whereas those from the intestine derive largely from the
chemical effects of food (16). Hence, with the pylorus closed, gastric loads limit ingestion solely on the basis of their volume, rather
than their nutrient content, osmolarity, or pH (17). Although
the stomach can sense nutrients (for example, to regulate gastrin
release) (18), this does not seem to contribute to satiation. The
stomach wall is endowed with discrete neural sensors of tension
(19), stretch (20), and volume (14). Output from these mechanoreceptors is relayed to the brain by vagal and spinal sensory nerves
(14, 21), using a complex array of neurotransmitters and neuromodulators, including glutamate, acetylcholine, nitric oxide, calcitonin-gene-related peptide, substance P, galanin, and cocaine-andamphetamine-related transcript (14).
Bombesin-related peptides (for example, gastrin-releasing peptide
and neuromedin B), which are produced by gastric myenteric neurons, can reduce food intake when delivered pharmacologically
to humans and other animals (2). Because it is not clear, however,
whether these peptides are regulated by ingested nutrients, they are
not discussed in this review of meal-related GI signals.
Intestinal satiation
The generally accepted assertion that “gastric satiation is volumetric, intestinal satiation is nutritive” (16) reflects the importance of
nutrients in mediating intestinal satiation, with a limited role for
distention. Intestinal nutrient infusions reduce food intake in many
species, including humans (14) — an effect that commences within
seconds of nutrient infusion, indicating that at least some of the
associated satiation signals emanate from the gut, rather than from
postabsorptive sources (22). These, and other, findings demonstrate
14	

that the intestines play a dominant role in satiation. Many intestinal
satiation signals inhibit gastric emptying, and this probably helps
limit ingestion by enhancing gastric mechanoreceptor stimulation.
However, sham feeding experiments show that a delay of gastric emptying is not required for intestinal signals to elicit satiation (14).
Mediators of intestinal satiation include a cadre of gut peptides
that are secreted from enteroendocrine cells in response to ingested food. These messengers diffuse through interstitial fluids to
activate nearby nerve fibers and/or enter the bloodstream to function as hormones (Figure 2). In conjunction with gastric distention, satiation peptides educe the perception of GI fullness, promoting meal termination. Standards for physiologically satiating
peptides were articulated in the publication describing the first
such agent, cholecystokinin (CCK) (2, 4). According to these criteria, a satiation factor should be released during food ingestion,
and exogenous administration of it should decrease meal size in a
dose-dependent manner — rapidly, transiently, and at physiologic
concentrations, without causing illness.
Upper-intestinal satiation: CCK
CCK is the archetypal intestinal satiation peptide, first described
as such three decades ago (4). It is produced by I cells in the duodenal and jejunal mucosa, as well as in the brain and enteric nervous
system. Intestinal CCK is secreted in response to luminal nutrients,
especially lipids and proteins. The CCK prepropeptide is processed
by endoproteolytic cleavage into at least six peptides, ranging from
8 to 83 amino acids in length (23). The multiple bioactive forms
pertinent to feeding share a common carboxy-terminal octapeptide with an O-sulfated tyrosine. The major circulating moieties
are CCK8, CCK22, CCK33, and CCK58, although recent evidence
suggests that CCK58 might be the only relevant endocrine form
in some species (24). CCK peptides interact with two receptors
expressed in the gut and brain. CCK receptor 1 (CCK1R, formerly
known as CCK-A, for “alimentary”) predominates in the GI system,
whereas CCK2R (formerly known as CCK-B, for “brain”) predominates in the brain. Through endocrine and/or neural mechanisms,
CCK regulates many GI functions, including satiation.

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Table 1
Selected GI and pancreatic peptides that regulate food intake
Peptide	


CCK	
GLP1	
Oxyntomodulin	
PYY3–36	
Enterostatin	
APO AIV	
PP	
Amylin	
GRP and NMB	
Gastric leptin	
Ghrelin	

Main site of synthesis	


Proximal intestinal I cells	
Distal-intestinal L cells	
Distal-intestinal L cells	
Distal-intestinal L cells	
Exocrine pancreas	
Intestinal epithelial cells	
Pancreatic F cells	
Pancreatic ? cells	
Gastric myenteric neurons	
Gastric chief and P cells	
Gastric X/A–like cells	

Receptors mediating 
feeding effects	


Sites of action of peripheral 
peptides germane to feeding 
Hypothalamus	Hindbrain	
Vagus nerve	

CCK1R	
X	
X	
X	
GLP1R	
X?	
X?	
X	
GLP1R and other	
X	
Y2R	
X	
X	
F1-ATPase ? subunit	
X	
Unknown	
X	
X	
Y4R, Y5R	
X	
X	
CTRs, RAMPs	
X	
X	
GRPR	
X	
X	
Leptin receptor	
?	
?	
X	
Ghrelin receptor	
X	
X	
X	

Effect on 
food intakeA	
?
?
?
?
?
?
?
?
?
?
?

CTRs, calcitonin receptors; RAMPs, receptor activity–modifying proteins; GRP, gastrin-releasing peptide; NMB, neuromedin B; GRPR, GRP receptor. X?
indicates that it is unclear whether physiologically relevant quantities of GLP1 from the gut evade DPP4-mediated degradation in blood to activate GLP1
receptors in the brain, although these receptors might interact with CNS GLP1 to regulate food intake. ? indicates that it seems very unlikely that gastric
leptin interacts in a physiologically meaningful way with leptin receptors in the hypothalamus or hindbrain, which are important targets of leptin secreted
from adipocytes. AEffect of peripheral peptides on food intake. In some cases, central administration yields opposite results.

When peripherally injected immediately before a meal, CCK
decreases meal size in a dose-dependent manner without affecting water intake or causing illness (4). Exogenous CCK also
triggers a stereotyped sequence of behaviors that rats normally
display upon meal completion, suggesting that it evokes the perception of satiation without internal food stimuli (25). Typifying
a short-acting satiation signal, the anorectic effects of CCK are
very short-lived and undetectable if the peptide is injected more
than 30 minutes before meals.
Satiating effects of CCK have been confirmed in numerous species, including humans, in whom the carboxy-terminal octapeptide
reduces meal size and duration (26). Pharmacologic and genetic
experiments indicate that CCK1R mediates CCK-induced satiation
(27, 28). This receptor is expressed on vagal afferents, and peripheral
CCK administration increases vagal-afferent firing, as well as neuronal
activity in the hindbrain region receiving visceral vagal input (29, 30).
Furthermore, both subdiaphragmatic vagotomy and selective vagal
deafferentation decrease the anorectic effects of peripheral CCK?
(31–33). These findings identify a critical vagal pathway for CCKinduced satiation. However, CCK1R is also expressed in the hindbrain
and hypothalamus. Lesions of the hindbrain AP attenuate CCKinduced satiation (34), and CCK microinjections into several hypothalamic nuclei decrease food intake (35). These observations suggest
that CCK might relay satiation signals to the brain both directly and
indirectly, and/or that central CCK contributes to satiation.
As is mentioned above, CCK-induced satiation could result in
part from inhibition of gastric emptying, thereby augmenting
gastric mechanoreceptor stimulation. Some vagal-afferent fibers
respond synergistically to gastric distention and CCK (36), and
subthreshold doses of CCK reduce food intake in monkeys if combined with gastric saline preloads (37). Similarly, gastric distention
augments the anorectic effects of CCK8 in humans (38). However, other studies show no differences in the satiating capacity of
CCK8 between rats eating normally and those either sham fed or
fitted with closed pyloric cuffs (33, 39). These and other observations indicate that CCK causes satiation through mechanisms
additional to enhancing gastric distention signals.


The impact of eliminating CCK1R signaling supports a physiologic role for this receptor in satiation. Rats lacking CCK1R show
increased meal size and gradually become obese (27), a phenotype
possibly driven by overexpression of neuropeptide Y (NPY) in the
dorsomedial hypothalamus (40). The obesity is fairly mild, however, and is not present in CCK1R-deficient mice (28); this is consistent with the proposed function of CCK as a short-acting satiation
signal. CCK1R antagonists also increase meal size and food intake
in experimental animals (41, 42), and they increase hunger, meal
size, and caloric intake in humans (43).
Despite the role of CCK in terminating individual meals, its
importance in long-term body-weight regulation and its potential
as an antiobesity target are questionable. Chronic CCK administration in animals, with up to 20 peripheral injections per day, reduces
meal size, but this is offset by increased meal frequency, leaving body
weight unaffected (44). CCK administration decreases food intake
acutely in humans by shortening meals (45), but anorectic effects
dissipate after only 24 hours of continuous infusion (46). Not
surprisingly, trials of CCK1R agonists as antiobesity therapeutics
have been unsuccessful to date. The most important role for CCK
in body-weight regulation might be its synergistic interaction with
long-term adiposity signals, such as leptin (see below) (10, 11).
Lower-intestinal satiation: glucagon-like peptide-1
The ileal brake is a feedback phenomenon whereby ingested food
activates distal-intestinal signals that inhibit proximal GI motility
and gastric emptying (47). It is mediated by neural mechanisms
and several peptides that are also implicated in satiation. These
engage a behavioral brake on eating to complement the ileal brake,
restraining the rate of nutrient entry into the bloodstream (5). One
such peptide is glucagon-like peptide-1 (GLP1). It is cleaved from
proglucagon, which is expressed in the gut, pancreas, and brain
(48). Other proglucagon products include glucagon (a counterregulatory hormone), GLP2 (an intestinal growth factor), glicentin
(a gastric acid inhibitor), and oxyntomodulin. Although several of
these peptides are implicated in satiation, evidence is strongest for
GLP1 and oxyntomodulin.

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Figure 2
Topography of enteroendocrine cells and absorptive enterocytes on
a villus within the small-intestinal wall. Enteroendocrine cells sense
nutritive and non-nutritive properties of luminal food and, in response,
release satiation peptides from their basolateral aspect. These signals
diffuse through the lamina propria to activate nearby vagal- and spinalafferent fibers from neurons within the nodose and dorsal root ganglia,
respectively, as well as myenteric neurons. Satiation peptides can
also enter the bloodstream to act distantly as hormones. Gut-peptide
release is regulated not only by luminal nutrients but also by somatic
signals. The basolateral side of enteroendocrine cells bears receptors that respond to neurotransmitters, growth factors, and cytokines.
Neurotransmitters mediate duodenal-ileal communication to regulate
L cell secretion, and they enable central modulation of gut-peptide
release. Whether vagal- or spinal-afferent nerves are directly activated by ingested nutrients is uncertain. Although vagal- and spinalafferent fibers approach the abluminal aspect of enteroendocrine cells
and enterocytes, they do not form synapse-like contacts with these
epithelial cells, nor do they extend to the intestinal lumen. Some subepithelial nerve fibers might respond to luminal chemicals that diffuse
across the epithelium, such as FAs, but this applies only to short-chain
FAs, which do not efficiently elicit satiation (116). Other vagal-afferent
fibers respond selectively to intestinal carbohydrates or fats. Although
it is theoretically possible that these neurons sense nutrients in the
extracellular space, it is more clearly established that signaling molecules released from enteroendocrine cells mediate macronutrientspecific neural activation.

GLP1 is produced primarily by L cells in the distal small intestine and colon, where it colocalizes with oxyntomodulin and
peptide YY (PYY). Ingested nutrients, especially fats and carbohydrates, stimulate GLP1 secretion by indirect, duodenally activated neurohumoral mechanisms, as well as by direct contact
within the distal intestine (49). The two equipotent bioactive
forms, GLP17–36 amide and GLP17–37, are rapidly inactivated in
the circulation by dipeptidyl peptidase-4 (DPP4) (50). In addition
to engaging the ileal brake, GLP1 accentuates glucose-dependent
insulin release, inhibits glucagon secretion, and increases pancreatic ? cell growth (48). Therefore, DPP4-resistant GLP1 congeners are being developed to treat diabetes.
16	

GLP1 decreases food intake in several species (51, 52), including humans (53). Peripheral injections elicit satiety among normal-weight (54), obese (55), and diabetic (56) persons. Importantly, patients with diabetes treated with either GLP1 or the GLP1
receptor (GLP1R) agonist exenatide lose weight progressively in
trials lasting up to two years (57, 58). This is especially remarkable
because improved glycemic control achieved with other agents
typically promotes weight gain.
The mechanisms underlying GLP1-induced anorexia are not
fully known but involve vagal and possibly direct central pathways. Anorectic effects are mediated specifically by GLP1R, as
they are absent in GLP1R-deficient mice and are reversed with
selective GLP1R antagonists (59). GLP1R is expressed by the gut,
pancreas, brainstem, hypothalamus, and vagal-afferent nerves
(48). The vagus is required for peripheral GLP1-induced anorexia,
which is abolished by vagal transection or deafferentation (60, 61).
Whether peripheral GLP1 also functions through central receptors
is questionable. The peptide can cross the blood-brain barrier, but
it seems unlikely that physiologically relevant quantities of endogenous peripheral GLP1 evade peripheral DPP4 degradation and
penetrate the brain. However, GLP1 is produced by brainstem neurons that project to hindbrain and hypothalamic areas germane
to energy homeostasis, possibly regulating appetite. Activation of
hypothalamic GLP1R decreases food intake without causing illness, whereas GLP1R activation in the amygdala elicits malaise
(62). Although pharmacologic use of exenatide can stimulate the
illness pathway, nausea is not the only mechanism reducing food
intake. There is little correlation between the severity of nausea
and the amount of weight lost, and doses of exenatide too low to
cause nausea do promote weight loss.
Although GLP1 administration can reduce food intake, the
physiologic importance of GLP1 in feeding was challenged by the
observation that GLP1R-deficient mice have normal food intake
and body weight (63). Regardless of its physiologic significance
in energy homeostasis, GLP1R overstimulation offers an attractive pharmacologic antiobesity strategy, because it reduces body
weight while independently ameliorating diabetes.
Lower-intestinal satiation: oxyntomodulin
Like GLP1, oxyntomodulin is a proglucagon-derived peptide
secreted from distal-intestinal L cells in proportion to ingested calories. In rodents, exogenous administration decreases food intake
while increasing energy expenditure, and chronic injections reduce
body-weight gain (64, 65). In humans, i.v. infusion acutely lessens
hunger and single-meal food intake (66), and repeated injections
decreased body weight by 0.5 kg/wk more than placebo in a 4-week
trial (67). In this study, oxyntomodulin reduced buffet-meal intake
(without decreasing palatability) by 25% at the beginning of the
trial and by 38% at the end, indicating no tachyphylaxis. Replicating animal results, the regimen also increased activity-related
energy expenditure (68).
Although the mechanisms mediating these effects are enigmatic,
GLP1R is probably involved, since oxyntomodulin does not alter
feeding in GLP1R-deficient mice (59), and the GLP1R antagonist
exendin9–39 blocks oxyntomodulin-induced anorexia (64). Additional pathways are implicated, however, as oxyntomodulin binds
GLP1R 100 times less avidly than GLP1 does, yet they elicit anorexia at equimolar doses (64). The peptides also have different CNS
targets — oxyntomodulin activates neurons in the hypothalamus
(65), whereas GLP1 does so in the hindbrain and other autonomic

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control areas (69). Moreover, intrahypothalamic exendin9–39 inhibits anorectic effects of oxyntomodulin but not GLP1 (65), and
studies with GLP1R-deficient mice indicate that the two peptides
differentially regulate feeding and energy expenditure (59).
The crystal structure of oxyntomodulin has been solved, and this
advance should facilitate the rational design of oxyntomodulin
peptidomimetics to be tested as oral antiobesity pharmaceuticals.
Lower-intestinal satiation: PYY
The pancreatic polypeptide–fold (PP-fold) family includes PYY,
NPY, and PP. All are 36–amino acid peptides that require carboxyterminal amidation for bioactivity and share the PP-fold structural
motif. They interact with a family of receptors (Y1R, Y2R, Y4R,
Y5R, and Y6R) that couple to inhibitory G proteins. NPY is an
orexigenic hypothalamic neuropeptide; PP is discussed below.
PYY is produced mainly by distal-intestinal L cells, most of
which coexpress GLP1. It is secreted postprandially in proportion to caloric load, with a macronutrient potency of lipids being
greater than that of carbohydrates, which is greater than that of
proteins (70). As with GLP1, postprandial secretion is biphasic,
initially stimulated by atropine-sensitive neural projections from
the foregut, followed by direct nutrient stimulation in the hindgut
(71). PYY1–36 is rapidly proteolyzed by DPP4; unlike GLP1, however, the cleaved product, PYY3–36, is bioactive. Like GLP1, PYY delays
gastric emptying, contributing to the ileal brake (47).
A role for PYY3–36 in satiation was asserted in a recent set of studies
heralding this peptide as a promising antiobesity therapeutic (72,
73). It was reported that peripheral PYY3–36 administration, at doses
generating physiologic postprandial blood excursions, reduced food
intake and body weight in rats. In humans, i.v. infusion replicating
postprandial PYY3–36 concentrations lessened hunger and decreased
buffet-meal intake by 36%, without causing nausea, affecting food
palatability, or altering fluid intake. The reduced food intake was
not followed by compensatory hyperphagia. Interestingly, PYY3–36
levels were reported to be lower in obese than in lean persons, consistent with a role in obesity pathogenesis. Moreover, anorexia
induced by PYY3–36 was fully intact in obese individuals, in contrast
to obesity-associated resistance to the anorectic adiposity hormones
leptin and insulin. These findings suggested tantalizing therapeutic
potential for PYY3–36 and related peptidomimetics.
However, reports that PYY3–36 causes anorexia surprised some
investigators, because central administration of either PYY1–36 or
PYY3–36 potently increases food intake (74). To explain this paradox,
a mechanistic model was formulated, based on Y receptor subtype
selectivity and accessibility (72). PYY1–36 activates all Y receptors,
and orexigenic effects are predicted from its interactions with Y1R
and Y5R, which are expressed in the hypothalamic paraventricular
nucleus and are thought to mediate NPY-induced feeding. Accordingly, the feeding effects of central PYY are attenuated in both
Y1R-deficient and Y5R-deficient mice (75). PYY3–36 selectively activates Y2R and Y5R, and icv administration of this peptide might
increase food intake through Y5R. Circulating PYY3–36, however,
was hypothesized to gain access selectively to Y2R in the hypothalamic arcuate nucleus, an area believed by some to be accessible to
blood. In the hypothalamus, Y2R is a presynaptic autoinhibitory
receptor on orexigenic neurons that express both NPY and agoutirelated protein (AGRP), known as NPY/AGRP neurons. Therefore,
the model proposes that circulating PYY3–36 reduces food intake
by inhibiting NPY/AGRP neurons through Y2R, thereby derepressing adjacent anorectic melanocortin-producing cells, which


are inhibited by NPY/AGRP neurons (72). Consistent with this
model, the feeding effects of PYY3–36 are abolished by pharmacologic or genetic blockade of Y2R (61, 72, 76). Furthermore, PYY3–36
administration decreases hypothalamic NPY expression in vivo,
and it decreases NPY while increasing ?-melanocyte-stimulating
hormone release from hypothalamic explants. Finally, intra-arcuate injections of PYY3–36 inhibit food intake, whereas diffuse icv
injections do the opposite (72).
Despite these findings supporting a hypothalamic mechanism of
action of peripherally administered PYY3–36, Y2R is also expressed
by vagal-afferent terminals (77), and some investigators hypothesize vagal mediation. Supporting this assertion, anorectic effects
and arcuate neuronal activation elicited by peripheral PYY3–36 were
eliminated by either subdiaphragmatic vagotomy or transection of
hindbrain-hypothalamic pathways (60, 77).
Several laboratories reported difficulties in replicating anorectic effects of peripheral PYY3–36 administration, despite using
numerous rodent models, experimental protocols, and chemically
validated PYY3–36 preparations (78). However, several other groups
have confirmed anorectic and weight-reducing properties of this
peptide in rodents (61, 76, 79–83) and nonhuman primates (84).
Because stress reduces food intake, potentially masking additional
anorectic effects, differences in the habituation of animals to experimental procedures could explain some of these discrepancies (79),
although this does not settle the entire debate. The timing of injections is also important, efficacy being lost at certain times of day.
The original mechanistic model based on hypothalamic-Y2R-mediated NPY inhibition predicts that anorectic effects of PYY3–36 would
be maximal at times when arcuate NPY is elevated. Indeed, the initial findings were reported from rodents that were fasting or in the
early dark cycle — times when NPY is naturally induced (72).
In summary, the anorectic effects of peripheral PYY3–36 administration in rodents are subtle and vulnerable to vicissitudes of
animal handling, as well as the dose, route, and timing of injections. Although this might call into question the pragmatism
of PYY-based antiobesity therapeutics, anorectic effects of the
peptide seem to be more robust in primates than in rodents, and
the findings in humans have been corroborated (70). Nevertheless,
some pharmaceutical-industry support for clinical development
of intranasal PYY3–36 has abated because of insufficient efficacy.
Fat-specific satiation peptides: enterostatin and
apolipoprotein A-IV
Some GI peptides are specifically stimulated by fat ingestion
and subsequently regulate intake and/or metabolism of lipids.
Enterostatin is a pentapeptide cleaved from procolipase, which is
secreted from the exocrine pancreas in response to ingested fats
to facilitate their digestion. Procolipase is also produced in the
gut and several brain areas pertinent to energy homeostasis (85).
Both peripheral and central enterostatin administration decreases
dietary fat intake in animals, and enterostatin-receptor antagonists do the opposite (86). The mechanisms underlying these
effects seem complex but involve the F1-ATPase ? subunit as the
putative enterostatin receptor (87), with downstream mediators
including melanocortins and the 5-hydroxytryptamine (serotonin)
receptor 1B (88). Unfortunately, enterostatin administration to
humans has thus far shown no effects on food intake, appetite,
energy expenditure, or body weight (89).
Apolipoprotein A-IV (APO AIV) is a glycoprotein secreted from
the intestine in response to fat absorption and chylomicron forma-

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Figure 3
Similarities in nutrient-sensing mechanisms used by taste-receptor cells of the tongue and enteroendocrine cells of the intestine (exemplified by
an L cell). Several types of enteroendocrine cell throughout the gut express components of nutrient-sensing and signal-transduction systems
that were previously thought to be selective to taste-bud cells. These include apical G protein–coupled receptors for sweet and bitter chemicals;
the unusual G protein isoforms G?gustducin, G?3, and G?13; phospholipase C?2; and the TRPM5 Ca2+-activated Na+/K+ channel. Additional contributions from plasma membrane delayed-rectifying K+ channels and voltage-gated Ca2+ channels that are important for taste sensation in the
tongue have not yet been confirmed in enteroendocrine cells. In both cell types, the final common pathway for activation includes an increase in
intracellular calcium concentration. This triggers basolateral exocytosis of neurotransmitters from lingual taste-receptor cells into synapses with
nerve fibers that relay information to the hindbrain. In enteroendocrine cells, surges in intracellular calcium concentration trigger release from
the basolateral membrane of signaling molecules, including satiation peptides, which diffuse across extracellular fluids to enter the circulation or
to interact with nearby afferent nerve terminals from vagal, spinal, and myenteric neurons. IP3, inositol trisphosphate.

tion (90). It is used to package digested lipids for transit through
lymphatics to blood. It is also produced in the hypothalamic arcuate nucleus. Exogenous administration of APO AIV decreases meal
size, food intake, and weight gain in rats, whereas APO AIV–specific antibodies do the opposite (91). APO AIV is hypothesized to
represent a link between short- and long-term regulation of lipidrelated energy balance (90).
Pancreatic satiation peptides: PP and amylin
PP is produced in specialized islet cells under vagal control, and
its secretion is stimulated postprandially in proportion to caloric
load (92). Acting primarily on peripheral and central Y4R and Y5R,
it influences biliary and exocrine pancreatic function, gastric acid
18	

secretion, and GI motility. Whether PP has an important role in
energy homeostasis is controversial, in part because peripheral
administration decreases feeding, whereas central administration
increases it. Reminiscent of PYY, this disparity might result from
differential access to Y receptors — circulating PP decreasing food
intake through Y4R in the AP and central PP increasing it through
Y5R deeper in the brain. Peripheral PP injections reduce food
intake and weight gain in wild-type and genetically obese ob/ob
mice (93), and administration to humans decreases appetite and
food intake, independently of gastric emptying (94).
Amylin, a peptide cosecreted with insulin postprandially by pancreatic ? cells, inhibits gastric emptying, gastric acid, and glucagon secretion. It can also decrease meal size and food intake after

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peripheral or central administration (95, 96). In contrast to the
peripheral neural mechanisms engaged by many gut peptides,
amylin is a hormone that functions primarily on the AP (97). The
synthetic amylin analogue pramlintide is marketed for diabetes
treatment but also causes mild progressive weight loss for at least
26 weeks in humans (98).
Ghrelin: a unique orexigenic hormone
Ghrelin, an acylated peptide produced primarily by the stomach
and proximal small intestine, functions and is regulated oppositely to satiation peptides (99). It powerfully increases food intake
in diverse species (100), including humans (101), the only known
hormone to do so. Contrary to satiation peptides, ghrelin increases
GI motility and decreases insulin secretion. Also in contrast to satiation peptides, circulating levels surge shortly before meals and are
suppressed by ingested nutrients (with carbohydrates being more
effective than proteins, which are more effective than lipids). Postprandial suppression does not require luminal nutrient exposure
in either the stomach or the duodenum, where 80%–90% of ghrelin
production occurs, but results instead from neurally transmitted
(nonvagal) intestinal signals, augmented by insulin (99).
Ghrelin is implicated in mealtime hunger and meal initiation
because of its marked pre-meal surges (102). Moreover, ghrelin
enhances food intake by increasing the number of meals initiated, without altering their size, and it elicits numerous appetitive feeding behaviors. Preprandial ghrelin secretion seems to
be a cephalic response, possibly stimulated by the sympathetic
nervous system (103). Pre-meal ghrelin surges can be entrained
to regularly scheduled meals, and they might participate in the
anticipatory processes that enable animals to prepare for food
intake and nutrient disposition (104).
Beyond its proposed role in short-term feeding control, ghrelin
also fulfills established criteria for a hormone contributing to longterm body-weight regulation (99). First, circulating levels respond
in a compensatory manner to bidirectional body-weight changes
achieved by diverse means, increasing with weight loss and vice versa.
Second, ghrelin influences neuronal activity through its receptor in
several areas of the brain governing long-term energy homeostasis, including the hypothalamus (specifically arcuate NPY/AGRP
neurons), caudal brainstem, and mesolimbic reward centers. The
ghrelin receptor is also expressed by vagal-afferent nerves, which are
inhibited by ghrelin (opposite to satiation factors) (105), although
the importance of this for ghrelin-stimulated feeding is controversial. Third, chronic ghrelin administration increases body weight
through numerous anabolic effects on food intake, energy expenditure, and fuel utilization. Finally, pharmacologic ghrelin blockade
in adult animals decreases food intake and body weight, and mice
lacking ghrelin signaling resist diet-induced obesity (106, 107).
Because the obesity-resistant phenotypes of congenital ghrelindeficient and ghrelin receptor–deficient mice are subtle, the relative importance of ghrelin in energy homeostasis remains unclear,
and its efficacy as an antiobesity drug target is as yet unproven
in humans. Regardless of how physiologically vital ghrelin is in
energy homeostasis, however, it offers exciting potential for pharmacologic treatment of cachexia and GI motility disorders.
Mechanisms governing nutrient-stimulated peptide
secretion from enteroendocrine cells
The mechanisms by which food triggers release of GI satiation factors are more diverse than originally described and deserve special


attention. Various properties of food stimulate enteroendocrine
cells to secrete peptides that diffuse across the subepithelial lamina propria to activate vagal-, enteric-, and spinal-afferent nerves
and/or to enter the circulation (Figure 2). One mechanism mediating enteroendocrine cell activation, which regulates GLP1 release,
involves cellular uptake and intracellular metabolism of glucose.
This triggers peptide exocytosis via ATP-sensitive potassiumchannel closure, depolarization, and calcium-channel activation
— analogous to insulin secretion (108).
However, intestinal satiation and enteroendocrine cell activation
can occur without nutrient uptake or intracellular metabolism
(14, 109), by mechanisms resembling oral taste sensation (Figure
3). Both taste-receptor cells on the tongue and enteroendocrine
cells in the gut are polarized, with apical microvilli bearing receptors that detect chemical properties of food. In response to nutrients, signaling molecules are secreted from the basolateral sides of
both cell types, activating adjacent nerve terminals. Several enteroendocrine cell types throughout the gut express T1R2/3 sweet
taste receptors, T2R-family bitter receptors, and/or the taste-specific G protein G?gustducin, and these cells are activated by tastant
molecules (110–114). For example, intestinal L cells, which secrete
GLP1, oxyntomodulin, and PYY, express specialized isoforms of
molecules constituting a pathway for nutrient sensing and signal
transduction previously believed to be limited to taste-bud cells.
These components include sweet and bitter taste receptors; the?
G protein subunits ?gustducin, ?3, and ?13; phospholipase C?2 (which
increases intracellular Ca2+); and the TRPM5 Ca2+-activated Na+/
K+ channel (which depolarizes cells) (114). Importantly, taste-like
nutrient sensing is necessary for normal GLP1 secretion. The GLP1
response to both glucose and lipid gavage is absent in G?gustducindeficient mice, which consequently manifest impaired incretinmediated insulin secretion (115). In addition to stimulating peptide
release directly, sweet-taste-receptor activation by extracellular
tastants also upregulates glucose transporters in enteroendocrine
cells, possibly amplifying release of satiation peptides by enhancing
intracellular glucose uptake and metabolism (110).
Because the details of sweet-taste-receptor activation are understood at the atomic level, one can imagine rational design of noncaloric artificial sweeteners optimized for the combination of
palatable taste and potent L cell activation. These might supplement treatment of obesity and diabetes. Indeed, the nonabsorbable sweetener sucralose stimulates GLP1 release by taste receptor–dependent mechanisms (115).
CCK-producing STC-1 cells also express sweet and bitter taste
receptors, along with G?gustducin (110), and they respond to bitter
tastants with intracellular Ca2+ spikes and CCK release (113). This
fits with the strong CCK-stimulating ability of proteins, insofar as
bitterness in food derives disproportionately from proteins. Proteins also activate enteroendocrine cells through the extracellular
Ca2+-sensing G protein–coupled receptor (18), which recognizes the
aromatic amino acids tryptophan and phenylalanine — residues that
elicit intestinal satiation more effectively than other amino acids
(116). An interesting, unanswered question is whether the umami
receptor, which mediates protein taste sensation in the tongue,
contributes to enteroendocrine-cell protein detection. Similarly, we
wonder whether the ion channel salty and sour taste-bud receptors,
which are directly gated by Na+ and H+, respectively, might contribute to gut sensing of ionic and acidic properties of food.
Lipids effectively stimulate many satiation peptides, including
CCK, GLP1, oxyntomodulin, PYY, enterostatin, and APO AIV.

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19

review series
Figure 4
Central and peripheral sites at which the long-acting adiposity hormone leptin potentiates the actions of short-acting GI satiation factors.
Leptin-receptor signaling within the hypothalamus indirectly augments
hindbrain neuronal responses to gut satiation signals, such as CCK,
through hypothalamus-hindbrain projections involving oxytocin and
other neuropeptides (10, 11). Central responses to CCK are also augmented by leptin acting directly on the hindbrain. In the periphery, leptin
potentiates GI satiation signals both by enhancing gut-peptide secretion
(for example, GLP1 release from distal-intestinal L cells) and by heightening vagal-afferent responsiveness to gut peptides (for example, to
CCK from proximal-intestinal I cells). LepR, leptin receptor.

Fatty acids (FAs) must contain at least 12 carbons to activate?
I cells and stimulate CCK release (117); similarly, only long-chain
FAs elicit intestinal satiation (116). Enteroendocrine cells sense
FAs in part through the recently deorphanized receptor GPR120.
This cell-surface FA receptor is abundantly expressed on intestinal L cells, and it contributes to FA-induced GLP1 secretion (118).
Further research is needed to determine whether the FA receptors
GPR40–GPR43 are also involved, and whether enteroendocrine
cells detect lipids, as the tongue does, via the newly identified putative fat-taste receptor cofactor CD36 (119).
Interactions among long-term adiposity signals
and short-term satiation signals
Long-acting adiposity hormones that regulate body weight, such
as leptin and insulin, must ultimately influence eating behavior at
individual meals. Accordingly, leptin and insulin acting in the brain,
especially the hypothalamus, enhance central sensitivity to input
from short-acting peripheral satiation signals, such as CCK (10,
11). Emerging evidence suggests that analogous synergism between
long- and short-acting signals occurs in the gut (Figure 4). For example, leptin and insulin receptors are expressed on L cells, and activation of these receptors augments GLP1 secretion (120). Conversely,
and similarly to what occurs in the hypothalamus, L cells display
diet-induced leptin and insulin resistance, with diminished GLP1
release. These findings suggest that long- and short-acting anorectic
signals cooperate at the level of gut-peptide secretion.
Similar interactions occur at the level of vagal sensitivity to gut
peptides. A functional signaling isoform of the leptin receptor is
coexpressed with CCK1R by vagal-afferent nerve terminals in the
20	

stomach and duodenum (121). CCK activation of cultured vagal sensory neurons from these regions is enhanced by leptin (122), and the
two peptides function synergistically to increase discharge of vagalafferent fibers (123), just as they potentiate the anorectic actions
of each other (10, 11). Some authors speculate that these findings
establish a neuroanatomical substrate for complementary interactions between gastric leptin and intestinal CCK in short-term satiation. It is probably true that the gastric leptin secreted from chief cells
into the stomach lumen during meals travels to the duodenum and
stimulates CCK release (124). It is not clear, however, whether gastric leptin secreted from P cells into the circulation reaches duodenal
vagal fibers before passing through the liver and being diluted in the
general circulation, where leptin levels fluctuate only very minimally
with meals. Therefore, the enhancement of CCK-induced duodenal
vagal-afferent signaling by leptin might reflect a long-acting adiposity hormone (adipocyte leptin) increasing peripheral neural sensitivity to a short-acting GI satiation factor.
Just as the hypothalamus and hindbrain integrate input from
catabolic and anabolic peripheral signals reflecting energy status,
the vagus nerve seems to perform an analogous assimilative role
in the gut. GI vagal-afferent fibers display extensive colocalization of receptors for gut peptides that are anorexigenic, such as
CCK and leptin, as well as orexigenic, such as ghrelin, melaninconcentrating hormone (MCH), and orexins (125). At least some
of these receptors are regulated adaptively by alterations in nutritional state, and they interact with one another in a coordinated,
logical manner. For example, receptors for ghrelin and CCK are
coexpressed on vagal-afferent neurons (125), and these two ligands
exert antagonistic effects on vagal-afferent discharges (105). Similarly, catabolic gut peptides tend to suppress secretion of anabolic
gut peptides and vice versa, whereas ghrelin increases expression of
orexigenic cannabinoid-1 and MCH-1 receptors on vagal afferents
(125). These observations suggest that GI peptides act in a coordinated manner, belying their diffuse anatomical distribution. Moreover, alterations in nutritional state influence gut-brain satiation
signaling by recalibrating vagal sensitivity to GI signals.
Hopes for the future
The elegantly interconnected mechanisms by which the GI system
regulates food intake are a marvel of biology, but the redundancy
of both GI and CNS pathways governing energy homeostasis poses
formidable challenges for scientists designing antiobesity pharmaceuticals. Fortunately, our increasingly sophisticated understanding of these regulatory networks should facilitate the rational manipulation of their components to treat obesity, although
it may be necessary to influence more than one element of the
system jointly to achieve major weight reduction. Mounting evi-

The Journal of Clinical Investigation? ? ? http://www.jci.org? ? ? Volume 117? ? ? Number 1? ? ? January 2007

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dence indicates that the ability of certain bariatric operations to
promote profound weight loss and completely resolve type 2 diabetes results, in part, from their salutary modulation of several
gut peptides. These changes include stimulation of GLP1, PYY,
and oxyntomodulin, constraint of ghrelin secretion, and probably
other salient endocrine alterations. Continued research should
increasingly enable us to exploit these natural appetite-regulatory
systems pharmacologically to achieve at least some of the impressive effects of bariatric surgery with medications.
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Acknowledgments
This work was supported by NIH grants RO1 DK61516 and PO1
DK68384 (to D.E. Cummings).
Address correspondence to: David E. Cummings, University of
Washington, VA Puget Sound Health Care System, 1660 South
Columbian Way, S-111-Endo, Seattle, Washington 98108, USA.
Phone: (206) 764-2335; Fax: (206) 764-2689; E-mail: davidec@
u.washington.edu.

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