GASTROENTEROLOGY 2007;132:2116 2130

Gut Hormones and Appetite Control

A. M. WREN and S. R. BLOOM
Department of Metabolic Medicine, Imperial College London, London, England

Stephen R. Bloom, MD

Many peptides are synthesized and released from the

gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known
for some time, it is now evident that they also physiologically influence eating behavior. Our understanding of how neurohormonal gut brain signaling
regulates energy homeostasis has advanced significantly in recent years. Ghrelin is an orexigenic peptide produced by the stomach, which appears to act as
a meal initiator. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic
polypeptide, glucagon-like peptide 1, oxyntomodulin,
and cholecystokinin. Recent research suggests that
gut hormones can be manipulated to regulate energy
balance in humans, and that obese subjects retain
sensitivity to the actions of gut hormones. Gut hormone-based therapies may thus provide an effective
and well-tolerated treatment for obesity.

he gut is the most exciting endocrine organ in the

body. This remark from an endocrinologist may
once have been contentious in a gastroenterology journal. Currently, the neuroendocrine role of the gut in
energy homeostasis is a dynamic and rapidly expanding
field of scientific investigation that has united researchers
across many fields, as testified to by this special issue. The
concept of the gut as an endocrine organ is hardly new.
The gut peptide secretin was the first substance to be
termed a hormone, while the appetite inhibitory actions
of cholecystokinin (CCK) were first reported over 30 years
ago. However, in recent years, intensification of scientific
endeavor in this field has been motivated by the need to
develop new strategies to tackle the global pandemic of
obesity.
The prevalence of obesity in adults has increased by
over 75% worldwide since 1980.1 Given that obesity is
causally associated with cardiovascular disease, type 2
diabetes, hypertension, stroke, obstructive sleep apnoea,
and certain cancers, this has translated into healthcare
costs of over half a billion pounds every year in the

United Kingdom alone.2 Obesity is not only a problem in

the developed world, but is set to overtake infectious
diseases as the most significant contributor to ill health
worldwide, and has been classified as an epidemic by the
World Health Organization.3 The increasing prevalence
of obesity in younger generations suggests that this epidemic will continue to worsen.
Public health initiatives have failed to reverse the rising
incidence of obesity. Medical and behavioral interventions, with the exception of bariatric surgery, have limited success, in general promoting no more than 5%10%
reduction in body weight. Furthermore, weight regain,
even after this modest weight loss, is almost universal.4
There are good reasons for this, which can be understood
by examining the homeostatic mechanisms that defend
body weight. In attempting to lose weight by dieting, the
body faces compensatory starvation signals from the
gut and adipose tissue, all with a single aim of promoting
hunger and storage of calories as fat. The notion that
energy balance is tightly regulated to defend a set-point
body weight may seem contradictory to our common
experience that food intake varies widely day to day. Such
marked diurnal variation may have led to the popular
belief, particularly among lean individuals, that regulation of body weight is largely a matter of willpower. It is
hard to imagine such a view of the regulation of any
similarly important aspect of physiology, for example
blood pressure, persisting for so long. In fact, when
examined over the longer term, energy balance is extremely finely regulated.
During the evolution of the homeostatic mechanisms
regulating body weight, food shortage has been the
Abbreviations used in the paper: AgRP, agouti-related peptide; CCK,
cholecystokinin; CNS, central nervous system; GH, growth hormone;
GLP-1, glucagon-like peptide 1; NPY, neuropeptide Y; NTS, nucleus of
the solitary tract; POMC, pro-opiomelanocortin; PP, pancreatic
polypeptide; PWS, Prader-Willi syndrome; PYY, peptide YY.
2007 by the AGA Institute
0016-5085/07/$32.00
doi:10.1053/j.gastro.2007.03.048

May 2007

norm. The mechanisms that have allowed the human

race to survive famine may not be so well suited to the
current situation. The increasing incidence of obesity
coincides with widespread availability of highly palatable
food of high energy density that can be obtained without
having to expend energy. This review will focus on the
peptide hormone signals from the gut that communicate
the status of body energy stores to the brain and the
brain centers on which they act. These regulatory systems
are not only of academic interest, but are likely to underpin any future strategy to tackle obesity, by providing
drug targets for the holy grail of a safe sustainable weight
loss.
Currently available drug therapies have limited efficacy
and considerable side effects. Two agents are currently
licensed for weight loss. Orlistat inhibits dietary fat absorption, resulting in an additional loss of 3% to 4% of
body weight over diet alone in a 2-year period.5 It also
results in deficiency of fat-soluble vitamins and fairly
dramatic gastrointestinal side effects, which make it unacceptable for many patients. Sibutramine is a serotonin
and norepinephrine reuptake inhibitor that acts in the
central nervous system (CNS) to reduce energy intake
and increase energy expenditure. It has similar efficacy to
orlistat but also increases incidence of tachycardia and
hypertension. Both of these drugs only have data supporting treatment for up to 2 years. In the United Kingdom, national prescribing guidelines generally recommend withdrawal after 1 year, after which significant
weight regain is common.6
Several newer antiobesity therapies targeting CNS receptors are in development or have recently been marketed. Among these is rimonabant, a cannabinoid CB1
receptor antagonist. This appears to be an effective
weight-loss agent but is associated with high levels of
drop-out due to anxiety and depression.7 The CB1 receptor has a very wide distribution, both in the CNS and the
periphery, suggesting a wide range of physiologic functions.8 There is evidence that cannabinoids have neuroprotective, anti-inflammatory and antiatherosclerotic actions, and concerns have been raised that rimonabant
may promote diseases including multiple sclerosis and
ischemic heart disease.9,10 Clearly, the search for the ideal
antiobesity agent is not at an end.
At the other end of the appetite regulation spectrum,
there is a pressing need for more effective, better-tolerated appetite-stimulatory treatments. Loss of appetite
and weight are major causes of morbidity and mortality
in patients, including those with cancer, kidney failure,
human immunodificiency virus, cardiac failure, inflammatory conditions, and postoperatively. Weight loss has
an important impact on health economics. Undernutrition is estimated to increase the duration of 10% of
hospital admissions by an average of 5 days, costing
approximately 266 million annually in the United Kingdom.11 Although a comprehensive overview of anorexia

GUT HORMONES AND APPETITE CONTROL

2117

and cachexia is beyond the scope of this review, which

will focus mainly on obesity, the potential role of gut
hormones in this area will be briefly discussed.

Long-Term and Short-Term Energy

Balance Signals
Peripheral signals involved in regulation of body
weight and ingestive behavior are often categorized as
long-acting adiposity signals, such as insulin leptin and
other adipokines and short-acting gastrointestinal factors. Long-acting signals characteristically reflect the levels of energy stores and regulate body weight and the
amount of energy stored as fat over the long term. Shortacting gastrointestinal signals are typified by gut hormones such as CCK and mechanical factors, such as
gastric distension, which characteristically relay a sense of
fullness resulting in postprandial satiation and meal
termination. More recently identified appetite regulating
hormones from the gut, including the appetite inhibiting
hormone peptide YY (PYY) and the appetite-stimulating
hormone ghrelin, appear to blur the boundaries between
long- and short-term appetite signals, with evidence
emerging that they are involved in both regulation of
appetite on a meal-by-meal basis and also in longer term
energy balance. In addition, the incretin glucagon-like
peptide 1 (GLP-1), has been shown to inhibit appetite.
This is reviewed in detail elsewhere in this issue and will
not be covered here in depth. This review will focus on
the evidence for a role of the gut hormones ghrelin, PYY,
oxyntomodulin, and pancreatic polypeptide (PP) in the
short- and long-term regulation of energy balance.

Central Integration of Peripheral Signals

Clearly, peripheral hunger and satiety signals require central integration to allow efficient energy homeostasis. Neurohormonal signals from the gut and adipose tissue converge on the hypothalamus where they
are integrated, and in turn regulate energy intake and
energy expenditure. The reader is referred to a number of
excellent reviews of the hypothalamic neurocircuits regulating energy balance.1215 In brief, a vital component of
the hypothalamic regulatory circuits is the arcuate nucleus. Two key neuronal populations have been identified
within the arcuate nucleus with opposing effects on energy balance. A group of neurons in the medial arcuate
nucleus coexpress neuropeptide Y (NPY) and agouti-related peptide (AgRP) and act to stimulate food intake
and weight gain. In contrast, pro-opiomelanocortin
(POMC) and cocaine- and amphetamine-regulated transcript coexpressing neurons in the lateral arcuate nucleus
inhibit feeding and promote weight loss. The balance
between activity of these neuronal circuits is critical to
body weight regulation.
Satiety is also regulated by the hindbrain. The nucleus
of the solitary tract (NTS) and the area postrema, com-

2118

WREN AND BLOOM

GASTROENTEROLOGY Vol. 132, No. 6

Figure 1. Overview of peripheral factors regulating energy balance and their routes of signaling to the brain.

ponents of the dorsal vagal complex, receive inputs from

vagal afferents and circulating factors, and are reciprocally connected with hypothalamic nuclei controlling energy balance. These brainstem centers can also respond
independently to peripheral signals when communication with higher brain centers are surgically interrupted.16 In addition, cortical inputs in terms of emotional,
social, and learned behavior, as well as inputs from reward circuits, including the mesolimbic dopaminergic
system, all impact upon energy balance and communicate with the hypothalamus.
Peripheral feedback to the hypothalamus is complex,
as illustrated in Figure 1. Many circulating signals, including gut hormones, have direct access to the arcuate
nucleus. Leptin is the archetypal peripheral signal acting
directly on the arcuate nucleus.15,17 In contrast, other
peripheral signals influence the hypothalamus indirectly
via afferent neuronal pathways and brainstem circuits.
The most extensively characterized of these is CCK,
which binds to receptors on the vagus nerve, thus activating the NTS, which in turn, relays information to the
hypothalamus. Similarly, GLP-1R expressing neurons of
the NTS project to hypothalamic regions involved in
appetite control, including the arcuate, dorsomedial, and
paraventricular nuclei. In the cases of ghrelin and PYY,
there is evidence for both a direct action on the arcuate
nucleus and an action via the vagus nerve and brainstem.

Ghrelin, the Hunger Hormone

Ghrelin is the only known circulating orexigen. In
contrast, all the other peripheral factors that regulate
energy balance act to restrain eating and weight gain.
Ghrelin was discovered as an endogenous ligand for the
growth hormone (GH) secretagogue receptor (GHSR1a).18 However, early work on this peptide demonstrated a growth hormone-independent action to powerfully increase food intake and body weight. The
predominant focus of subsequent research has shifted
onto the role of ghrelin in energy balance.19 22

Ghrelin is a 28-amino acid peptide, cleaved from a

precursor, preproghrelin.18 It is principally synthesized in
endocrine cells of the stomach, termed X/A-like or ghrelin cells, and particularly found in the gastric fundus.18,23
About 2/3 to 3/4 of circulating ghrelin is of gastric
origin. Lesser concentrations of ghrelin are found
throughout the small intestine, with the duodenum producing approximately 10 times less than the stomach
and progressively lower concentrations found more distally.23,24 Ghrelin undergoes posttranslational modification with covalent attachment of a medium-chain fatty
acid, typically octanoic acid, to the serine-3 residue. This
acylation is entirely unique among biologically active
peptides and is required for ghrelin to bind to and activate its classical receptor, the GHS-R1a.18 The GHS-R1a
is widely expressed. In the CNS, it is found in areas
involved in regulation of appetite and energy balance
including hypothalamic nuclei, the dorsal vagal complex,
and the mesolimbic dopaminergic system.2527 Peripherally, it is expressed in the pituitary, and pharmacologically ghrelin acts at both pituitary and hypothalamic
levels to powerfully stimulate growth hormone secretion.18,20,28 30 The physiologic relevance of ghrelin in GH
regulation is debated. Ghrelin is not essential for GH
secretion, as ghrelin and GHS-R1a null mice are not
growth restricted, but it may play a role in augmentation
of GHRH-stimulated GH pulses.3133 GHS-R1a receptor
expression has also been described in diverse peripheral sites
including the myocardium, stomach, small intestine, pancreas, colon, adipose tissue, liver, kidney, placenta, and T
cells.25,26,34 An equally diverse series of biologic actions of
exogenous ghrelin have been documented, including effects
on glucose homeostasis, gut motility, pancreatic exocrine
secretion, cardiovascular function, immunity, and inflammation.33 The physiologic relevance of these actions remains unclear, and the major role of ghrelin is generally
accepted to be in regulation of energy balance. There is also
evidence for a number of pharmacologic actions of des-acyl
ghrelin, which must be mediated via receptors other than

May 2007

the GHS-R1a.35 The physiologic significance of these actions is contentious, as reviewed elsewhere.33,36 However,
experiments in GHS-R1a knockout mice have definitively
established that this receptor is required for the orexigenic
and GH stimulating effects of acylated ghrelin.32,37
When administered into the CNS, ghrelin stimulates
food intake as potently as NPY, previously the most
powerful known orexigen, and more powerfully than any
other substance examined.19 21 Ghrelin also stimulates
appetite and food intake when administered systemically
in rodents19,22 and humans.38 This property is unique to
ghrelin and not shared by any known neuropeptide or
circulating hormone. The duration of feeding stimulation in response to central or peripheral ghrelin administration is short, similar to that observed for central
NPY. Indeed, several lines of evidence suggest that ghrelin acts via arcuate NPY/AgRP neurons, almost all of
which express the GHS-R1a.39 Ghrelin stimulates feeding
most potently when injected directly into the arcuate
nucleus and also stimulates release of NPY from hypothalamic explants in vitro.22,30 Arcuate NPY/AgRP neurons are activated by ghrelin, as demonstrated by enhanced c-fos, NPY, and AgRP expression following
ghrelin administration and by electrophysiologic studies.21,40 43 Further, the orexigenic actions of ghrelin are
abolished in NPY/AgRP dual knockout mice and in mice
with postembryonic ablation of NPY/AgRP neurons.37,44
Although this neuronal population is the most wellcharacterized ghrelin target, there is also evidence for an
indirect action on these neurons via the vagus nerve.
Vagotomy abolishes the feeding and arcuate c-fos response to peripheral, but not central ghrelin administration.41,45 Other ghrelin targets include several other hypothalamic nuclei, the dorsal vagal complex of the
brainstem and components of the mesolimbic dopaminergic system. The GHS-R1a is also expressed in these
locations and microinjection of ghrelin directly into
these areas stimulates food intake.22,2527,46,47

Does Ghrelin Contribute to Preprandial

Hunger?
Several lines of evidence suggest that ghrelin may
regulate preprandial hunger. Circumstantially, the distribution of ghrelin, predominantly in the stomach and
upper small intestine, is ideal to monitor meal to meal
nutrient intake. The actions of exogenous ghrelin fulfill 1
of the minimum requirements for a meal initiator, that
is, stimulation of food intake when administered systemically, at doses that result in plasma concentrations similar to those found in the fasted (hungry) state. The onset
of action is rapid, duration is short, and ghrelin appears
to delay latency to feed and promote food-seeking behavior in rodents. Ghrelin stimulates food intake across a
broad range of species, including humans. The first 7, or
fewer, amino acids of ghrelin plus the octanoyl group on
the third serine residue constitute the minimum frag-

GUT HORMONES AND APPETITE CONTROL

2119

ment required for binding to and activation of the GHSR1a.48,49 These residues are highly conserved, suggesting
an important biologic role. Infusion of antighrelin antibodies into the rat brain inhibits fasting-induced feeding,
further supporting ghrelins role as an endogenous regulator of food intake.21
Plasma ghrelin levels were first noted to increase on
fasting and fall on refeeding in rodents, as would befit a
hunger signal.19,22 Subsequently, more detailed studies
have demonstrated preprandial plasma ghrelin elevation
in humans and animals fed at scheduled times.50 54 More
importantly, plasma ghrelin also peaks preprandially in
human subjects, who have been deprived of time cues,
initiating meals voluntarily.55 These plasma ghrelin
peaks correlated well with hunger scores. Postprandially,
plasma ghrelin is suppressed in proportion to calories
ingested, when macronutrient content and volume are
kept constant.56 Interestingly, fat appears to suppress
ghrelin less potently per calorie than carbohydrate or
protein.57,58 This may, in part, explain the reduced satiety
and enhanced weight gain associated with high-fat diets.
Taken together, these data strongly suggest a role for
ghrelin as a meal initiator. Whether ghrelin is the only, or
even a physiologically vital, hunger signal is as yet undetermined. This would require demonstration that interruption of ghrelin signaling, for example using antagonists or inducible knockouts, abolishes normal meal
initiation.

Ghrelin and Long-Term Energy

Homeostasis
In addition to a candidate role as a meal initiator,
ghrelin appears to participate in long-term energy balance. Chronic administration of ghrelin in rodents results in prolonged hyperphagia and weight gain.19,20 The
weight gain observed is greater than that expected for the
degree of hyperphagia, and may reflect several reported
actions of ghrelin that could combine to promote weight
gain. These include stimulation of adipogenesis, inhibition of apoptosis, transfer from fatty acid oxidation to
glycolysis for energy expenditure, and inhibition of sympathetic nervous system activity.19,35,59,60 There is 1 case
report of an individual with a malignant gastric ghrelinoma, who had extremely high circulating ghrelin concentrations and remained obese with preserved appetite,
despite advanced and eventually fatal malignant disease.61 Thus, prolonged elevation of plasma ghrelin certainly promotes adiposity, in contrast to the classical
short-term appetite regulator CCK, where prolonged administration does not reduce body weight. However, this
does not prove that endogenous ghrelin physiologically
regulates body weight.
In humans, ghrelin levels are inversely correlated with
adiposity, being low in the obese, higher in lean subjects,
and markedly elevated in subjects who are cachectic due
to a diverse range of conditions including anorexia ner-

2120

WREN AND BLOOM

vosa, cancer, and chronic cardiac failure.62 67 This has

been interpreted as an adaptive response to restrain further overeating in the obese or to stimulate it in the
underweight. This hypothesis is supported by longitudinal studies. Ghrelin is increased in response to weight
loss achieved either by diet alone or diet and exercise, and
is suppressed by overfeeding or successful treatment of
anorexia nervosa.64,68 70 Thus, ghrelin levels alter, in the
opposite direction to leptin, to reflect nutritional status
and body fat stores, supporting a role in long-term body
weight maintenance. An exception to this observation is
subjects with Prader-Willi syndrome (PWS), who have
very high fasting and postprandial ghrelin levels, which
may contribute to their obesity.71,72 It is unclear whether
hyperghrelinaemia drives the extreme hyperphagia associated with this syndrome. It has been noted that ghrelin
is not elevated in young children with PWS, in whom
hyperphagia has not yet developed.73 However, somatostatin infusion in PWS subjects suppresses ghrelin
without suppressing appetite.74 This might suggest that
factors other than elevated ghrelin drive hyperphagia in
PWS, although concomitant suppression of anorectic gut
hormones by somatostatin is a likely confounding factor.
If ghrelin is critical for body weight maintenance, reduction in ghrelin should promote weight loss and restoration of ghrelin should promote weight regain. This
has been demonstrated in mice undergoing total gastrectomy that have an 80% reduction in circulating ghrelin
associated with weight loss. Replacement of ghrelin to
physiologic levels results in weight regain. However, mice
with global deletions of ghrelin or the GHS-R1a were
initially reported to have minimal disruption of body
weight homeostasis. As always with such mouse models,
one must consider confounding by developmental adaptation. A clear example of this can be found in the
NPY/AgRP system on which ghrelin is thought to act.
NPY/AgRP dual null mice or mice in which the arcuate
NPY/AgRP neurons are destroyed shortly after birth exhibit minimal phenotype, whereas destruction of these
neurons later in development causes marked anorexia
and weight loss.44,75 Further studies on mice lacking
ghrelin or the GHS-R1a have demonstrated resistance to
diet induced obesity in mature mice.27,76 The phenotype
of ghrelin null mice might be further complicated by the
observation that the gene that codes for ghrelin has been
found to code for another peptide, named obestatin.
Obestatin was originally reported to reduce food intake
when administered peripherally or intracerebroventricularly, and to reduce body weight gain when administered
peripherally. These effects were proposed to be mediated
by the orphan G protein-coupled receptor, GPR39. Much
speculation followed as to why the same gene would
produce an orexigenic and an anorectic signal. However,
subsequent reports have not supported the initial findings and suggest that obestatin may not signal via GPR39
or play a role in the regulation of food intake.77,78 Mice

GASTROENTEROLOGY Vol. 132, No. 6

devoid of ghrelin signaling certainly lack the extreme

phenotypes associated with mice lacking leptin signaling.
However, taken together, data from knockout models are
compatible with a role for ghrelin in long-term energy
homeostasis.

Ghrelin as a Drug Target

Given that circulating ghrelin is already low in
obese subjects, one might question how much therapeutic benefit could be obtained from further ghrelin suppression. However, it has been reported that the rapid
postprandial drop in circulating ghrelin is attenuated in
obesity.79 It has also been shown that obese subjects may
be more sensitive to appetite stimulation by exogenous
ghrelin.80 Thus, inhibition of ghrelin may have therapeutic potential, particularly in enhancing further weight
loss and preventing weight regain following diet induced
weight loss, when ghrelin levels become elevated.
Several major pharmaceutical companies have pursued
programs investigating ghrelin inhibition. Interestingly,
the GHS-R1a exhibits constitutive activity, suggesting
that an inverse agonist may be more therapeutically useful than an antagonist.81 Another strategy is to design
compounds that bind to ghrelin itself and prevent interaction with its receptor. A novel group of molecules
called RNA spiegelmers, oligonucleotides containing Lribose, have been designed that are highly effective at
blocking interaction of ghrelin with the GHS-R1a in vitro
and in vivo. Antighrelin spiegelmers inhibit ghrelininduced GH secretion and reduce food intake and adiposity
in mice fed a high-fat diet, but have no effect in ghrelin
knockout mice.82 84 However, to date, no ghrelin-blocking products have progressed as far as phase I trials.
Indeed, there would be theoretical safety concerns about
such agents in view of the possible role of ghrelin in
regulation of the growth axis,18 as well as reported beneficial cardiovascular85 87 and anti-inflammatory88 effects
of ghrelin. Regulation of octanoylation of ghrelin may
provide an alternative drug target that is, as yet, relatively
unexplored. A more direct therapeutic application of
ghrelin is in the treatment of anorexia and cachexia. To
this end, proof of principle studies have demonstrated
that ghrelin stimulates appetite in patients with anorexia
and weight loss due to cancer and chronic kidney disease,
and may also improve meal enjoyment, without any adverse effects.89,90 Ghrelin administration by intravenous
infusion over 3 weeks results in weight gain in patients
with cardiac cachexia and chronic obstructive pulmonary
disease.91,92 However, weight gain may have been in part
attributable to improved general well-being, cardiac function, and respiratory muscle strength, rather than a sole
effect directly on energy balance. In addition these were
open-label studies and therefore did not control for placebo effect. Intravenous infusion is not a practical route
for chronic administration in most therapeutic settings.
However, ghrelin is effective when given by subcutaneous

May 2007

injection in healthy lean individuals and in malnourished

patients on peritoneal dialysis.90,93 Further placebo-controlled trials of long-term subcutaneous ghrelin administration in anorectic/cachectic patients are required to
establish whether this may be a useful therapy. In addition, a wide variety of orally active agonists for the GHSR1a were developed throughout the 1980s and 1990s,
before the discovery of ghrelin as an endogenous ligand,
which may have therapeutic potential in this context.94,95

Satiety Signals
After a meal, nutrients pass into the stomach and
intestine, and a number of gastrointestinal signals are
released. These peptides and other signals act to optimize
the digestive process, and some also function as shortterm satiety signals and possibly long-term regulators of
body weight.

CCK
CCK is the prototypical satiety hormone. It is now
over 30 years since CCK was first shown to inhibit food
intake, and it remains 1 of the most intensively studied of
the gut hormones.96 99 CCK is widely distributed within
the gastrointestinal tract, but the majority is synthesized
in the duodenum and jejunum. It is rapidly released into
the surrounding tissues and circulation in response to
nutrients in the gut, in particular, fat and protein-rich
meals, with levels rising approximately 5-fold postprandially. In addition to inhibiting food intake, its main
actions include delaying gastric emptying, stimulating
pancreatic enzyme secretion, and stimulating gall bladder
contraction. Together these actions promote the effective
digestion of fat and protein in the small intestine by
matching the delivery of nutrient with the capacity to
digest it.97,98
There are 2 distinct G protein-coupled CCK receptor
subtypes. In the rat, CCK-A (also called CCK-1) receptors
are found in the pancreas, on vagal afferent and enteric
neurons. CCK-A receptors are also found throughout the
brain, including the nucleus of the solitary tract, area
postrema, and dorsomedial hypothalamus. CCKB receptors are distributed throughout the brain, are present in
the afferent vagus nerve, and are found within the stomach.97,98
Administration of CCK, to humans and animals, inhibits food intake by reducing meal size and duration.96
Although at high dose nausea and taste aversion have
been detected, at low dose, feeding is inhibited without
these effects.100 The main receptor at which CCK exerts
these effects is the CCK-A receptor.101 Only the sulphated form of CCK binds with high affinity to the
CCK-A receptor, and it is only this form that inhibits
food intake.96 Recent work suggests that CCK-A receptors expressed by vagal afferent neurons are a particularly
important target for CCK in producing sensations of
satiety, as well as inhibiting gastric emptying and stimu-

GUT HORMONES AND APPETITE CONTROL

2121

lating pancreatic digestive enzyme secretion.99 It is

thought that the reduction in food intake may be mediated by a paracrine/neurocrine effect because high concentrations of CCK, which occur only local to the site of
release, are required.102 Thus, locally released CCK may
increase vagal tone, without a significant increase in
plasma CCK level.
As would be expected if CCK is a satiety signal, CCK-A
receptor antagonists increase calorie intake and reduce
satiety, suggesting endogenous CCK plays a physiologic
role in appetite regulation.103 CCK alone may be a very
short-term modulator of appetite. It has a half-life of
only 12 minutes, and it is not effective at reducing meal
size if the peptide is administered more than 15 minutes
before a meal.96 Furthermore, chronic administration of
CCK alone does not result in weight loss. However,
greater body weight loss is reported with a combination
of peripheral CCK and central leptin administration than
with central leptin administration alone.104 Thus, the
short-term meal terminator CCK may interact with leptin, a long-term signal of adiposity.
Some, but not all, data from rodent models with reduced CCK signaling support a role for CCK in regulation of long-term energy balance. Chronic administration
of either CCK antibodies or CCK-A receptor antagonists
results in weight gain in rodent models but with no
significant increase in food intake.105,106 In addition, the
CCK-A receptor knockout rat (but not the knockout
mouse) is hyperphagic and obese.107 The use of CCK as a
potential novel obesity therapy is in some doubt. In
animals, repeated preprandial administration of CCK reduces food intake but it also increases meal frequency,
with no resulting effect on body weight.108 Furthermore,
continuous CCK administration is ineffective after the
first 24 hours.109

PYY and PP
PYY, PP, and NPY are members of the PP-fold
peptide family and are both putative circulating satiety
factors. In addition to a shared tertiary structure, the
PP-fold structural motif, there is significant homology
between peptide sequences within the family. They all
have 36 amino acids, contain several tyrosine residues,
and require C-terminal amidation for biologic activity.
The PP-fold family exert their effects via the Y family of
G protein-coupled receptors. Four receptor subtypes have
been identifiedY1, Y2, Y4, and Y5all of which are
expressed in the hypothalamus.110 Y1 and Y5 have both
been put forward as the putative receptors via which NPY
exerts its orexigenic action. The Y2 receptor is thought to
function as an autoinhibitory presynaptic receptor, expressed on NPY neurons, and to mediate the anorectic
actions of PYY, while the Y4 receptor appears to mediate
the anorectic actions of PP.

2122

WREN AND BLOOM

PYY
PYY occurs in 2 forms: PYY136 and PYY336. PYY336,
the major circulating form (11), is a truncated 34-amino
acid form created by cleavage of the N-terminal Tyr-Pro
residues by dipeptidyl peptidase IV (DPPIV).111 Although
full-length PYY binds with similar affinity to all Y receptors,
PYY336 shows selectivity for the Y2 receptor, for which it has
high affinity, and some affinity for Y1 and Y5 receptors.110
PYY is secreted from entero-endocrine L-cells These
PYY immunoreactive cells are found throughout the entire gastrointestinal tract, but particularly in the distal
portion. PYY immunoreactivity is almost absent in the
stomach, sparse in the duodenum and jejunum, common
in the ileum and colon, and at very high levels in the
rectum (the converse pattern of that for ghrelin). The
pattern of secretion is also a mirror image of that found
for ghrelin; that is, PYY is released into the circulation
following meals and suppressed by fasting.112
PYY has long been known to exert numerous effects on
the gastrointestinal tract. Administration of PYY increases the absorption of fluids and electrolytes from the
ileum after a meal and inhibits pancreatic and gastric
secretions, gallbladder contraction, and gastric emptying.113 Peripheral administration of PYY, like ghrelin,
also exerts effects on numerous other body systems. For
example, it reduces cardiac output, causes vasoconstriction, and reduction in glomerular filtration rate, plasma
renin, and aldosterone activity. The physiologic significance of these numerous actions has not been established.

Does PYY Contribute to Postprandial

Satiety?
The pattern of PYY secretion in response to a meal
raises the possibility that it may be a physiologic satiety
signal, acting to terminate the meal and stimulating
coordinated gastrointestinal responses to aid digestion
and absorption. PYY levels rise to a plateau at 12 hours
postprandially, with these peak levels influenced by both
the number of calories and the composition of the food
consumed.112,114 The onset of PYY release occurs before
nutrients have reached the predominant sites of PYY
production in the distal gastrointestinal tract. This implies that peptide release may occur via a neural reflex,
possibly through the vagus nerve.
Systemic administration of PYY336 inhibits food intake in rodents and humans.115119 Initially, these findings were contentious, with several authors unable to
reproduce feeding inhibition in rodents.120 A probable
explanation for this apparent conflict is that the effects
of anorectic agents in rodents are easily masked by stress,
causing a reduction of food intake in the control group.
Thus, significant inhibition of feeding by PYY336 cannot
be detected in rodents that are not fully acclimatized to
experimental procedures or following transfer to a novel
environment.121

GASTROENTEROLOGY Vol. 132, No. 6

In humans, intravenous infusion of PYY336 reduces

appetite and food intake at a subsequent meal by about
1/3. Although initial reports detected inhibition of food
intake at plasma PYY concentrations in the physiologic
range, others have only detected an effect at pharmacologic doses.115,116,119 Thus, although there remains some
debate over whether PYY336 is a physiologic meal terminator in humans, appetite inhibition in response to exogenous PYY, in both lean and obese individuals, is a
robust and reproducible finding.

PYY and Long-Term Energy

Homeostasis
If circulating PYY336 is a long-term negative regulator of body weight, analogous to leptin, then chronic
systemic administration would be predicted to result in
weight loss. This has been reported in some but not all
rodent models, with more consistent effects observed
using intravenous administration and with dosage pattern also playing an important role.122 However, data
from knockout mice provide more convincing evidence
for a long-term role for PYY in regulation of energy
balance. Three separate knockout models have been generated, 2 of which develop obesity.123125 One model did
not become obese. This model also had disruption of
expression of the PP gene.123 One would not predict that
loss of a second putative anorectic signal would attenuate
obesity. However, subtle differences in technique and
background strain have frequently been reported to result in differing phenotypes in other knockout mouse
models. In 1 of the obese PYY null mouse models administration of PYY corrected the phenotype, suggesting that
obesity was truly being driven by PYY deficiency.125
In contrast to leptin, circulating levels of PYY are not
elevated in human obesity, and obese individuals retain
full sensitivity to the anorectic actions of PYY336.116 It
has been reported that obese subjects have lower fasting
and postprandial circulating PYY than lean subjects.114,116,26,127 To produce an equivalent stimulation of
PYY and equivalent satiety, obese individuals needed to
consume a much greater caloric load than their lean
counterparts.114 However, not all studies have detected a
difference in fasting PYY concentrations between lean
and obese groups.128,129
Current data suggest that impaired postprandial PYY
release may, at least, impair satiety and help to maintain
obesity, if not act as a primary driver of initial development of obesity. Whether or not reduced PYY signaling is
a primary cause of obesity, it is certainly true that retained PYY sensitivity in the obese makes it an attractive
therapeutic target.

Mechanism of Action of PYY

The exact mechanism whereby PYY336 inhibits
appetite and food intake is contentious. Interestingly, in

May 2007

contrast to peripheral administration, intracerebroventricular administration of PYY stimulates food intake.

This is thought to be via an action on Y1 and Y5 receptors in the paraventricular nucleus, the second-order neurons targeted by orexigenic arcuate nucleus NPY neurons.
Several lines of investigation suggest a direct anorectic
action of circulating PYY336 on the arcuate nucleus. c-fos
is observed in the arcuate nucleus in response to peripheral administration of PYY336 and direct microinjection
into the arcuate nucleus inhibits feeding. This action is
thought to be via autoinhibitory Y2 receptors on the
orexigenic NPY neurons. In support of this hypothesis, a
highly specific Y2 agonist inhibits feeding following intraarcuate injection, while the anorectic actions of
PYY336 are absent in the Y2 knockout mouse and
blocked by a Y2 receptor antagonist.115,130 Furthermore,
PYY336 reduces expression of NPY in the arcuate nucleus
and release of NPY from hypothalamic explants. Electrophysiologic studies suggest that PYY336 directly inhibits
activity of arcuate NPY neurons, thereby secondarily disinhibiting anorectic POMC neurons.115 However, the picture appears to be more complex than a simple action on
the arcuate nucleus. First, POMC neuronal disinhibition
does not appear to be necessary for the action of PYY336,
as it retains efficacy in mice with deficient melanocortin
signaling.131 Second, there is now evidence for an action
of PYY336 at the level of the vagus and of the dorsal vagal
complex.132 The relative contribution of these various
putative sites of action to physiologic appetite regulation
remains unclear. The ascending vagal brainstem hypothalamic pathways have, however, been implicated in
mediating sensations of nausea. In keeping with this,
PYY336 has, at high doses, been reported to cause conditioned taste avoidance in rodents and nausea in humans.114,119,133 However, lower doses inhibit appetite and
food intake in rodents and humans without aversive
effects or nausea.114,115,119,133 Coupled with the observation that PYY null mice become obese, this suggests a role
for PYY in appetite regulation independent of aversive
effects. Drug companies developing analogues of PYY for
treatment of obesity will need to be mindful of this
potentially narrow therapeutic window to design successful agents.

PP
PP is produced largely in the endocrine pancreas,
but also in the exocrine pancreas, colon, and rectum. Like
PYY, PP is released in response to a meal, in proportion to
the caloric load, and inhibits appetite.134 Pancreatic and
gastrointestinal hormones can also regulate circulating
PP levels. Ghrelin, motilin, and secretin rapidly stimulate
PP release, whereas somatostatin and its analogs significantly reduce plasma PP concentrations. PP binds with
greatest affinity to Y4 receptors (with greater affinity than
PYY) and Y5 receptors.110

GUT HORMONES AND APPETITE CONTROL

2123

The role of PP in appetite regulation has been investigated for over 30 years. It was initially noted that ob/ob
mice lacked pancreatic PP cells, and peripheral administration of PP could reduce their food intake and body
weight.135 Peripheral administration of PP resulting in
physiologic plasma levels has been shown to reduce food
intake in normal mice, with associated reduction in gastric emptying, and gastric expression of ghrelin, and
increased vagal tone.136 PP also increased oxygen consumption and stimulated sympathetic activity, leading to
the suggestion that PP may also increase energy expenditure. In normal-weight human volunteers infusion of
PP reduces food intake without altering gastric emptying.137 Subjects with PWS are reported to have suppressed basal and postprandial PP levels, while PP administration to PWS subjects reduced food intake.138,139 It is,
therefore, possible that PP deficiency contributes to the
hyperphagia in this obesity syndrome.
Apart from its acute effects on appetite and food
intake, PP may also modulate long-term energy balance.
Transgenic mice that overexpress PP have a lean phenotype with reduced food intake.140 Repeated administration of PP to ob/ob mice decreases body weight gain and
ameliorates insulin resistance and dyslipidemia.136 However, rodents with diet-induced obesity are less sensitive
to the anorectic actions of PP. Long-term energy stores
may influence the circulating PP levels as well as shortterm food intake. Plasma PP is increased in individuals
with anorexia nervosa, and there have been reports of
suppressed plasma PP in obese subjects. However, the
effects of obesity on circulating concentrations of PP are
conflicting; others have found no difference between lean
and obese subjects or between obese subjects before and
after weight loss. The effects of PP on appetite and body
weight in obese humans are unknown. Further investigation in obese subjects may indicate whether PP has the
potential to be a novel treatment for obesity.
PP, like PYY, has opposing effects on appetite, depending on the route of administration. Injection of PP into
the third ventricle stimulates daytime food intake in
satiated rats.141 Similarly, central injection of PP has the
opposite effect to peripheral administration on gastric
motility, stimulating rather than inhibiting gastric emptying. These contrasting effects of central and peripheral
administration of PP probably reflect differing sites of
receptor activation. PP is unable to cross the blood brain
barrier. Circulating PP therefore acts on the CNS via
areas that have a deficient blood brain barrier, such as
the area postrema. The passage of PP into the area postrema has been demonstrated by autoradiographic studies and neuronal activation by expression of the immediate early gene, c-fos, in the area postrema.142 The
anorectic effect seen after peripheral administration of
PP probably occurs via the Y4, which is highly expressed
in this region. The receptor mediating the orexigenic
effect of PP after central injection is unclear. The stimu-

2124

WREN AND BLOOM

Figure 2. Overview of differential preproglucagon processing in pancreas vs brain and gut. MPGF, major proglucagon fragment; GRRP,
glicentin-related pancreatic polypeptide; GLP, glucagon-like peptide;
SP, spacer peptide.

lation of food intake is blunted in Y5 knockout mice but

not by Y5 receptor antisense oligonucleotides.

Oxyntomodulin and GLP-1

Oxyntomodulin and GLP-1 are products of the
preproglucagon gene. Preproglucagon is expressed in the
pancreas, L-cells of the intestine, and in the NTS of the
brainstem and undergoes differential processing by prohormone convertase 1 and 2 depending on the site of
synthesis.143,144 as illustrated in Figure 2. In the pancreas,
classical preproglucagon processing yields glucagon and
the apparently inactive N-terminal fragment glicentinrelated pancreatic polypeptide while the GLP sequences
remain within a larger peptide, major proglucagon fragment. The posttranslational processing in the gut and
brain are very similar. In these tissues, the glucagon
sequence remains in a larger peptide, glicentin, which is
thought to be inactive. Glicentin is further cleaved to
yield oxyntomodulin and glicentin-related pancreatic
polypeptide. Oxyntomodulin is a 37-amino acid peptide
comprising the 29 amino acids of pancreatic glucagon
with an eight amino acid C-terminal extension, sometimes called spacer peptide 1. The other major products
of preproglucagon processing in gut and brain are the 2
glucagon-like peptides, GLP-1 and GLP-2.
GLP-1 and oxyntomodulin, along with PYY and CCK,
are released from intestinal L-cells in response to inges-

GASTROENTEROLOGY Vol. 132, No. 6

tion of nutrients and appear to act in part as satiety

signals as well as possibly participating in long-term body
weight regulation. GLP-1 is the most powerful known
incretin in humans, and manipulation of the GLP-1 system forms the basis of several major new treatments for
type 2 diabetes. These include a subcutaneously administered DPPIV-resistant GLP-1R agonist, exendin-4, a
peptide component of gila monster saliva marketed as
exenatide (Byetta), as well as orally active DPPIV inhibitors. The role of GLP-1 and other incretins in appetite
regulation is reviewed extensively elsewhere in this issue
and will not be discussed here in detail. However, in brief,
central administration of GLP-1, both intracerebroventricularly and into the paraventricular nucleus, reduces
calorie intake in animal models, while the GLP-1 receptor
antagonist exendin 9-39 increases food intake.145
Chronic administration of GLP-1 into the CNS attenuates weight gain146 and peripheral GLP-1 injection inhibits food intake in rodents and humans. Evidence suggests
GLP-1 secretion is reduced in obese subjects, and weight
loss normalizes the levels.147 Reduced GLP-1 secretion
could, therefore, contribute to obesity, and replacement
may restore satiety. Obese subjects receiving subcutaneous GLP-1 for 5 days, just before each meal, reduced their
calorie intake by 15% and lost 0.5 kg in weight.148

Oxyntomodulin
Oxyntomodulin inhibits calorie intake in rodents
when given either centrally or peripherally, and results in
decreased weight gain when administered peripherally.149 151 Oxyntomodulin is also an effective anorectic
peptide in human subjects. An infusion of oxyntomodulin to normal-weight human subjects reduced immediate
calorie intake by 19.3% and was effective at reducing food
intake up to 12 hours postinfusion.152 Part of its anorectic effect may be via suppression of plasma ghrelin levels.
Peripheral administration of oxyntomodulin, at postprandial concentrations, reduces circulating ghrelin by
around 15%20% in rodents and 44% in human subjects.151,152 It is possible that postprandial oxyntomodulin release may contribute to the normal physiologic
inhibition of plasma ghrelin after meals.
In contrast to GLP-1, oxyntomodulin is a much less
potent incretin but may have more potent effects on
weight loss. Although acute oxyntomodulin infusion in
humans reduces food intake, it only causes a small increase in plasma insulin without affecting plasma glucose.152 When administered 3 times daily in overweight
volunteers for 4 weeks, subcutaneous oxyntomodulin
resulted in 2.3 kg weight loss compared with 0.5 kg in the
control group.153 Enhanced weight loss in response to
oxyntomodulin may be due to an additional effect of
oxyntomodulin to increase energy expenditure. Acute administration of oxyntomodulin has been shown to increase voluntary activity in human subjects and to in-

May 2007

crease heart rate in rodents.151,154 The circulating levels of

oxyntomodulin in obesity remain to be established.
Both GLP-1 and oxyntomodulin are thought to exert
their effects via the GLP-1 receptor (GLP-1R). Antagonists of the GLP-1R, such as exendin (9 39), antagonize
the effect of both GLP-1 and oxyntomodulin, and both
peptides are ineffective in the GLP-1 receptor knockout
mouse.155 However, the affinity of oxyntomodulin for
GLP-1R is approximately 2 orders of magnitude less than
that of GLP-1, yet both peptides appear to be similarly
effective at reducing food intake. It is possible there may
be a separate oxyntomodulin receptor not yet cloned. The
GLP-1R is present in the NTS in the brainstem and the
hypothalamic arcuate nucleus. The mechanisms of action
of GLP-1 and oxyntomodulin appear to be similar but
not identical. Peripheral and central GLP-1 administration have been reported to activate neurons in the hypothalamic arcuate nucleus and paraventricular nucleus,
NTS, and area postrema.144 In addition, ablation of vagal brainstem hypothalamic projections attenuates
feeding inhibition by GLP-1.132 Although systemic oxyntomodulin administration results in a similar pattern of
neuronal activation to GLP-1, intraarcuate administration of exendin 9-39 blocks the anorectic effects on oxyntomodulin but not GLP-1, suggesting a direct action on
the arcuate nucleus.151
The duration of inhibition of food intake in response
to peripheral oxyntomodulin administration is short, necessitating 3 times daily subcutaneous injection in weight
loss studies in humans.153 This may be due to rapid
cleavage of the 2 N-terminal amino acid residues by
DPPIV, as observed for GLP-1 and PYY. DDPIV resistant
analogs of oxyntomodulin may, thus, have greater therapeutic potential than the native peptide.

Dietary Manipulation of Gut Hormones

It has been suggested that a cause of the current
obesity epidemic may be that modern processed foods
bypass our natural satiety mechanisms. Low-fat diets
are the most well-established means of dietary weight
loss. It has been reported that weight loss in response
to a low-fat diet does not produce the expected elevation in plasma ghrelin.156,157 This may be due to an
increase in the proportion of calories consumed as
carbohydrate that more potently suppresses ghrelin
per calorie consumed than does fat. High-protein diets
have also become popular in recent years as a means to
promote satiety and weight loss. Diets high in protein
have recently been reported to elevate circulating PYY
and enhance satiety more effectively than other macronutrients;125 however, previous data suggested that, at
a single meal, higher plasma concentrations of PYY
were stimulated by high-fat isocaloric meals, compared
with protein or carbohydrate.112 It is an intriguing
possibility that designer diets may help promote the

GUT HORMONES AND APPETITE CONTROL

2125

most favorable gut hormone profile to allow sustained

weight loss.

A Coordinated Response to Obesity

In designing an optimal treatment for obesity,
based upon physiologic satiety mechanisms, perhaps
our biggest clues come from the field of bariatric
surgery. The only treatment to date associated with
dramatic and sustained weight loss in the morbidly
obese is gastric bypass surgery. However, its cost and
associated morbidity and mortality make it an impractical treatment for the majority of obese patients and it
is generally reserved for the morbidly obese. Gastric
bypass results in significant increases in plasma PYY,
GLP-1, and oxyntomodulin while ghrelin either falls or
fails to rise, despite significant weight loss.158,159 Interestingly, bypass patients report dramatically reduced
hunger long before substantial weight loss occurs. Furthermore, in rodent models, many of the beneficial
effects of bypass can be mimicked by gut hormone
administration.158 Could the altered gut hormones following gastric bypass be sending fullness signals
resulting in sustained weight loss, in contrast to the
starvation signals that accompany diet-induced
weight loss, promoting weight regain? It is notable
that the changes in the 4 gut hormones above all favor
weight loss following gastric bypass. This coordinated
action, mimicking natural satiety, may be a key to
effective antiobesity therapy. As noted above, individual gut hormones administered at high concentrations
have been associated with aversive behaviors in rodents
and nausea in humans. We have reported that low
doses of PYY336 and GLP-1 inhibit food intake additively.160 Analogous to current treatment for hypertension where several agents are commonly used, a smart
cocktail of gut hormone-based drugs may prove a more
effective antiobesity treatment than targeting a single
system. This approach could potentially provide the
sustained weight loss offered by gastric bypass surgery,
without the associated morbidity and mortality. The
major therapeutic disadvantage of gut hormones is
their short duration of action and the requirement for
subcutaneous or intravenous administration. In the
GLP-1 system, degradation-resistant analogs and drugs
that inhibit enzymes that degrade the endogenous
hormone have already been brought to market for the
treatment of type 2 diabetes. Similar approaches may
be successful for oxyntomodulin, PYY, and PP, while
intranasal delivery systems or development of orally
active small molecule mimetics could avoid the need
for administration by injection.
Obesity is the most significant growing health concern
worldwide. Current treatments, barring bariatric surgery,
are insufficiently effective. Many drugs in development
do not target physiologic satiety mechanisms and have
worrisome side effects attributable to the ubiquitous

2126

WREN AND BLOOM

distribution of the receptor systems targeted. Recent data

suggests that gut hormones regulate when and how
much we eat for every meal and offer a safe, logical drug
target. Mimicking natural satiety mechanisms by delivering combinations of gut hormones may replace bariatric
surgery as the only truly effective antiobesity treatment.
References
1. Flegal KM. Epidemiologic aspects of overweight and obesity in
the United States. Physiol Behav 2005;86:599 602.
2. Bourn J. Tackling obesity in England. Report by the comptroller
and auditor general. England: The Stationery Office, House of
Commons, 2001.
3. WHO. Obesity: preventing and managing the global epidemic.
Report of a WHO consultation on obesity. Geneva, Switzerland:
Author, 2004.
4. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002;346:
591 602.
5. Curran MP, Scott LJ. Spotlight on orlistat in the management of
patients with obesity. Treat Endocrinol 2005;4:127129.
6. Finer N. Pharmacotherapy of obesity. Best Pract Res Clin Endocrinol Metab 2002;16:717742.
7. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S.
Effects of the cannabinoid-1 receptor blocker rimonabant on
weight reduction and cardiovascular risk factors in overweight
patients: 1-year experience from the RIO-Europe study. Lancet
2005;365:1389 1397.
8. Howlett AC. The cannabinoid receptors. Prostaglandins Other
Lipid Mediat 2002;68-69:619 631.
9. van OB, Killestein J, Polman C. Effect of rimonabant on weight
reduction and cardiovascular risk. Lancet 2005;366:368 369.
10. Hirschel B. Effect of rimonabant on weight reduction and cardiovascular risk. Lancet 2005;366:369 370.
11. Kings Fund. A positive approach to nutrition as a treatment.
Report of a working party charied by JE Lennard-Jones. 2003.
12. Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ. The
arcuate nucleus as a conduit for diverse signals relevant to
energy homeostasis. Int J Obes Relat Metab Disord 2001;
25(Suppl 5):S63S67.
13. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG.
Central nervous system control of food intake. Nature 2000;
404:661 671.
14. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting
appetite-regulating pathways in the hypothalamic regulation of
body weight. Endocr Rev 1999;20:68 100.
15. Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004;116:337350.
16. Grill HJ, Smith GP. Cholecystokinin decreases sucrose intake in
chronic decerebrate rats. Am J Physiol 1988;254:R853R856.
17. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman
JM. Positional cloning of the mouse obese gene and its human
homologue. Nature 1994;372:425 432.
18. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa
K. Ghrelin is a growth-hormone-releasing acylated peptide from
stomach. Nature 1999;402:656 660.
19. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in
rodents. Nature 2000;407:908 913.
20. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S,
Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR.
The novel hypothalamic peptide ghrelin stimulates food intake
and growth hormone secretion. Endocrinology 2000;141:4325
4328.
21. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S. A role for ghrelin in the central regulation
of feeding. Nature 2001;409:194 198.

GASTROENTEROLOGY Vol. 132, No. 6

22. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal l, Cohen MA,
Batterham RL, Taheri S, Stanley SA, Ghatei MA, Bloom SR.
Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001;
50:2540 2547.
23. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M. Ghrelin, a
novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal
tracts of rats and humans. Endocrinology 2000;141:4255
4261.
24. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T,
Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T,
Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K.
Stomach is a major source of circulating ghrelin, and feeding
state determines plasma ghrelin-like immunoreactivity levels in
humans. J Clin Endocrinol Metab 2001;86:4753 4758.
25. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, van der Ploeg LH, Howard AD. Distribution
of mRNA encoding the growth hormone secretagogue receptor
in brain and peripheral tissues. Brain Res Mol Brain Res 1997;
48:2329.
26. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits
M. The tissue distribution of the mRNA of ghrelin and subtypes
of its receptor, GHS-R, in humans. J Clin Endocrinol Metab
2002;87:2988.
27. Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK. Expression of ghrelin receptor mRNA in the rat and the mouse brain.
J Comp Neurol 2006;494:528 548.
28. Date Y, Murakami N, Kojima M, Kuroiwa T, Matsukura S, Kangawa K, Nakazato M. Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochem Biophys Res Commun 2000;275:477 480.
29. Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A,
Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y,
Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K. Ghrelin
strongly stimulates growth hormone release in humans. J Clin
Endocrinol Metab 2000;85:4908 4911.
30. Wren AM, Small CJ, Fribbens CV, Neary NM, Ward HL, Seal LJ,
Ghatei MA, Bloom SR. The hypothalamic mechanisms of the
hypophysiotropic action of ghrelin. Neuroendocrinology 2002;
76:316 324.
31. Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither
growth nor appetite. Mol Cell Biol 2003;23:79737981.
32. Sun Y, Wang P, Zheng H, Smith RG. Ghrelin stimulation of
growth hormone release and appetite is mediated through the
growth hormone secretagogue receptor. Proc Natl Acad Sci U S
A 2004;101:4679 4684.
33. Van Der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological,
physiological, pathophysiological, and pharmacological aspects
of ghrelin. Endocr Rev 2004;25:426 457.
34. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA,
Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J,
Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS,
Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M,
Sirinathsinghji DJS, Dean DC, Melillo DG, van der Ploeg LH. A
receptor in pituitary and hypothalamus that functions in growth
hormone release. Science 1996;273:974 977.
35. Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA,
Robinson IC, Wells T. Ghrelin and des-octanoyl ghrelin promote
adipogenesis directly in vivo by a mechanism independent of
the type 1a growth hormone secretagogue receptor. Endocrinology 2004;145:234 242.
36. Cummings DE, Foster-Schubert KE, Overduin J. Ghrelin and
energy balance: focus on current controversies. Curr Drug Targets 2005;6:153169.

May 2007

37. Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR,
Frazier EG, Shen Z, Marsh DJ, Feighner SD, Guan XM, Ye Z,
Nargund RP, Smith RG, van der Ploeg LH, Howard AD, MacNeil
DJ, Qian S. Orexigenic action of peripheral ghrelin is mediated
by neuropeptide Y (NPY) and agouti-related protein (AgRP). Endocrinology 2004;145:20072012.
38. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG,
Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite
and increases food intake in humans. J Clin Endocrinol Metab
2001;86:59925995.
39. Willesen MG, Kristensen P, Romer J. Co-localization of growth
hormone secretagogue receptor and NPY mRNA in the arcuate
nucleus of the rat. Neuroendocrinology 1999;70:306 316.
40. Dickson SL, Luckman SM. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing
factor neurons in the rat arcuate nucleus following systemic
injection of the GH secretagogue, GH-releasing peptide-6. Endocrinology 1997;138:771777.
41. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M,
Katsuura G, Makino S, Fujino MA, Kasuga M. A role of ghrelin in
neuroendocrine and behavioral responses to stress in mice.
Neuroendocrinology 2001;74:143147.
42. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression.
Endocrinology 2000;141:4797 4800.
43. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove
KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML,
Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P,
Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL.
The distribution and mechanism of action of ghrelin in the CNS
demonstrates a novel hypothalamic circuit regulating energy
homeostasis. Neuron 2003;37:649 661.
44. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster
Z, Ghatei MA, Bloom SR. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J
2005;19:1680 1682.
45. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M. The role of the gastric afferent
vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 2002;123:1120 1128.
46. Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN,
de Barioglio SR. Differential role of the hippocampus, amygdala,
and dorsal raphe nucleus in regulating feeding, memory, and
anxiety-like behavioral responses to ghrelin. Biochem Biophys
Res Commun 2004;313:635 641.
47. Naleid AM, Grace MK, Cummings DE, Levine AS. Ghrelin induces feeding in the mesolimbic reward pathway between the
ventral tegmental area and the nucleus accumbens. Peptides
2005;26:2274 2279.
48. Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL,
Silva MV, Warren VA, Howard AD, van der Ploeg LH, Heck JV.
Structurefunction studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for
activation of growth hormone secretagogue receptor 1a. J Med
Chem 2000;43:4370 4376.
49. Matsumoto M, Kitajima Y, Iwanami T, Hayashi Y, Tanaka S,
Minamitake Y, Hosoda H, Kojima M, Matsuo H, Kangawa K.
Structural similarity of ghrelin derivatives to peptidyl growth
hormone secretagogues. Biochem Biophys Res Commun 2001;
284:655 659.
50. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE,
Weigle DS. A preprandial rise in plasma ghrelin levels suggests
a role in meal initiation in humans. Diabetes 2001;50:1714
1719.
51. Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M,
Landgraf R, Folwaczny C. Post-prandial decrease of circulating

GUT HORMONES AND APPETITE CONTROL

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

2127

human ghrelin levels. J Endocrinol Invest 2001;24:

RC19 RC21.
Drazen DL, Vahl TP, DAlessio DA, Seeley RJ, Woods SC. Effects
of a fixed meal pattern on ghrelin secretion: evidence for a
learned response independent of nutrient status. Endocrinology
2006;147:2330.
Sugino T, Yamaura J, Yamagishi M, Ogura A, Hayashi R, Kurose
Y, Kojima M, Kangawa K, Hasegawa Y, Terashima Y. A transient
surge of ghrelin secretion before feeding is modified by different
feeding regimens in sheep. Biochem Biophys Res Commun
2002;298:785788.
Miura H, Tsuchiya N, Sasaki I, Kikuchi M, Kojima M, Kangawa K,
Hasegawa Y, Ohnami Y. Changes in plasma ghrelin and growth
hormone concentrations in mature Holstein cows and threemonth-old calves. J Anim Sci 2004;82:1329 1333.
Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D.
Plasma ghrelin levels and hunger scores in humans initiating
meals voluntarily without time- and food-related cues. Am J
Physiol Endocrinol Metab 2004;287:E297E304.
Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC,
Weigle DS. Postprandial suppression of plasma ghrelin level is
proportional to ingested caloric load but does not predict intermeal interval in humans. J Clin Endocrinol Metab 2004;89:
1319 1324.
Monteleone P, Bencivenga R, Longobardi N, Serritella C, Maj M.
Differential responses of circulating ghrelin to high-fat or highcarbohydrate meal in healthy women. J Clin Endocrinol Metab
2003;88:5510 5514.
Overduin J, Frayo RS, Grill HJ, Kaplan JM, Cummings DE. Role of
the duodenum and macronutrient type in ghrelin regulation.
Endocrinology 2005;146:845 850.
Choi K, Roh SG, Hong YH, Shrestha YB, Hishikawa D, Chen C,
Kojima M, Kangawa K, Sasaki S. The role of ghrelin and growth
hormone secretagogues receptor on rat adipogenesis. Endocrinology 2003;144:754 759.
Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M. Central
ghrelin modulates sympathetic activity in conscious rabbits.
Hypertension 2002;40:694 699.
Tsolakis AV, Portela-Gomes GM, Stridsberg M, Grimelius L,
Sundin A, Eriksson BK, Oberg KE, Janson ET. Malignant gastric
ghrelinoma with hyperghrelinemia. J Clin Endocrinol Metab
2004;89:3739 3744.
Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E,
Heiman ML. Circulating ghrelin levels are decreased in human
obesity. Diabetes 2001;50:707709.
Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M,
Nozoe S, Hosoda H, Kangawa K, Matsukura S. Plasma ghrelin
levels in lean and obese humans and the effect of glucose on
ghrelin secretion. J Clin Endocrinol Metab 2002;87:240 244.
Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL,
Heiman ML, Lehnert P, Fichter M, Tschop M. Weight gain decreases elevated plasma ghrelin concentrations of patients with
anorexia nervosa. Eur J Endocrinol 2001;145:669 673.
Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C,
Dardennes R, Mounier C, Zizzari P, Lang F, Epelbaum J, Estour
B. Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women. J Clin Endocrinol
Metab 2003;88:109 116.
Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, Hosoda H, Shimizu W, Yamagishi M, Oya H, Koh H,
Yutani C, Kangawa K. Elevated circulating level of ghrelin in
cachexia associated with chronic heart failure: relationships
between ghrelin and anabolic/catabolic factors. Circulation
2001;104:2034 2038.
Shimizu Y, Nagaya N, Isobe T, Imazu M, Okumura H, Hosoda H,
Kojima M, Kangawa K, Kohno N. Increased plasma ghrelin level
in lung cancer cachexia. Clin Cancer Res 2003;9:774 778.

2128

WREN AND BLOOM

68. Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Christiansen JS, Jorgensen JO. Weight loss increases circulating
levels of ghrelin in human obesity. Clin Endocrinol (Oxf) 2002;
56:203206.
69. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. Plasma ghrelin levels after diet-induced
weight loss or gastric bypass surgery. N Engl J Med 2002;346:
16231630.
70. Ravussin E, Tschop M, Morales S, Bouchard C, Heiman ML.
Plasma ghrelin concentration and energy balance: overfeeding
and negative energy balance studies in twins. J Clin Endocrinol
Metab 2001;86:4547 4551.
71. Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE,
Frayo RS, Schwartz MW, Basdevant A, Weigle DS. Elevated
plasma ghrelin levels in Prader Willi syndrome. Nat Med 2002;
8:643 644.
72. DelParigi A, Tschop M, Heiman ML, Salbe AD, Vozarova B, Sell
SM, Bunt JC, Tataranni PA. High circulating ghrelin: a potential
cause for hyperphagia and obesity in prader-willi syndrome.
J Clin Endocrinol Metab 2002;87:54615464.
73. Erdie-Lalena CR, Holm VA, Kelly PC, Frayo RS, Cummings DE.
Ghrelin levels in young children with Prader-Willi syndrome. J Pediatr 2006;149:199 204.
74. Tan TM, Vanderpump M, Khoo B, Patterson M, Ghatei MA,
Goldstone AP. Somatostatin infusion lowers plasma ghrelin
without reducing appetite in adults with Prader-Willi syndrome.
J Clin Endocrinol Metab 2004;89:4162 4165.
75. Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated
in neonates. Science 2005;310:683 685.
76. Wortley KE, Del Rincon JP, Murray JD, Garcia K, Iida K, Thorner
MO, Sleeman MW. Absence of ghrelin protects against earlyonset obesity. J Clin Invest 2005;115:35733578.
77. Holst B, Egerod KL, Schild E, Vickers SP, Cheetham S, Gerlach
LO, Storjohann L, Stidsen CE, Jones R, Beck-Sickinger AG,
Schwartz TW. GPR39 signaling is stimulated by zinc ions but not
by obestatin. Endocrinology 2007;148:1320.
78. Nogueiras R, Pfluger P, Tovar S, Myrtha A, Mitchell S, Morris A,
Perez-Tilve D, Vazquez MJ, Wiedmer P, Castaneda TR, Dimarchi
R, Tschop M, Schurmann A, Joost HG, Williams LM, Langhans
W, Dieguez C. Effects of obestatin on energy balance and growth
hormone secretion in rodents. Endocrinology 2007;148:2126.
79. English PJ, Ghatei MA, Malik IA, Bloom SR, Wilding JP. Food fails
to suppress ghrelin levels in obese humans. J Clin Endocrinol
Metab 2002;87:2984.
80. Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G,
Ghatei MA, Small C, Bloom SR. Ghrelin increases food intake in
obese as well as lean subjects. Int J Obes (Lond) 2005;29:
1130 1136.
81. Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW.
High constitutive signaling of the ghrelin receptoridentification
of a potent inverse agonist. Mol Endocrinol 2003;17:2201
2210.
82. Helmling S, Maasch C, Eulberg D, Buchner K, Schroder W, Lange
C, Vonhoff S, Wlotzka B, Tschop MH, Rosewicz S, Klussmann S.
Inhibition of ghrelin action in vitro and in vivo by an RNASpiegelmer. Proc Natl Acad Sci U S A 2004;101:13174 13179.
83. Kobelt P, Helmling S, Stengel A, Wlotzka B, Andresen V, Klapp
BF, Wiedenmann B, Klussmann S, Monnikes H. Anti-ghrelin
Spiegelmer NOX-B11 inhibits neurostimulatory and orexigenic
effects of peripheral ghrelin in rats. Gut 2006;55:788 792.
84. Shearman LP, Wang SP, Helmling S, Stribling DS, Mazur P, Ge
L, Wang L, Klussmann S, MacIntyre DE, Howard AD, Strack AM.
Ghrelin neutralization by a ribonucleic acid-SPM ameliorates
obesity in diet-induced obese mice. Endocrinology 2006;147:
15171526.

GASTROENTEROLOGY Vol. 132, No. 6

85. Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S,

Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, Surico
N, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M,
Muccioli G, Ghigo E, Graziani A. Ghrelin and des-acyl ghrelin
inhibit cell death in cardiomyocytes and endothelial cells
through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002;159:
1029 1037.
86. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya
H, Hayashi Y, Kangawa K. Hemodynamic and hormonal effects
of human ghrelin in healthy volunteers. Am J Physiol Regul Integr
Comp Physiol 2001;280:R1483R1487.
87. Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu
W, Hosoda H, Hirota Y, Ishida H, Mori H, Kangawa K. Chronic
administration of ghrelin improves left ventricular dysfunction
and attenuates development of cardiac cachexia in rats with
heart failure. Circulation 2001;104:1430 1435.
88. Dixit VD, Taub DD. Ghrelin and immunity: a young player in an
old field. Exp Gerontol 2005;40:900 910.
89. Neary NM, Small CJ, Wren AM, Lee JL, Druce MR, Palmieri C,
Frost GS, Ghatei MA, Coombes RC, Bloom SR. Ghrelin increases energy intake in cancer patients with impaired appetite:
acute, randomized, placebo-controlled trial. J Clin Endocrinol
Metab 2004;89:28322836.
90. Wynne K, Giannitsopoulou K, Small CJ, Patterson M, Frost G,
Ghatei MA, Brown EA, Bloom SR, Choi P. Subcutaneous ghrelin
enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebocontrolled trial. J Am Soc Nephrol 2005;16:21112118.
91. Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W,
Ueno K, Kitakaze M, Miyatake K, Kangawa K. Effects of ghrelin
administration on left ventricular function, exercise capacity,
and muscle wasting in patients with chronic heart failure. Circulation 2004;110:3674 3679.
92. Nagaya N, Itoh T, Murakami S, Oya H, Uematsu M, Miyatake K,
Kangawa K. Treatment of cachexia with ghrelin in patients with
COPD. Chest 2005;128:11871193.
93. Druce MR, Neary NM, Small CJ, Milton J, Monteiro M, Patterson
M, Ghatei MA, Bloom SR. Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers.
Int J Obes (Lond) 2006;30:293296.
94. Bowers CY. Unnatural growth hormone-releasing peptide begets
natural ghrelin. J Clin Endocrinol Metab 2001;86:1464 1469.
95. Smith RG, Palyha OC, Feighner SD, Tan CP, McKee KK, Hreniuk
DL, Yang L, Morriello G, Nargund R, Patchett AA, Howard AD.
Growth hormone releasing substances: types and their receptors. Horm Res 1999;51(Suppl 3):1 8.
96. Gibbs J, Young RC, Smith GP. Cholecystokinin decreases food
intake in rats. J Comp Physiol Psychol 1973;84:488 495.
97. Dockray GJ. Peptides of the gut and brain: the cholecystokinins.
Proc Nutr Soc 1987;46:119 124.
98. Moran TH. Cholecystokinin and satiety: current perspectives.
Nutrition 2000;16:858 865.
99. Dockray G. Gut endocrine secretions and their relevance to
satiety. Curr Opin Pharmacol 2004;4:557560.
100. West DB, Greenwood MR, Marshall KA, Woods SC. Lithium
chloride, cholecystokinin and meal patterns: evidence that cholecystokinin suppresses meal size in rats without causing malaise. Appetite 1987;8:221227.
101. Asin KE, Gore PA Jr, Bednarz L, Holladay M, Nadzan AM. Effects
of selective CCK receptor agonists on food intake after central
or peripheral administration in rats. Brain Res 1992;571:169
174.
102. Reidelberger RD, Solomon TE. Comparative effects of CCK-8 on
feeding, sham feeding, and exocrine pancreatic secretion in
rats. Am J Physiol 1986;251:R97105.
103. Beglinger C, Degen L, Matzinger D, DAmato M, Drewe J. Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake

May 2007

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

and hunger feelings in humans. Am J Physiol Regul Integr Comp

Physiol 2001;280:R1149 R1154.
Matson CA, Reid DF, Cannon TA, Ritter RC. Cholecystokinin and
leptin act synergistically to reduce body weight. Am J Physiol
Regul Integr Comp Physiol 2000;278:R882R890.
McLaughlin CL, Baile CA, Buonomo FC. Effect of CCK antibodies
on food intake and weight gain in Zucker rats. Physiol Behav
1985;34:277282.
Meereis-Schwanke K, Klonowski-Stumpe H, Herberg L, Niederau C. Long-term effects of CCK-agonist and -antagonist on
food intake and body weight in Zucker lean and obese rats.
Peptides 1998;19:291299.
Moran TH, Katz LF, Plata-Salaman CR, Schwartz GJ. Disordered
food intake and obesity in rats lacking cholecystokinin A receptors. Am J Physiol 1998;274:R618 R625.
West DB, Fey D, Woods SC. Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J
Physiol 1984;246:R776 R787.
Crawley JN, Beinfeld MC. Rapid development of tolerance to the
behavioural actions of cholecystokinin. Nature 1983;302:703
706.
Larhammar D. Structural diversity of receptors for neuropeptide
Y, peptide YY and pancreatic polypeptide. Regul Pept 1996;65:
165174.
Eberlein GA, Eysselein VE, Schaeffer M, Layer P, Grandt D,
Goebell H, Niebel W, Davis M, Lee TD, Shively JE. A new
molecular form of PYY: structural characterization of human
PYY(336) and PYY(136). Peptides 1989;10:797 803.
Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM,
Bloom SR. Human distribution and release of a putative new gut
hormone, peptide YY. Gastroenterology 1985;89:1070 1077.
Adrian TE, Savage AP, Sagor GR, Allen JM, Bacarese-Hamilton
AJ, Tatemoto K, Polak JM, Bloom SR. Effect of peptide YY on
gastric, pancreatic, and biliary function in humans. Gastroenterology 1985;89:494 499.
Le Roux CW, Batterham RL, Aylwin SJ, Patterson M, Borg CM,
Wynne KJ, Kent A, Vincent RP, Gardiner J, Ghatei MA, Bloom SR.
Attenuated peptide YY release in obese subjects is associated
with reduced satiety. Endocrinology 2006;147:3 8.
Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA,
Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD,
Bloom SR. Gut hormone PYY(3-36) physiologically inhibits food
intake. Nature 2002;418:650 654.
Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ,
Frost GS, Ghatei MA, Bloom SR. Inhibition of food intake in
obese subjects by peptide YY3-36. N Engl J Med 2003;349:
941948.
Chelikani PK, Haver AC, Reidelberger RD. Intravenous infusion
of peptide YY(336) potently inhibits food intake in rats. Endocrinology 2005;146:879 888.
Adams SH, Won WB, Schonhoff SE, Leiter AB, Paterniti JR Jr.
Effects of peptide YY[3-36] on short-term food intake in mice
are not affected by prevailing plasma ghrelin levels. Endocrinology 2004;145:4967 4975.
Degen L, Oesch S, Casanova M, Graf S, Ketterer S, Drewe J,
Beglinger C. Effect of peptide YY3-36 on food intake in humans.
Gastroenterology 2005;129:1430 1436.
Tschop M, Castaneda TR, Joost HJ, Thone-Reinke C, Klaus S,
Hagan MM, Chandler PC, Oswald KD, Benoit SC, Seeley RJ,
Kinzig KP, Moran TH, Beck-Sickinger AG, Koglin N, Rodgers RJ,
et al. Does gut hormone PYY 3-36 decrease food intake in
rodents? Nature 2004;430:1 4.
Abbott CR, Small CJ, Sajedi A, Smith KL, Parkinson JR, Broadhead LL, Ghatei MA, Bloom SR. The importance of acclimatisation and habituation to experimental conditions when investigating the anorectic effects of gastrointestinal hormones in the
rat. Int J Obes (Lond) 2006;30:288 292.

GUT HORMONES AND APPETITE CONTROL

2129

122. Chelikani PK, Haver AC, Reeve JR, Jr., Keire DA, Reidelberger
RD. Daily, intermittent intravenous infusion of peptide YY(336)
reduces daily food intake and adiposity in rats. Am J Physiol
Regul Integr Comp Physiol 2006;290:R298 R305.
123. Schonhoff S, Baggio L, Ratineau C, Ray SK, Lindner J, Magnuson MA, Drucker DJ, Leiter AB. Energy homeostasis and gastrointestinal endocrine differentiation do not require the anorectic hormone peptide YY. Mol Cell Biol 2005;25:4189 4199.
124. Boey D, Lin S, Karl T, Baldock P, Lee N, Enriquez R, Couzens M,
Slack K, Dallmann R, Sainsbury A, Herzog H. Peptide YY ablation in mice leads to the development of hyperinsulinaemia and
obesity. Diabetologia 2006;49:1360 1370.
125. Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K,
Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ. Critical
role for peptide YY in protein-mediated satiation and bodyweight regulation. Cell Metab 2006;4:223233.
126. Roth CL, Enriori PJ, Harz K, Woelfle J, Cowley MA, Reinehr T.
Peptide YY is a regulator of energy homeostasis in obese
children before and after weight loss. J Clin Endocrinol Metab
2005;90:6386 6391.
127. Alvarez BM, Borque M, Martinez-Sarmiento J, Aparicio E, Hernandez C, Cabrerizo L, Fernandez-Represa JA. Peptide YY secretion in morbidly obese patients before and after vertical
banded gastroplasty. Obes Surg 2002;12:324 327.
128. Stock S, Leichner P, Wong AC, Ghatei MA, Kieffer TJ, Bloom SR,
Chanoine JP. Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in
anorexic, obese, and control female adolescents. J Clin Endocrinol Metab 2005;90:21612168.
129. Korner J, Bessler M, Cirilo LJ, Conwell IM, Daud A, Restuccia
NL, Wardlaw SL. Effects of Roux-en-Y gastric bypass surgery on
fasting and postprandial concentrations of plasma ghrelin, peptide YY, and insulin. J Clin Endocrinol Metab 2005;90:359
365.
130. Abbott CR, Small CJ, Kennedy AR, Neary NM, Sajedi A, Ghatei
MA, Bloom SR. Blockade of the neuropeptide Y Y2 receptor with
the specific antagonist BIIE0246 attenuates the effect of endogenous and exogenous peptide YY(336) on food intake.
Brain Res 2005;1043:139 144.
131. Halatchev IG, Ellacott KL, Fan W, Cone RD. Peptide YY336 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology 2004;145:25852590.
132. Abbott CR, Monteiro M, Small CJ, Sajedi A, Smith KL, Parkinson
JR, Ghatei MA, Bloom SR. The inhibitory effects of peripheral
administration of peptide YY(336) and glucagon-like peptide-1
on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res 2005;1044:127131.
133. Halatchev IG, Cone RD. Peripheral administration of PYY(336)
produces conditioned taste aversion in mice. Cell Metab 2005;
1:159 168.
134. Track NS, McLeod RS, Mee AV. Human pancreatic polypeptide:
studies of fasting and postprandial plasma concentrations. Can
J Physiol Pharmacol 1980;58:1484 1489.
135. Malaisse-Lagae F, Carpentier JL, Patel YC, Malaisse WJ, Orci L.
Pancreatic polypeptide: a possible role in the regulation of food
intake in the mouse. Hypothesis. Experientia 1977;33:915
917.
136. Asakawa A, Inui A, Yuzuriha H, Ueno N, Katsuura G, Fujimiya M,
Fujino MA, Niijima A, Meguid MM, Kasuga M. Characterization
of the effects of pancreatic polypeptide in the regulation of
energy balance. Gastroenterology 2003;124:13251336.
137. Batterham RL, Le Roux CW, Cohen MA, Park AJ, Ellis SM,
Patterson M, Frost GS, Ghatei MA, Bloom SR. Pancreatic
polypeptide reduces appetite and food intake in humans. J Clin
Endocrinol Metab 2003;88:3989 3992.

2130

WREN AND BLOOM

138. Zipf WB, ODorisio TM, Cataland S, Sotos J. Blunted pancreatic

polypeptide responses in children with obesity of Prader-Willi
syndrome. J Clin Endocrinol Metab 1981;52:1264 1266.
139. Berntson GG, Zipf WB, ODorisio TM, Hoffman JA, Chance RE.
Pancreatic polypeptide infusions reduce food intake in PraderWilli syndrome. Peptides 1993;14:497503.
140. Ueno N, Inui A, Iwamoto M, Kaga T, Asakawa A, Okita M,
Fujimiya M, Nakajima Y, Ohmoto Y, Ohnaka M, Nakaya Y,
Miyazaki JI, Kasuga M. Decreased food intake and body weight
in pancreatic polypeptide-overexpressing mice. Gastroenterology 1999;117:14271432.
141. Clark JT, Kalra PS, Crowley WR, Kalra SP. Neuropeptide Y and
human pancreatic polypeptide stimulate feeding behavior in
rats. Endocrinology 1984;115:427 429.
142. Whitcomb DC, Taylor IL, Vigna SR. Characterization of saturable
binding sites for circulating pancreatic polypeptide in rat brain.
Am J Physiol 1990;259:G687G691.
143. Holst JJ. On the physiology of GIP and GLP-1. Horm Metab Res
2004;36:747754.
144. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;
3:153165.
145. Turton MD, OShea D, Gunn I, Beak SA, Edwards CM, Meeran K,
Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith
DM, Ghatei MA, Herbert J, Bloom SR. A role for glucagon-like
peptide-1 in the central regulation of feeding. Nature 1996;379:
69 72.
146. Meeran K, OShea D, Edwards CM, Turton MD, Heath MM, Gunn
I, Abusnana S, Rossi M, Small CJ, Goldstone AP, Taylor GM,
Sunter D, Steere J, Choi SJ, Ghatei MA, Bloom SR. Repeated
intracerebroventricular administration of glucagon-like peptide1-(736) amide or exendin-(9 39) alters body weight in the rat.
Endocrinology 1999;140:244 250.
147. Verdich C, Toubro S, Buemann B, Lysgard MJ, Juul HJ, Astrup A.
The role of postprandial releases of insulin and incretin hormones in meal-induced satiety effect of obesity and weight
reduction. Int J Obes Relat Metab Disord 2001;25:1206
1214.
148. Naslund E, King N, Mansten S, Adner N, Holst JJ, Gutniak M,
Hellstrom PM. Prandial subcutaneous injections of glucagonlike peptide-1 cause weight loss in obese human subjects. Br J
Nutr 2004;91:439 446.
149. Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM,
Ghatei MA, Bloom SR. Oxyntomodulin inhibits food intake in the
rat. Endocrinology 2001;142:4244 4250.
150. Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA, Bloom SR.
Repeated ICV administration of oxyntomodulin causes a greater
reduction in body weight gain than in pair-fed rats. Am J Physiol
Endocrinol Metab 2002;283:E1173E1177.
151. Dakin CL, Small CJ, Batterham RL, Neary NM, Cohen MA,
Patterson M, Ghatei MA, Bloom SR. Peripheral oxyntomodulin

GASTROENTEROLOGY Vol. 132, No. 6

152.

153.

154.

155.

156.

157.

158.

159.

160.

reduces food intake and body weight gain in rats. Endocrinology

2004;145:26872695.
Cohen MA, Ellis SM, Le Roux CW, Batterham RL, Park A, Patterson M, Frost GS, Ghatei MA, Bloom SR. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin
Endocrinol Metab 2003;88:4696 4701.
Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG,
Wren AM, Frost GS, Meeran K, Ghatei MA, Bloom SR. Subcutaneous oxyntomodulin reduces body weight in overweight and
obese subjects: a double-blind, randomized, controlled trial.
Diabetes 2005;54:2390 2395.
Wynne K, Park A, Small C J, Meeran K, Ghatei M A, Frost G,
Bloom S R. Oxyntomodulin increases energy expenditure in
addition to decreasing energy intake in overweight and obese
humans: a randomised controlled trial. Int J Obes (Lond) 2006;
30:1729 1736.
Baggio LL, Huang Q, Brown TJ, Drucker DJ. Oxyntomodulin and
glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 2004;127:
546 558.
Weigle DS, Duell PB, Connor WE, Steiner RA, Soules MR, Kuijper JL. Effect of fasting, refeeding, and dietary fat restriction on
plasma leptin levels. J Clin Endocrinol Metab 1997;82:561
565.
Reinehr T, Roth CL, Alexy U, Kersting M, Kiess W, Andler W.
Ghrelin levels before and after reduction of overweight due to a
low-fat high-carbohydrate diet in obese children and adolescents. Int J Obes (Lond) 2005;29:362368.
Le Roux CW, Aylwin SJ, Batterham RL, Borg CM, Coyle F, Prasad
V, Shurey S, Ghatei MA, Patel AG, Bloom SR. Gut hormone
profiles following bariatric surgery favor an anorectic state,
facilitate weight loss, and improve metabolic parameters. Ann
Surg 2006;243:108 114.
Cummings DE, Shannon MH. Ghrelin and gastric bypass: is
there a hormonal contribution to surgical weight loss? J Clin
Endocrinol Metab 2003;88:2999 3002.
Neary NM, Small CJ, Druce MR, Park AJ, Ellis SM, Semjonous
NM, Dakin CL, Filipsson K, Wang F, Kent AS, Frost GS, Ghatei
MA, Bloom SR. Peptide YY3-36 and glucagon-like peptide17-36 inhibit food intake additively. Endocrinology 2005;
146:5120 5127.

Received November 16, 2006. Accepted January 2, 2007.

Address requests for reprints to: Stephen R. Bloom, MD, Department of Metabolic Medicine, Imperial College London, Hammersmith
Campus, 6th Floor, Commonwealth Building, Du Cane Road, London,
W12 0NN, England. e-mail: s.bloom@imperial.ac.uk; fax: (44) 20 8383
3142.