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Endocrine Reviews 27(7):719 –727
Copyright © 2006 by The Endocrine Society
doi: 10.1210/er.2006-0028
Gut Peptides in the Regulation of Food Intake and
Energy Homeostasis
Kevin G. Murphy, Waljit S. Dhillo, and Stephen R. Bloom
Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 ONN,
United Kingdom
Gut hormones signal to the central nervous system to influence energy homeostasis. Evidence supports the existence of
a system in the gut that senses the presence of food in the
gastrointestinal tract and signals to the brain via neural and
endocrine mechanisms to regulate short-term appetite and
satiety. Recent evidence has shown that specific gut hormones administered at physiological or pathophysiological
concentrations can influence appetite in rodents and humans.
Gut hormones therefore have an important physiological role
in postprandial satiety, and gut hormone signaling systems
represent important pharmaceutical targets for potential antiobesity therapies. Our laboratory investigates the role of gut
hormones in energy homeostasis and has a particular interest in
this field of translational research. In this review we describe
our initial studies and the results of more recent investigations
into the effects of the gastric hormone ghrelin and the intestinal
hormones peptide YY, pancreatic polypeptide, glucagon-like
peptide-1, and oxyntomodulin on energy homeostasis. We also
speculate on the role of gut hormones in the future treatment of
obesity. (Endocrine Reviews 27: 719 –727, 2006)
I. Introduction
II. Gastrointestinal Hormones and Energy Homeostasis
A. Ghrelin
B. Pancreatic polypeptide (PP)
C. Peptide YY (PYY)
D. Glucagon-like peptide-1 (GLP-1)
E. Oxyntomodulin
III. The Future of Obesity Treatment
signals are thought to be the hypothalamus and the brain stem.
In particular, the hypothalamus interprets neural and humoral
inputs and integrates these data to provide a picture of the
body’s state of energy balance, which is then used to coordinate
feeding and energy expenditure. Many of the long-term signals
communicating information regarding the body’s energy
stores, endocrine status, and general health appear to be humoral, in particular the adipose hormone leptin and the pancreatic hormone insulin. It is believed that short-term signals,
including gut hormones and neural signals from higher brain
centers and the gut, regulate meal initiation and termination.
Both short-term and long-term signals can also affect energy
expenditure via sympathetic nervous efferents to brown adipose tissue and by effecting the secretion of various pituitary
hormones (2).
The mechanisms that regulate short-term, postprandial satiety are still being established. Evidence supports the existence
of a system in the gut that senses the presence of food in the
gastrointestinal tract and signals to the brain via neural and
endocrine mechanisms to regulate short-term appetite and satiety. The gut releases more than 20 peptide hormones in response to specific stimuli, and the release of a number of these
hormones is sensitive to changes in gut nutrient content. Recent
evidence has shown that specific gut hormones administered at
physiological or pathophysiological concentrations can influence appetite in rodents and humans (3– 8). Gut hormones
therefore have an important physiological role in postprandial
satiety, and gut hormone signaling systems represent important pharmaceutical targets for potential antiobesity therapies.
I. Introduction
T
HE GASTROINTESTINAL TRACT is the largest endocrine
organ in the body and an important source of regulatory
peptide hormones. The gut peptide secretin was the first substance given the name “hormone.” Early studies into the gut
endocrine system focused on the role of gut hormones in the
peripheral regulation of gastrointestinal function, for example,
secretin on pancreatic secretion, cholecystokinin on gall bladder
contraction, and gastrin on gastric acid release. It was not until
the 1970s, a period during which a number of novel gut hormones were identified, that it became clear that gut hormones
signaled to the central nervous system (CNS), often in profound
and subtle ways. In 1973, cholecystokinin became the first gut
hormone demonstrated to influence appetite, paving the way
for many seminal studies into the role of the brain-gut axis in
energy homeostasis (1).
The most important CNS target centers for these peripheral
First Published Online October 31, 2006
Abbreviations: AgRP, Agouti-related protein; CNS, central nervous
system; CTA, conditioned taste aversion; GHS-R, GH secretagogue receptor; GLP-1, glucagon-like peptide-1; NPY, neuropeptide Y; NTS,
nucleus of the solitary tract; PP, pancreatic polypeptide; PPY, peptide
YY; PWS, Prader-Willi syndrome.
Endocrine Reviews is published by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
endocrine community.
II. Gastrointestinal Hormones and Energy
Homeostasis
A. Ghrelin
Ghrelin is a circulating peptide hormone derived predominantly from the stomach. It is the endogenous ligand for the
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Endocrine Reviews, December 2006, 27(7):719 –727
GH secretagogue receptor (GHS-R), and the only peripherally active orexigenic hormone discovered to date. Ghrelin is
28 amino acids long and exists in a form with an acyl side
chain attached to the serine found at position 3. This acyl
group appears vital to the binding of ghrelin to the GHS-R
and to its subsequent orexigenic effects (9).
After its discovery in 1999 (9), it was found that ghrelin
could stimulate appetite (3, 10, 11). We demonstrated that
peripheral administration of acylated ghrelin potently stimulated feeding in rodents. This effect appeared to be mediated via the hypothalamus, because administration of ghrelin into the third cerebral ventricle also stimulated feeding
(3). Chronic intracerebroventricular administration of ghrelin increased body weight and adiposity in rats (12). Excitingly, ghrelin also increases appetite in humans. In a randomized double-blind crossover study, iv infusion of ghrelin
in healthy volunteers, at 5 pmol/kg䡠min (to achieve circulating levels similar to those observed after a 24-h fast),
increased food intake at a free-choice buffet by almost 30%
and significantly increased appetite. Ghrelin had no effect on
gastric emptying at this dose, and this, in conjunction with
the rodent data, suggested that its effects are centrally mediated rather than secondary to effects on the stomach (4).
Because iv administration is an impractical route for potential pharmaceutical agents, we have since demonstrated that
a bolus sc injection of 3.6 nmol/kg ghrelin can also increase
food intake and induce appetite to a similar degree (13).
The mechanism or mechanisms by which ghrelin stimulates
feeding are contentious. There is evidence that ghrelin signals
via the hypothalamus. In particular, an important role has been
suggested for the hypothalamic arcuate nucleus. Ghrelin has a
particularly potent effect on feeding after administration into
the arcuate nucleus (12), which is in accord with neuronal activation data after central administration of ghrelin in rats (11).
Orexigenic neuropeptide Y (NPY) and agouti-related protein
(AgRP)-expressing neurons in the arcuate nucleus may play an
important role. Central injection of ghrelin activates NPY/
AgRP neurons and NPY and AgRP antibodies, and NPY antagonists block the orexigenic actions of ghrelin (11). Ghrelin
does not stimulate food intake in NPY and AgRP double knockout mice (14). We have demonstrated that transgenic mice with
postembryonic ablation of NPY/AgRP neurons do not respond
to ghrelin, suggesting that the desensitization to ghrelin in
NPY/AgRP embryonic knockouts is not due to developmental
changes (15). In agouti mice, ectopic production of agouti protein antagonizes central melanocortin 4 receptors. We have
shown that ghrelin does not increase food intake in these mice,
demonstrating that disrupting the hypothalamic melanocortin
system can cause ghrelin resistance (16).
There is also strong evidence that the vagus nerve is required to mediate the orexigenic effects of ghrelin. Vagotomy
abolishes ghrelin-stimulated feeding in animal models (17,
18). We have found that ghrelin does not stimulate appetite
in humans after surgical procedures involving vagotomy
(19). Ghrelin may therefore signal to the hypothalamus via
the vagus and the brain stem. Interestingly, ghrelin expression has been detected in neurons adjacent to the third ventricle (20). The importance of these neurons in energy homeostasis is currently unknown. However, it is possible that
endogenous central and peripheral ghrelin signaling play
Murphy et al. • Gut Hormones and Appetite
different roles in the regulation of food intake and energy
expenditure, which might explain the equivocal effects of
central and peripheral administration of exogenous ghrelin.
Further ambiguity is conferred to the investigation of
ghrelin physiology by the existence of different forms of
ghrelin that have been reported to have different effects.
Although des-acylated ghrelin does not bind to the GHS-R
and does not increase food intake, it may have other biological roles, possibly mediated by as yet undiscovered
GHS-R subtypes (21). It has been reported that intracerebroventricular and peripheral administration of des-acylated
ghrelin reduces food intake in fasted mice (22). However, we
have found ip injection of des-acylated ghrelin to have no effect
on food intake in fed or fasted mice (23). Interestingly, it has
recently been reported that the gene that codes for ghrelin also
codes for another peptide, named “obestatin,” which reduces
food intake (24). Further studies are necessary to understand the
relative roles of the different forms of ghrelin and how ghrelin
signaling is integrated with obestatin signaling.
The reported inimical effects of acylated and des-acylated
forms of ghrelin on food intake mean that the ability to measure
specific forms of ghrelin is particularly vital to such studies. We
have recently found evidence that suggests that the majority of
circulating acylated ghrelin is bound to larger molecules,
whereas des-acylated ghrelin circulates as free peptide (25).
These data emphasize the importance of assay specificity and
suggest that assays measuring specific forms of ghrelin will be
more useful in determining its physiological role than those that
detect both acylated and des-acylated forms.
Ghrelin has also been reported to play a role in glucose
homeostasis and adipocyte function. We have found that acylated ghrelin potentiates insulin-induced glucose uptake in adipocytes from specific fat depots, but the relevance of this effect
in normal physiology remains to be determined (26).
The factors regulating plasma ghrelin levels can provide
vital evidence as to the physiological role of peripheral
ghrelin. Circulating ghrelin concentrations rise with fasting
and fall after a meal (27). This primary regulation by food
intake is in accord with the suggested role of ghrelin as a
“hunger hormone” (10). Although calorie intake appears to
be the primary regulator of plasma ghrelin levels, the exact
mechanisms mediating ghrelin release are unknown. Dextrose and parenteral nutrition infusions decrease ghrelin levels but do not reduce hunger, suggesting that the role of
ghrelin may be more complex (28). Intraduodenal infusion of
long-chain fatty acids suppresses circulating ghrelin levels,
although not in the presence of a lipase inhibitor, suggesting
that fat digestion is required to influence ghrelin release (29).
The length of the fatty acid chain also appears to be important
to ghrelin secretion, because intraduodenal infusion of dodecanoic acid, a fatty acid containing 12 carbon atoms, decreases plasma ghrelin, but infusion of decanoic acid, which
only contains 10 carbon atoms, does not (30).
Circulating ghrelin concentrations are also regulated by
longer term changes in energy homeostasis. Ghrelin levels
are lower in humans with higher body weight and rise after
diet-induced weight loss (31). The usual postprandial fall in
plasma ghrelin is absent or attenuated in the obese, suggesting that ghrelin may be involved in the pathophysiology of
obesity (32, 33). We have shown that iv ghrelin administra-
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Murphy et al. • Gut Hormones and Appetite
tion stimulates appetite in obese humans, suggesting that
they are not ghrelin resistant (34).
Prader-Willi syndrome (PWS) is a genetic syndrome characterized by severe hyperphagia, short stature, and mental
retardation. PWS patients are hypogonadal and have GH
deficiency. The PWS phenotype is thought to be a consequence of hypothalamic developmental abnormalities. Interestingly, fasting and postprandial ghrelin levels are higher
relative to obesity in PWS patients (35–37). However, somatostatin infusion in PWS patients does reduce ghrelin without influencing appetite. This implies that factors besides
ghrelin may be responsible for PWS hyperphagia, although
it is also possible that concomitant reductions in anorectic gut
hormones compensate for the reduction in ghrelin (38).
The years since the discovery of ghrelin have seen the
emergence of a considerable research literature on this hormone. Ghrelin antagonists have been touted as potential
obesity drugs. Ghrelin and GHS-R knockout mice were
found not to have profoundly altered food intake or body
weight on a normal diet (39, 40). Subsequently, it has been
shown that GHS-R knockout mice are resistant to diet-induced obesity (41, 42) and favor fat as a metabolic substrate
when on a high-fat diet (43). GHS-R antagonists may therefore have beneficial effects in obese humans. Knockout models have also provided further evidence for the role of ghrelin
in glucose homeostasis. Diabetic ghrelin knockout mice show
less dramatic hyperphagia than controls (44), and ablating
ghrelin attenuates diabetes in the ob/ob obese mouse (45).
In addition to the therapeutic potential of blocking ghrelin
signaling, a number of patient groups would benefit from the
development of appetite-inducing therapies.
Intensive care unit patients have been shown to have reduced ghrelin levels compared with healthy controls (46).
This is despite weight loss and reduced food intake, which
would normally increase plasma ghrelin levels (27, 31, 47). It
is therefore possible that changes in ghrelin may be partly
responsible for the loss of appetite and weight often observed
in these patients. If reduced ghrelin levels are even partially
responsible for the loss of appetite in certain patient groups,
ghrelin administration would be an apposite appetite-inducing treatment. We have demonstrated that iv ghrelin can
increase food intake and meal appreciation in cancer patients
with reported loss of appetite (48) and that sc ghrelin administration increases short-term food intake in dialysis patients (49). Ghrelin also increases gastric emptying in patients
with diabetic gastroparesis, independent of vagal tone, suggesting that it may be a potential prokinetic agent in such
patients (50). The ghrelin system therefore may prove to have
clinical utility in a number of important diseases.
B. Pancreatic polypeptide (PP)
PP is a 36-amino acid peptide released from the endocrine
pancreas. Soon after it was first identified, we discovered that
PP was released into the circulation after a meal (51, 52). PP
has a number of reported peripheral effects on the gastrointestinal tract. Our early experiments established the pharmacodynamics of PP in man (53) and its effects on pancreatic
and biliary output (54).
PP is released in proportion to meal calorie content, al-
Endocrine Reviews, December 2006, 27(7):719 –727 721
though it is interesting to note that lipid digestion is required
to generate the lipid-induced rise in circulating PP (29). As
early as 1977, it was demonstrated that PP could reduce food
intake in mice (55). However, it was not until 2003 that we
demonstrated that iv infusion of PP at 10 pmol/kg䡠min levels
to healthy human volunteers reduced food intake (7). We
have since found that infusions at half this dose can also
significantly reduce food intake (our unpublished data). The
precise mechanism by which the anorectic effect of PP is
mediated is unknown. PP signals via the Y family of receptors and binds with greatest affinity to the Y4 and Y5 receptors. PP may directly activate neurons in the area postrema,
where Y4 receptors are highly expressed (56).
It has been suggested that the anorectic effects of iv PP
administration in humans are secondary to delayed gastric
emptying. We found that infusing bovine PP at 2 pmol/
kg䡠min to achieve levels twice those observed after a normal
mixed breakfast in man had no effect on gastric emptying
(57). Similarly, infusion of human PP at 10 pmol/kg䡠min
significantly inhibited food intake in man with no detectable
effect on gastric emptying (7). However, others have found
that human PP inhibits gastric emptying of solid food at
infusion rates as low as 0.75 or 2.25 pmol/kg䡠min (58). These
discrepancies may reflect the different forms of the hormone
used or the different infusion protocols. The presence of PP
binding sites and the activation of neurons in the area postrema after PP administration suggests that PP is having a
central effect, but it is currently unknown whether this central activity is directly regulating food intake (56).
In animal models, peripheral PP administration increases
energy expenditure in addition to its effects on food intake
(59). Chronic administration of PP to obese mice slows body
weight gain, and peripheral overexpression of PP reduces
food intake and body weight (60). In our human study, a
90-min infusion of PP significantly reduced not only acute
food intake at a buffet meal 2 h after the infusion but also
reduced food intake for the following 24 h (7). PP therefore
appears to have the potential to act as a long-term appetite
suppressor and thus may be a suitable target for antiobesity
drug design.
C. Peptide YY (PYY)
PYY is a 36-amino acid peptide structurally related to PP
and NPY and was first isolated and characterized in 1980
(61). PYY is found throughout the human small intestine at
tissue concentrations that increase distally, with the highest
levels detected in the colon and rectum (62). Peripheral administration of full-length PYY has several biological effects,
including delayed gastric emptying and reduced gastric secretion in man (63, 64).
PYY is released postprandially (62) from the L cells of the
gut, where it is co-stored with glucagon-like peptide-1
(GLP-1) (65). However, the major form of PYY stored in the
gut and found in the circulation is the N-terminally truncated
PYY3–36 (66). The different forms of PYY have different receptor affinities, reflecting their different biological effects.
Although full-length PYY binds with similar affinity to all of
the members of the Y receptor family, PYY3–36 has high
affinity only for the Y2 and a lesser affinity for Y1 and Y5
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Endocrine Reviews, December 2006, 27(7):719 –727
receptors. In 2002, we published data demonstrating that
peripheral administration of PYY3–36 at physiological doses
significantly reduced food intake in rodents and man (5).
Although there was initial contention regarding the effects of
PYY3–36 on appetite (5, 67), a number of groups have now
conclusively demonstrated that PYY3–36 reduces food intake
in rodents, primates, and man (68 –75). Handling, acclimatization, and habituation of rodents to experimental conditions are vital to the success of PYY3–36 feeding studies (76,
77). PYY knockout mice show disrupted regulation of energy
homeostasis. However, the phenotype is not straightforward. Aged female mice lacking PYY have increased body
weight and fat mass. Male knockout mice are resistant to
obesity but have higher fat mass and lower glucose tolerance
than wild types when fed a high-fat diet. These findings
suggest that PYY is important in energy and glucose homeostasis. The sexual dimorphism observed has been suggested to be due to differences in the hypothalamo-pituitary
somatotrophic axis between the sexes (78). Another study
found no differences in food intake and body weight between wild-type and PYY knockout mice. However, these
mice also lacked PP, which may have implications for the
development of the energy homeostatic system (79).
PYY3–36 may be less responsible for the postprandial reduction in food intake than regulating the size or timing of
subsequent meals. Plasma levels of endogenous PYY peak in
the second hour after a meal (5, 6, 62). In our studies, PYY3–36
reduced food intake 2 h after the infusion had stopped, when
circulating PYY had returned to basal levels, and continued
to reduce food intake for the subsequent 12 h (5).
The mechanism by which PYY3–36 reduces food intake is
contentious. PYY3–36 is thought to act via the Y2 receptor. Administration of PYY3–36 does not reduce appetite in Y2 knockout
mice (5), and the anorectic effects of PYY3–36 can be blocked in
rats by the coadministration of a specific Y2 antagonist (80). We
reported that PYY3–36 activated anorectic proopiomelanocortin
(POMC) expressing neurons in the arcuate nucleus. Certainly,
direct intra-arcuate injection of PYY3–36 reduces food intake in
rats (5). However, it has been reported subsequently that
PYY3–36 inhibits both POMC and NPY neurons, suggesting that
it may be via reduced NPY signaling that PYY3–36 exerts its
effects (81). This is in accord with results showing that the
melanocortin system is not essential for the anorectic actions of
PYY3–36 (16, 68, 77). The anorectic effects of PYY3–36 may also be
partly mediated via the vagal nerve (82).
PYY3–36 may have utility as an obesity therapy. Circulating
PYY levels are lower in the obese, suggesting that low PYY
levels may have a causative role in the development of obesity (6, 66). We and others have found food intake and body
weight to be reduced in animals chronically treated with
peripheral PYY3–36 (5, 72, 83). Importantly, PYY3–36 can reduce food intake in obese volunteers, suggesting that obesity
is not a PYY-resistant state (6).
There is debate as to whether PYY3–36 reduces food intake
by activating physiological food reduction circuits or by having an aversive effect. Different groups have published contradictory data as to whether PYY3–36 causes conditioned
taste aversion (CTA) in rodents, and thus whether the effects
of PYY3–36 on food intake are secondary to unpleasant side
effects (84, 85). We have found that doses of PYY3–36 that
Murphy et al. • Gut Hormones and Appetite
result in circulating levels of PYY within the physiological
range reduce food intake in humans without causing nausea
or any other ill effects (5, 6). Others have found that pharmacological doses of PYY3–36 are required to reduce food
intake and that nausea can occur at high doses (75). In recent
studies, we found that high doses of PYY3–36 were associated
with nausea in humans (our unpublished data). This is unsurprising. Hunger, satiety, and nausea may be points along
the same physiological spectrum (86). Nausea is associated
with high-dose administration of several satiety-inducing
gut hormones and their analogs, including cholecystokinin
(86), GLP-1 (87), exenatide (88, 89), and oxyntomodulin (90).
Interestingly, we found no greater inhibition of food intake
at supraphysiological plasma PYY levels than at lower doses
previously investigated (our unpublished data; also, Refs. 5
and 6). It is possible that PYY acts at physiological levels to
mediate postprandial satiety and only causes nausea at
pathophysiological levels. Fasting levels of PYY are chronically elevated in several gastrointestinal diseases associated
with appetite loss (91). It is possible that the reduced gastric
emptying and delayed gastrointestinal transit described after
administration of PYY3–36 (64, 92) are responses designed to
reduce the nutrient load on the diseased small intestine while
increasing transit and, hence, absorption time. Similarly, the
nausea reported in response to high levels of PYY3–36 may be
an adaptation to reduce further stress on the gut in specific
pathophysiological states. It has been suggested that PYY
might act as an endogenous defense against diarrhea (93).
Very high levels of PYY3–36 may therefore have powerful
aversive effects to avoid further stress on the gut, but these
effects may not be responsible for the normal PYY3–36-induced reduction of food intake. In our recent study, we found
that the subjective feeling of nausea was short-lived and
lasted for no more than 30 min. Interestingly, PYY3–36 reduced food intake after nausea levels had returned to baseline, suggesting an independent effect (our unpublished
data). Similarly, recent work by others has shown that although high doses of PYY3–36 cause CTA in rodents, lower
doses can reduce food intake without causing CTA (94).
D. Glucagon-like peptide-1 (GLP-1)
GLP-1 is a neuropeptide hormone produced by posttranslational processing of the preproglucagon gene in the CNS
and the gut. We were the first to demonstrate the potent
anorectic effects of intracerebroventricular administration of
GLP-1 in rodents. GLP-1 neurons in the nucleus of the solitary tract (NTS) extend to regions of the hypothalamus important in the regulation of food intake (95). In 1988, we
identified high-affinity binding sites for GLP-1 in the hypothalamus and the brain stem (96). Subsequently, we found
that GLP-1 reduced food intake in fasted rats and activated
neurons in the arcuate and paraventricular nuclei of the
hypothalamus, and that blocking GLP-1 receptor signaling
with the GLP-1 receptor antagonist, exendin (9 –39), doubled
food intake in satiated rats. Our findings suggested that
central GLP-1 could induce satiety (97) and might also increase energy expenditure by raising body temperature (98).
Repeated intracerebroventricular injection of GLP-1 reduced
food intake and body weight in rats. Conversely, blocking
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Murphy et al. • Gut Hormones and Appetite
endogenous GLP-1 signaling by repeated central administration of exendin (9 –39) increased food intake and body
weight, providing further evidence that GLP-1 is a physiological mediator of appetite (99).
Leptin may signal in part through the central GLP-1 system.
We demonstrated that the long isoform leptin receptor was
expressed in GLP-1 neurons extending from the NTS and that
exendin (9 –39) blocked the effects of leptin on food intake and
body weight (100). In subsequent experiments, we showed that
intracerebroventricular leptin administration prevents the reduction in hypothalamic GLP-1 peptide content observed in
pair-fed food-restricted rats, and peripheral leptin increases
hypothalamic GLP-1 peptide in food-restricted mice (101).
However, leptin does reduce food intake in GLP-1 receptor
knockout mice (102), demonstrating that GLP-1 signaling is not
necessary to mediate the biological effects of leptin. Leptin is
known to act via a number of central neuropeptide signals (2,
103, 104). Whether the efficacy of leptin in the GLP-1 receptor
knockout mouse is maintained because of developmental compensation or because of the ability of the mature energy homeostasis circuitry to signal via alternative routes is unknown.
Peripheral GLP-1 can also influence glucose and energy homeostasis. It is therefore difficult to tease apart peripheral and
central GLP-1 signaling pathways. It has been reported that
both peripheral and central GLP-1 administration activate neurons in the arcuate nucleus, the hypothalamic paraventricular
nucleus, NTS, and area postrema (82, 95, 105, 106). How the
central and peripheral GLP-1 systems interact and are integrated into the bodywide energy homeostasis is unknown.
GLP-1 is released into the circulation after a meal, and
proglucagon expression is decreased in the small intestine by
fasting (107). The physical form of a meal appears to have a
greater influence on GLP-1 release than its fat content (108).
We discovered that GLP-1 acts as a physiological incretin
(109, 110) and suppressor of gastric acid secretion (111) in
man. Administration of exendin-4 reduces fasting and postprandial glucose in humans (112). We were the first group to
investigate the effects of chronic sc GLP-1 treatment in type
2 diabetes mellitus. Three weeks of sc GLP-1 treatment significantly improved postprandial glycemic control in patients with poorly controlled type 2 diabetes mellitus (113,
114). Peripheral GLP-1 infusion has been reported to cause
a dose-dependent reduction in food intake in humans (115).
We confirmed that peripheral administration of the GLP-1
receptor agonist, exendin-4, significantly reduced food intake in healthy volunteers (112). Clinical trials have shown
that exenatide, a long-acting agonist of the GLP-1 receptor,
is useful in the regulation of glucose homeostasis in type 2
diabetes mellitus. Interestingly, exenatide does not only enhance insulin secretion and suppress glucagon release. In
30-wk phase 3 clinical trials, it also reduced body weight
(116 –118). Not all patients showed weight loss, and exenatide is not approved as an obesity treatment. However,
these results do demonstrate that gut hormone systems have
the potential to reduce body weight.
E. Oxyntomodulin
Like GLP-1, oxyntomodulin is a product of the preproglucagon gene released into the circulation postprandially.
Endocrine Reviews, December 2006, 27(7):719 –727 723
Originally characterized as an inhibitor of gastric acid secretion, like GLP-1, oxyntomodulin also reduces food intake
when administered centrally to rodents or peripherally to
rodents or humans (8, 119 –121).
Oxyntomodulin binds to the GLP-1 receptor. However,
although the affinity of oxyntomodulin for the GLP-1 receptor is much lower than that of GLP-1, oxyntomodulin and
GLP-1 are equally efficacious at inhibiting food intake. Oxyntomodulin may reduce food intake via a different pathway
to GLP-1 (119). However, both oxyntomodulin and GLP-1
have been shown to cause similar patterns of neuronal activation after peripheral administration (105). Oxyntomodulin has been suggested to bind to a specific oxyntomodulin
receptor. However, the anorectic effects of oxyntomodulin
are blocked by exendin (9 –39) (122) and abolished in GLP-1
receptor knockout mice (105). Although it is possible that
developmental changes in the GLP-1 receptor knockout
mouse affect the functioning of another discrete oxyntomodulin receptor, and that exendin (9 –39) also binds to this
putative oxyntomodulin receptor, it seems more likely that
oxyntomodulin does reduce food intake via the GLP-1 receptor. GLP-1 receptors are found in the brainstem and the
arcuate nucleus. The different biological effects of oxyntomodulin and GLP-1 may therefore be due to differences in
local breakdown, tissue penetration, or possibly context-dependent changes in receptor signaling, such as the receptor
activity modifying proteins that regulate the specificity of the
calcitonin receptor-like receptor (123). The GLP-1 receptor
agonist exenatide has recently been approved for the treatment of type 2 diabetes mellitus in the United States, and
exenatide treatment is associated with weight loss (116 –118).
However, it is possible that peptide analogs based on the
structure of oxyntomodulin will prove more efficacious at
promoting weight loss than those based on GLP-1.
Preliminary data suggest that oxyntomodulin may prove
useful as an obesity drug. Chronic central or peripheral administration of oxyntomodulin reduces weight gain in rats
(119, 120). Intravenous infusion of oxyntomodulin to supraphysiological levels reduces food intake in humans (8).
Further work is required to elucidate the physiological significance of oxyntomodulin in human appetite, but it is interesting to note that oxyntomodulin levels are, like PYY,
increased in particular pathophysiological conditions associated with reduced appetite (124).
We have recently performed studies demonstrating that
oxyntomodulin can cause weight loss in humans. In a 4-wk
study in which overweight and obese volunteers self-administered oxyntomodulin or saline three times daily, the oxyntomodulin-treated group ate significantly less. This substantial
reduction in appetite was well-maintained over the 4-wk study
period. Oxyntomodulin treatment also resulted in significant
weight loss of an additional 0.45-kg weight loss per week compared with saline, accompanied by changes in the levels of
adipose hormones consistent with a loss of body fat (90).
Rats chronically treated with oxyntomodulin lose more
weight than pair-fed controls, suggesting that oxyntomodulin
may also increase energy expenditure (120). Excitingly, the results of our latest human oxyntomodulin study suggested that
oxyntomodulin also promotes energy expenditure in humans.
Overweight and obese volunteers again self-administered
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724
Endocrine Reviews, December 2006, 27(7):719 –727
oxyntomodulin, although this time for only four days. Energy
expenditure was measured by indirect calorimetry and combined heart rate and movement monitoring, and food intake
was assessed by a test meal. Oxyntomodulin administration
significantly reduced energy intake at the study meal and increased activity-related energy expenditure by more than 25%
(125). Oxyntomodulin is thus the first therapy shown to suppress appetite and concurrently increase spontaneous activity.
Normal dieting reduces energy expenditure, making it difficult
to lose weight. Oxyntomodulin, in contrast, increases energy
expenditure as it reduces energy intake. Long-term trials are
now required to investigate the utility of oxyntomodulin as an
obesity drug.
III. The Future of Obesity Treatment
There is currently available an effective treatment for obesity that achieves and sustains substantial weight loss. Unfortunately, the associated costs and mortality rate of bariatric surgery make it impractical to treat the rising levels of
obesity in the developed world. Thus, the search continues
for a pharmaceutical answer to the obesity epidemic. Current
antiobesity drugs are only moderately effective, and all have
associated side effects. Excitingly, bariatric surgery appears
to reduce weight loss by changing the circulating gut hormone profile. We have demonstrated that postprandial circulating levels of GLP-1, oxyntomodulin, and PYY are elevated after Roux-en-Y gastric bypass in humans and
jejunointestinal bypass in rodents (126, 127).
Gut hormones may represent a novel pathway by which
to tackle the obesity crisis. In comparison with the drugs
currently available and in development that influence central
neurotransmitter systems to reduce appetite, pharmaceutical
agents that hijack gut hormone signaling systems have several clear advantages. Gut hormone-based therapies would
specifically target appetite circuits. If, as the evidence suggests, endogenous gut hormones regulate appetite physiologically, then one might expect fewer side effects. Although
high doses of gut hormones may cause aversive effects, it
may be possible to administer lower doses of gut hormones
in combination. We have demonstrated that low doses of
PYY3–36 and GLP-1 can additively reduce food intake in
rodents and man (128). It may be that obesity treatment will
rely on combination therapy, as does, for example, the treatment for hypertension. In addition, gut hormones are released on a daily basis throughout life, suggesting that tachyphylaxis may be less of a problem than with other drugs.
The major disadvantages of gut hormones are their relatively short half-lives and the fact that they cannot be orally
administered. The design of breakdown-resistant analogs
might increase the length of time such drugs would remain
active in the circulation. Eventually, the hope is that new
administration techniques could be developed, for example
depot injections or nasal inhalers, and that small molecule
mimetics could be designed for oral administration.
In conclusion, gut hormones physiologically regulate energy homeostasis, and commandeering gut hormone signaling systems provides a promising target for antiobesity
therapies.
Murphy et al. • Gut Hormones and Appetite
Acknowledgments
Address all correspondence and requests for reprints to: Prof. S. R.
Bloom, Department of Metabolic Medicine, Imperial College Faculty of
Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN,
United Kingdom. E-mail: [email protected]
Disclosure Statement: S.R.B. is a director of Thiakis, a new company
interested in exploiting the use of oxyntomodulin and PYY in the treatment of obesity.
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gastric bypass suggests gut adaptation and explains altered satiety.
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127. le Roux CW, Aylwin SJ, Batterham RL, Borg CM, Coyle F, Prasad
V, Shurey S, Ghatei MA, Patel AG, Bloom SR 2006 Gut hormone
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128. Neary NM, Small CJ, Druce MR, Park AJ, Ellis SM, Semjonous
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Endocrine Reviews is published by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
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