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TRENDS in Endocrinology and Metabolism
Vol.15 No.6 August 2004
Gut hormones and the control of
appetite
Caroline J. Small and Stephen R. Bloom
Department of Metabolic Medicine, Division of Investigative Science, Imperial College London, Hammersmith Campus,
Du Cane Road, London, W12 ONN, UK
Obesity is the main cause of premature death in the UK.
Worldwide its prevalence is accelerating. It has been
hypothesized that a gut nutriment sensor signals to
appetite centres in the brain to reduce food intake after
meals. Gut hormones have been identified as an
important mechanism for this. Ghrelin stimulates, and
glucagon like peptide-1, oxyntomodulin, peptide YY
(PYY), cholecystokinin and pancreatic polypeptide inhibit, appetite. At physiological postprandial concentrations they can alter food intake markedly in humans
and rodents. In addition, in obese humans fasting levels
of PYY are suppressed and postprandial release is
reduced. Administration of gut hormones might provide
a novel and physiological approach in anti-obesity
therapy. Here, we summarize some of the recent
advances in this field.
Obesity is a major health problem in the developed world
with a dramatic influence on morbidity and mortality, in
addition to major economic consequences. Treating the
complications of obesity costs the National Health Service
in the UK over half a billion pounds per year [1].
Prevention of obesity is a priority for individuals and
governments worldwide.
There are several approaches currently used for the
treatment of obesity. All have problems and none, except
for bariatric surgery, is very effective. The drug Orlistat
blocks the absorption of dietary fat and reviews suggest
that it results in an additional loss of 3–4% of body weight
over diet alone in a two-year period [2]. However, it might
lead to socially unacceptable side effects and deficiency in
vitamins A and E. Treatments such as Sibutramine act
within the central nervous system (CNS) to reduce energy
intake and increase energy expenditure [3,4]. Sibutramine has a similar efficacy to Orlistat, but its use is limited
by side effects, particularly tachycardia and hypertension
[5]. Although these therapies are helpful in the short to
medium term, their effectiveness is limited in the long
term. The most efficacious and long-lasting treatment for
obesity is gastrointestinal bypass surgery. In one longterm study the mean weight loss was 29.5 kg 13–15 years
post-bypass [6]. Although surgery initially reduces calorie
absorption, its sustained effect results from a reduction in
appetite. Bypass surgery alters circulating gut hormones,
such as peptide YY (PYY) [7] and ghrelin [8,9], and its
Corresponding author: Stephen R. Bloom ([email protected]).
Available online 2 July 2004
long-term action on appetite might be secondary to these
alterations in circulating hormones.
Previous work on cholecystokinin (CCK) and ghrelin
have suggested that there is a gut nutriment sensor that
signals to appetite centres in the brain to reduce appetite
after meals. It has become increasingly apparent that the
gut endocrine system plays an important physiological
role in postprandial satiety. Recent work has identified the
gut hormones PYY, oxyntomodulin and pancreatic polypeptide (PP), which inhibit appetite, and ghrelin, which
stimulates appetite. These hormones are active within the
plasma range seen in humans and represent a novel
approach to the treatment of obesity. Here, we examine
how these gut hormones influence appetite and whether
they could contribute to the treatment of obesity.
The hypothalamic appetite circuits
The hypothalamus and the dorsal vagal complex appear to
be important CNS regions directly regulating appetite
([10] and extensively reviewed in Ref. [11]). Recently, some
of the main neural circuits involved have been identified.
The arcuate nucleus of the hypothalamus plays an
integrative role in appetite regulation; for example, by
receiving signals from the periphery via the brainstem
[10–12]. Receptors for the gut hormones are found on
these neuronal populations within the arcuate nucleus.
The arcuate nucleus can also be directly influenced by
circulating factors, because it is partially outside the
blood–brain barrier. There are two well characterized
neuronal populations involved – appetite inhibiting
proopiomelanocortin and cocaine- and amphetamineregulated transcript coexpressing neurones, and appetite
stimulating neuropeptide Y (NPY) and agouti related
peptide coexpressing neurones [10–13]. Both of these
neuronal populations project to the paraventricular
nucleus (PVN) and other important nuclei involved in
the regulation of food intake. The PVN also receives
important inputs from other hypothalamic nuclei; for
example, melanin-concentrating hormone-producing
neurones from the lateral hypothalamic area, and other
brain areas, such as the brainstem and amygdala.
Mutations disrupting these hypothalamic systems cause
obesity in human [14,15].
Ghrelin
Ghrelin is a circulating hormone synthesized in the
stomach [16]. It is the endogenous ligand for the growth
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hormone secretagogue receptor, which is expressed in the
arcuate nucleus and other hypothalamic and brain stem
nuclei [17,18]. Ghrelin levels are highest in the fasting
state, rising sharply before and falling within one hour of a
meal [9]. Ghrelin peaks are of similar magnitude before
each meal of the day and ghrelin might be involved in meal
initiation [19].
Ghrelin potently stimulates food intake following
peripheral administration in humans [20], and similar
results have been obtained in rats [21–23]. Peripheral
ghrelin potently stimulates feeding in rodents, with the
maximum effect being seen within one hour of administration [23]. A dose of ghrelin that stimulates feeding
achieves similar circulating levels to those seen after a
24-h fast [24], suggesting that ghrelin regulates day to day
food intake. Chronic peripheral ghrelin administration
leads to a significant increase in cumulative food intake
and body weight gain, with no attenuation in feeding
stimulation with multiple injections [22,24]. This weight
gain is mainly the result of increased fat deposition, and
might also be caused by decreased energy expenditure in
addition to increased food intake [22].
In rats, circulating ghrelin acts, at least in part,
through the arcuate nucleus [12,25]. However, it is
important to note that both the arcuate c-fos neuronal
activation and the stimulation of food intake following
ghrelin administration require an intact vagal nerve [26].
Ghrelin is suppressed in obesity [27]. It is not known
whether this is associated with a reduced or increased
sensitivity to ghrelin. However, obesity is associated with
an increased arcuate c-fos response to peripheral ghrelin
administration in rats [28].
Leptin
In 1994, the adipocyte hormone leptin was discovered [29],
which circulates at concentrations proportional to fat
mass and inhibits food intake [30]. In addition, circulating
leptin falls during starvation and exhibits a diurnal
pattern [30,31]. Leptin crosses the blood–brain barrier to
act via its receptor to inhibit orexigenic and stimulate
anorexigenic neuropeptides in the arcuate nucleus of the
hypothalamus, leading to a reduction in food intake
[13,32]. Leptin activates other hypothalamic nuclei such
as the dorsomedial hypothalamus (DMH), PVN and
ventromedial hypothalamus (VMH) [33–35]. However,
the relative contribution of these hypothalamic nuclei to
mediating the effects of leptin remains controversial.
Leptin has been shown to have synergistic actions with
CCK [33]. Leptin is believed to play an important role in
energy balance, particularly the response of the body to
fasting [31]. Clinical trials have shown that administration of leptin has little effect on body weight in the
obese [36,37].
Cholecystokinin
CCK is a hormone produced by mucosal endocrine cells in
the upper small intestine and released postprandially. It is
also a neurotransmitter with a very wide distribution,
being the most abundant neuropeptide in the CNS [38].
CCK is known to inhibit food intake in humans and
rodents [39,40]. Although CCK was shown in 1973 to alter
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Vol.15 No.6 August 2004
food intake, it is still not clear whether this effect is
physiologically relevant [41–43]. Following peripheral
administration of CCK at doses just sufficient to inhibit
food intake, synthesis of c-fos, a marker of neuronal
activation, is limited to the brainstem, in the nucleus of
the solitary tract and the dorsal vagal nucleus [44]. Rats
lacking functional CCKA receptors are diabetic, hyperphagic and obese [45]. However, the CCKA receptordeficient mouse has normal body weight [46].
Peptide YY
In 1985, it was reported that a newly extracted gut
peptide, a member of the NPY family with a tyrosine at
both ends, named peptide YY (PYY), was produced by gut
endocrine cells and released into the circulation after
meals [47]. Both PYY 1–36 and PYY 3–36 are stored in
the gut mucosal endocrine cells and present in the
circulation [48].
Peripheral administration of PYY was first reported in
1993 to decrease appetite [49]. In addition, when PYY
3–36 is administered peripherally in the mouse, rat or
human there is a marked inhibition of food intake [50].
The pattern of c-fos synthesis in the brain after peripheral
administration of PYY 3–36 showed a marked induction of
c-fos in the arcuate nucleus. Injection of PYY 3–36 directly
into the arcuate nucleus inhibited food intake and chronic
administration of PYY 3–36 leads to a decrease in food
intake and body weight. Addition of PYY 3–36 to ex vivo
hypothalamic explants inhibited release of NPY and
stimulated release of a-melanocyte stimulating hormone
(a-MSH). Peripheral administration of PYY 3–36 in rats
caused a decrease in the synthesis of mRNA encoding
arcuate NPY. PYY 3–36 has a high affinity for the Y2R.
The appetite inhibitory effect was also seen with a Y2Rspecific agonist and was absent in the Y2R-deficient
mouse [50]. It appears that circulating PYY 3–36 inhibits
appetite by acting directly on the arcuate nucleus via the
Y2R, a presynaptic inhibitory autoreceptor [13,50].
In human volunteers, infusion of PYY 3–36 to mimic
accurately postprandial concentrations reduced food
intake by 30% in a placebo-controlled double-blinded
crossover study [50]. These data demonstrate that PYY
physiologically inhibits appetite in humans and suggest
that it is important in the every-day regulation of food
intake. Interestingly, obese subjects have a lower fasting
basal PYY and exhibit a diminished postprandial rise in
PYY [51]. There is a highly significant negative
correlation between PYY and body mass index (BMI)
(rZK0.89, nZ24, P!0.001). Caloric intake during a
buffet lunch two hours after the infusion of PYY 3–36
was decreased by 30% in obese subjects (P!0.0005) and
31% in lean subjects (P!0.0001). The PYY infusion also
caused a significant decrease in the cumulative 24-h
caloric intake in both obese and lean subjects [51]. These
recent findings suggest that, unlike leptin, obesity is not
associated with PYY resistance. Whether this is the
cause or a result of their obesity is unclear.
Pancreatic polypeptide
PP, a hormone produced by the PP cells of the islets of
Langerhans, has been reported to reduce appetite in
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TRENDS in Endocrinology and Metabolism
several animal models [52–55]. The PP receptor (Y4R) is
present in both the brainstem and arcuate nucleus [56],
regions of the brain known to be involved in appetite
regulation. It was unclear to what extent PP might be
physiologically involved in appetite regulation in animals
and whether it has this effect in humans [57–59].
However, a 90-min PP infusion of 10 pmol kgK1 minK1 in
healthy volunteers produces a 25.3%G5.8% reduction in
food intake over 24 h [60]. More importantly, the inhibition of food intake was sustained, such that energy
intake, as assessed by food diaries, was significantly
reduced on both the evening of the study and the following
morning [60].
Glucagon-like peptide-1 (7–36) amide
Glucagon-like peptide-1 (7–36) amide (GLP-1) is produced
by processing of the gene encoding preproglucagon in both
the gut and brain [61]. It is released from the gut into the
circulation in response to nutrient intake. Physiological
actions of peripheral GLP-1 in humans include stimulation of insulin release [62].
GLP-1 receptors are found in the brainstem, arcuate
nucleus and PVN. Intracerebroventricular (i.c.v) or direct
administration into the paraventricular nucleus of GLP-1
to rats potently inhibits food intake, whereas the specific
GLP-1 receptor antagonist, exendin 9–39, causes an
increase in food intake [63].
Peripheral administration of GLP-1 in humans and
rats inhibits food intake and, in rats, also results in c-fos
synthesis in the brainstem [64–66]. These and other
findings suggest that the main site for appetite inhibition
by peripheral GLP-1 is the dorsal vagal complex, acting, in
part, directly through the area postrema. The importance
of circulating GLP-1 in appetite control in humans is
currently unclear. However, GLP-1 decreases gastric
emptying and this might have effects on food intake [67].
Infusions mimicking postprandial concentrations produce
only a small, although reproducible, reduction in appetite
and food intake [68,69].
Oxyntomodulin
Oxyntomodulin (Oxm) is also a product of post-translational processing of preproglucagon in the intestine and
the CNS [61]. In addition, it is released postprandially and
i.c.v administration of Oxm inhibits food intake in the rat
with greater potency than does GLP-1 [70]. Oxm appears
to act via a GLP-1-like receptor, because its anorectic
actions are blocked by coadministration of the GLP-1
receptor antagonist, exendin 9–39 [70]. Recently, it was
shown that Oxm is also a potent inhibitor of food intake
when administered intraperitoneally (IP) to rats [71]. IP
administration of Oxm resulted in c-fos synthesis in the
arcuate nucleus, a region partially outside the blood–brain
barrier, but there was little activation of neurones in the
nucleus of the solitary tract in the brainstem. These
experiments show that Oxm has a very different pattern of
neuronal activation from that of GLP-1. When the
antagonist exendin 9–39 was injected into the arcuate
nucleus, circulating Oxm no longer inhibited food intake,
suggesting an arcuate site of action. By contrast, the effect
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Vol.15 No.6 August 2004
261
of circulating GLP-1, acting via the brainstem, was
unaffected.
Intravenous infusion of Oxm in 13 healthy subjects in a
randomized double-blind placebo-controlled crossover
study significantly reduced ad libitum calorie intake
of a free choice buffet meal (mean decrease 19.3%G5.6%,
P !0.01) and caused a significant reduction in hunger
scores. In addition, cumulative 12-h caloric intake was
significantly reduced by infusion of Oxm (mean decrease
11.3%G6.2%, P !0.05). Fasting levels of ghrelin were
significantly suppressed by Oxm (mean reduction 44%G
10% of postprandial decrease, P !0.01) [72].
Gut hormones and obesity
Obesity can be thought of as a state of chronic adaptation
to the hormonal changes of increased fat mass. Results to
date suggest that increased BMI is associated with
increased plasma leptin and decreased plasma ghrelin
and PYY [27,30]. Obese people have a similar sensitivity
to the appetite inhibitory effects of exogenous PYY 3–36
infusion as lean people [51]; that is, no ‘PYY resistance’.
However, the sensitivity to ghrelin infusion remains to be
established. Although the gastric oxyntic glands appear to
be capable of producing ever-increasing concentrations of
ghrelin in states of under-nutrition, could it be that the
low levels of PYY in obesity are the result of L-cell failure?
PYY replacement could therefore provide a realistic
therapeutic anti-obesity treatment.
The only treatment so far that has achieved lasting
weight reduction is gastric and intestinal bypass surgery.
In one series, mean weight loss at 15 years post-bypass
surgery was 29.5 kg [6]. However, the morbidity and
mortality associated with bypass surgery, in addition to
practical and financial constraints, usually limit this
approach to the severely obese patient (BMI >40 kg mK2).
Interestingly, the success of bypass surgery can be as
much hormonal as mechanical, because induced malabsorption is usually only temporary, whereas the reduction
of appetite is permanent. Plasma ghrelin levels were
recently measured in patients who had undergone gastric
bypass. Circulating ghrelin levels were 77% lower in the
bypass group compared with BMI-matched controls, and
the usual pre-meal peaks were lost [9]. However, more
recent reports suggest that the effects are more complex
and for full review see [8]. After bypass surgery, there is a
significant rise in plasma PYY [73]. A recent study has
shown that, in rats, bypass surgery results in a threefold
increase in circulating PYY, with a 21% reduction in body
weight after 28 days [74].
Therefore, the success of bypass surgery might, in part,
be the result of a decrease in circulating ghrelin and an
increase in circulating PYY. These changes in gut
hormones act on the arcuate nucleus of the hypothalamus,
either through the median eminence or via the brainstem.
Thus, altered gut signals following bypass surgery could
explain why bypass patients frequently describe amazingly reduced hunger after surgery.
Summary and conclusions
Several new chemical entities are being developed by
pharmaceutical companies to target receptor systems
262
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TRENDS in Endocrinology and Metabolism
involved in appetite regulation. However, these same
systems also affect many other CNS functions, because
they use the same receptors; for example the serotonin
system. The peripheral administration of natural gut
hormones as therapeutic agents has the advantage of
targeting only the relevant brain appetite systems. Gut
hormones are released every day after meals without side
effects and continue to exert their effect without escape.
Thus, the administration of the naturally occurring gut
hormone might offer a long-term therapeutic approach to
weight control, without deleterious side effects.
Acknowledgements
We acknowledge the contribution of the following clinical training fellows
who have worked, or are currently working, in the department: A. Wren,
N. Martin, N. Neary, R. Batterham and M. Cohen. In addition, we thank
C. Dakin for her work on oxyntomodulin and C. Abbott for her
contribution to the hypothalamic group, G. Frost and S. Ellis for their
invaluable dietetics support and the Wellcome Trust and Medical
Research Council [MRC Programme Grant (S.R. Bloom, M.A. Ghatei
and C.J. Small) number G7811974] for supporting this work.
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