Clinical Endocrinology (2004) 60, 153–160
doi: 10.1046/j.1365-2265.2003.01839.x
Review
Blackwell Publishing Ltd.
Appetite regulation: from the gut to the hypothalamus
Nicola Marguerite Neary*, Anthony Peter Goldstone†
and Stephen Robert Bloom*
*Department of Metabolic Medicine, Faculty of Medicine,
Imperial College of Science Technology and Medicine,
Hammersmith Campus and †Department of
Endocrinology, St Bartholomew’s Hospital, London, UK
(Received 28 July 2002; returned for revision 4 September 2002;
finally revised 28 March 2003; accepted 8 April 2003)
Introduction
Obesity is a serious medical condition whose prevalence is rising.
Figures from the Health Survey for England show that, in 1980,
8% of women and 6% of men were classified as obese, as defined
by a body mass index (BMI) of greater than 30 kg /m2. By 2001,
these proportions had increased to 26% and 22%, respectively,
with 55% of women and 66% of men being overweight
(BMI > 25 kg/m2; Health Survey for England, 2001), reflecting
a worldwide trend which is most marked in, but not restricted
to, the developed world. Most of us in affluent countries live in
a privileged land of plenty where high calorie foods are easily
available and in which we have a limited need for exercise. The
rising prevalence of obesity in children is of particular concern
(Chinn & Rona, 2001).
Obesity is associated with significant morbidity and mortality,
which can be attributed to increased risk of a number of medical
conditions (Kopelman, 2000) including type II diabetes mellitus,
hypertension and coronary heart disease, the most common cause
of premature mortality in the obese population. Less well known
are the associations between obesity and several cancers including breast, endometrial, prostate and bowel cancer (Daling et al.,
2001). Obesity predisposes to osteoarthritis particularly in the
large weight-bearing joints and to respiratory problems including
obstructive sleep apnoea. Thus obesity poses an immense and
increasing public health burden.
Despite the increase in population obesity described above, it
should not be forgotten , in individual people, energy balance is
usually very precise. Daily intake of food is highly variable and
correlates poorly with energy expenditure, whereas over longer
periods body weight is stable in most adults (Edholm, 1977). In
this article, we will explore how appetite and food intake are
Correspondence: Professor S. R. Bloom, Department of Metabolic
Medicine, Faculty of Medicine, Imperial College of Science Technology
and Medicine, Hammersmith Campus, Du Cane Road, London W12
ONN, UK. Tel: +44 020 8383 3242; Fax: +44 020 8383 3142.
E-mail: [email protected]
© 2003 Blackwell Publishing Ltd
regulated peripherally by adipose tissue and the gastrointestinal
tract, and how these signals are relayed in the hypothalamus
(Fig. 1). We will discuss which of these pathways might be pharmacologically manipulated.
Peripheral hormones regulating appetite
Insulin
Almost 50 years ago, Kennedy (1953) postulated that there
was a circulating factor, related to or arising from adipose
tissue, that regulated the hypothalamic control of food intake
to achieve the usual long-term stability of body weight and
fat mass. Insulin was the first hormone postulated to be such a
factor. The rise in circulating insulin in response to a glucose
load is proportional to fat mass, and insulin reaches the CNS
via receptor-mediated transport across the blood–brain barrier.
CNS administration of insulin to rodents, either into the third
ventricle or directly into the hypothalamus, causes a reduction
in food intake (Baura et al., 1993). However, patients with
type II diabetes who are commenced on insulin tend to gain
rather than lose weight, probably as a result of a loss of the
anorexigenic effect of hyperglycaemia and the lipogenic actions
of insulin.
Leptin
In 1994 there was a major breakthrough when the obese (ob) gene
was identified from examination of naturally occurring mutant
ob/ob mice (Zhang et al., 1994). The protein encoded by the
ob gene was named leptin from the Greek leptos meaning thin,
synthesized predominantly in adipose tissue. Circulating leptin
levels are directly proportional to adiposity in animals and humans
and correlate better with total fat mass than with body weight
(Considine et al., 1996). Central and peripheral administration
of leptin in rodents cause a profound decrease in food intake and
weight loss (Friedman & Halaas, 1998). However it is the central
intracerebroventricular (ICV) route that is the more potent, suggesting that leptin’s actions are mediated chiefly through the
hypothalamus. The ob/ob mouse, completely deficient in leptin,
is hyperphagic, hyperinsulinaemic and very obese and the leptin
receptor defective db/db mouse has a similar phenotype (Chua
et al., 1996). Chronic administration of leptin to the ob/ob mouse
results in sustained reduction in body weight, and reduced food
intake but has no effect on the db/db mouse.
Leptin increases hours after a meal in rodents and after several
days of overeating in humans (Kolaczynski et al., 1996).
153
154 N. M. Neary et al.
Fig. 1 Circulating gastrointestinal and
adipocyte hormones and neuronal circuits
involved in energy homeostasis. Solid lines
represent net stimulatory effect, dashed lines
represent net inhibitory effect.
Conversely, leptin levels fall dramatically with fasting. The magnitude of these responses is disproportionate to changes in fat mass,
suggesting that leptin may act to stabilize body weight before a
major change in weight occurs. In starvation, in which leptin
levels are further reduced, there is activation of the hypothalamo–
pituitary axis (HPA) and suppression of reproduction, the
thyroid axis and the immune system (Ahima et al., 1996; Lord
et al., 1998). When leptin is administered in the fasting state,
these effects are blunted. Thus leptin plays a key role in signalling
and survival in times of food deprivation as well as in food excess.
The importance of the leptin pathways in the control of human
body weight has been demonstrated by the childhood-onset
obesity and hyperphagia associated with rare congenital leptin
deficiency in humans. Treatment of three leptin-deficient children
with recombinant leptin has led to a significant reduction in
hyperphagia and fat mass (Farooqi et al., 2002). However, the
vast majority of obese people have high circulating leptin concentrations due to normal ob genes and reflecting their high fat
mass (Considine et al., 1996). Leptin treatment appears to be safe
and well-tolerated, but has been of limited benefit in treating
obesity in nonleptin-deficient people (Mantzoros & Flier, 2000).
It remains to be seen whether leptin may be better at maintaining
rather than inducing weight loss.
Gastrointestinal peptides
Ghrelin
In 1999 ghrelin was identified as the endogenous ligand for the
growth hormone secretagogue receptor (GHS-R). It is a small
28 amino acid peptide with an acyl side chain which is essential
for its biological action (Kojima et al., 1999). Interestingly, ghrelin is synthesized predominantly in the stomach. In addition to
stimulating GH, ghrelin has been shown to increase food intake
when administered both peripherally and centrally (Wren et al.,
2000). Although there are many peptides that have orexigenic
actions when administered centrally, ghrelin is the only peptide
hormone found to stimulate appetite when administered
peripherally.
Ghrelin is thought to signal premeal hunger and meal initiation. Endogenous levels of ghrelin in man rise on fasting and fall
rapidly on re-feeding with sharp peaks occurring just before each
meal (Cummings et al., 2001). Ghrelin also appears to play a role
in longer-term appetite regulation and energy balance. Chronic
administration of ghrelin in rodents leads to continuing hyperphagia and weight gain independent of GH secretion (Tschop
et al., 2000). Circulating ghrelin decreases in response to chronic
overfeeding and increases in response to chronic negative energy
balance associated with exercise or anorexia nervosa. Whereas
obese people usually have high plasma leptin they have low
plasma ghrelin (Tschop et al., 2001).
Intravenous ghrelin is effective in stimulating food intake in
humans. A recent study has shown a 28% increase in food intake
from a free buffet meal in healthy volunteers with a ghrelin infusion compared with saline control (Wren et al., 2001). Additionally, there were increases in subjective hunger as measured by
visual analogue scales. Ghrelin or a synthetic analogue could be
a possible therapy to increase food intake in cachexia and anorexia. Conversely, an antagonist at the ghrelin GHS-R receptor
could be an obesity treatment. The challenge in any antiobesity
© 2003 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 153 – 160
Obesity and appetite regulation 155
drug is to find an agent that reduces appetite and food intake
without affecting other endocrine systems. In the case of ghrelin,
one would want to block the feeding effects at the GHS-R without significantly reducing circulating GH. Circulating ghrelin
achieves its orexigenic action through stimulation of hypothalamic neurones (Nakazato et al., 2001), and inhibitory actions
on the gastric vagal afferent nerve (Date et al., 2002).
Peptide YY
Peptide YY (PYY) is secreted from the endocrine L cells of the
small and large bowel, and released into the circulation after
meals. PYY is a member of the neuropeptide Y (NPY) family
with a tyrosine residue at both ends. The main form of PYY in
both the gut mucosal endocrine cells and the circulation, is PYY
3–36 (Grandt et al., 1994). Peripheral administration of PYY 3–
36 leads to a marked inhibition in food intake. In human volunteers, an exogenous infusion accurately mimicking postprandial
PYY 3–36 concentrations reduced food intake by 30% when
compared with saline control in a double-blinded cross-over
study with no adverse effects (Batterham et al., 2002). PYY336 has a high affinity for the Y2 receptor (Y2R), a member of
the NPY receptor family. The pattern of c-fos neuronal activation
following peripheral administration of PYY 3–36 suggests that
its action is via the hypothalamus, where the Y2 is located.
In contrast with the negligible effect on appetite caused by the
normal daily fluctuations in circulating leptin (Sinha et al.,
1996), PYY 3–36 inhibits food intake in rodents and man at physiological concentrations. Thus PYY 3–36 is likely to be important
in the everyday regulation of food intake. Further work is needed
to determine whether PYY 3–36 is effective in obese people, and
whether the Y2 receptor could be a future drug target.
Glucagon-like-peptide-1
Glucagon-like-peptide 1 (GLP-1) is co-secreted with PYY in
response to nutrients in the gut. The precursor prepro-glucagon
is cleaved tissue-specifically – in the pancreas it forms glucagon
whereas in the intestinal L cells it gives rise to GLP-1. Central
ICV injection of GLP-1 powerfully inhibits feeding in rodents
(Turton et al., 1996).
GLP-1 plays an additional role in enhancing insulin secretion
and suppressing glucagon secretion after a meal, functioning as
an incretin (Kreymann et al., 1987). The plasma insulin response
to a given rise in plasma glucose is much greater after an oral
glucose load than after an intravenous glucose infusion and
this difference can be attributed to the rise in circulating GLP-1
and gastric inhibitory polypeptide (GIP) stimulated by the oral
glucose.
GLP-1 is the most powerful incretin known in man. Infusion
of GLP-1 to healthy volunteers increases plasma insulin levels
© 2003 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 1 5 3 – 160
and inhibits glucagon release (Kreymann et al. 1987). Human
data on whether GLP-1 inhibits feeding in humans is conflicting.
A recent meta-analysis shows that GLP-1 causes a small dosedependent inhibition of food intake in both lean and overweight
subjects (Verdich et al., 2001). Reduction in the rate of gastric
emptying may contribute to the increased satiety induced by
GLP-1.
The combination of enhanced insulin release with probable
reduction of food intake makes GLP-1 an attractive treatment for
patients with type II diabetes. A 6-week trial of three subcutaneous
GLP-1 premeal injections per day improved glycaemic control by
increasing insulin levels and inhibiting glucagon compared with
placebo control with no adverse effects (Todd et al., 1997).
Exendin-4, the GLP-1 receptor agonist with a longer biological
action than GLP-1, is currently undergoing phase III clinical
trials (Egan et al., 2002). An alternative therapeutic strategy is
to target the enzymes such as dipeptidyl peptidase-4 (DPP4),
which catalyse the breakdown of GLP-1. After 4 weeks of three
subcutaneous premeal injections of the DPP4 inhibitor NVP
DPP728, there was an improvement in glycaemic control compared with placebo, but without the additional benefit of weight
loss (Ahren et al., 2002).
Cholecystokinin
Cholecystokinin (CCK) was the first gut hormone shown to
inhibit feeding following exogenous administration in rodents
(Gibbs et al., 1973). CCKA receptors, present on the vagus nerve
and pyloric sphincter, are bound exclusively by the sulphated
forms of CCK and are active in reducing food intake (Moran,
2000). Other well-known functions of CCK include the stimulation of pancreatic enzyme secretion and gallbladder contraction
– effects mediated via both CCKA and CCKB receptors.
Peripheral CCK has a rapid but relatively short-lived effect on
feeding, exerting its maximum inhibition within 30 min postinjection (Moran, 2000) which is consistent with a role in mediating satiety and meal termination. High-dose CCK may also cause
nausea, vomiting and taste aversion, although lower doses have
been shown to inhibit feeding without inducing these effects
(West et al., 1987). However, tolerance is exhibited with prolonged CCK administration after 24 h (Crawley & Beinfeld,
1983). Although meal size was persistently reduced with the
CCK infusion, there was compensatory increase in meal number.
There is, however, evidence that CCK may play a role in longerterm energy regulation by synergizing the actions of leptin.
Central leptin administration potentiates the feeding inhibition
of peripheral CCK and the CCK/leptin combination results in
greater weight loss over 24 h than does leptin alone (Matson
et al., 1997). This synergy may occur by CCK activating brain
stem neurones that project to the hypothalamus combined with
leptin’s direct hypothalamic actions.
156 N. M. Neary et al.
NTS neurones to the PVN and lateral hypothalamus, such as
GLP-1 neurones, and projections of serotoninergic neurones of
the Raphe nuclei to the arcuate nucleus. The role of the brain
stem in appetite and feeding regulation has been examined using
experimental decerebrate rats in which connections between the
brain stem and forebrain are severed surgically (Grill & Smith,
1988). The decerebrate rats were able to compensate for changes
in the composition of individual meals offered to them. However,
when challenged with a reduction in meal number from three to
two per day, intact rats compensated by increasing their food
intake at each meal, but the decerebrate rats failed to adjust their
meal size. Thus while the brain stem plays a role in individual
meal size, the hypothalamus is required for long-term energy
balance and appetite regulation.
Fig. 2 Hypothalamic nuclei involved in energy homeostasis (lateral view)
ARC, arcuate nucleus (known as the infundibular nucleus in humans);
PVN, paraventricular nucleus; VMH, ventromedial hypothalamus; DMH,
dorsomedial hypothalamus; LH, lateral hypothalamic area; OC, optic chiasm.
Central appetite regulation
The hypothalamus
The hypothalamus can be subdivided into nuclei consisting of
collections of neurones with discrete functions (Fig. 2). Neuronal
projections between these nuclei and to and from other areas in
the brain enable the hypothalamus to integrate signals from the
brain, the peripheral circulation and the gastrointestinal tract to
regulate energy intake and expenditure.
The arcuate nucleus (ARC), termed infundibular nucleus in
man, is situated at the base of the hypothalamus. This is an elongated arc-shaped collection of neuronal cell bodies which express
receptors for many of the hormones and neuropeptides that are
known to regulate feeding. The arcuate nucleus is a privileged
site which can sample the peripheral circulation through semipermeable capillaries in the underlying median eminence, and is
thus in an ideal position to integrate hormonal signals for energy
homeostasis. The paraventricular nucleus (PVN) is adjacent to the
superior part of the third ventricle in the anterior hypothalamus.
The PVN is the main site of corticotrophin-releasing hormone
(CRH) and TRH secretion, in addition to being richly supplied
with neuronal projections from the ARC. Thus the PVN plays a
role in the integration of nutritional signals with the thyroid and
HPA axes.
The brain stem
One of the satiety signals following a meal is from afferent fibres
of the vagus nerve to the brain stem (Williams et al., 2001). The
hypothalamus and brain stem are linked via projections from
Orexigenic hypothalamic neuropeptides
NPY and Agouti-related protein (AgRP)
NPY is a 36 amino acid neuropeptide which is one of the most
potent orexigenic agents known. A single ICV injection acutely
stimulates feeding in rodents. Chronic administration of NPY
into the hypothalamic PVN leads to sustained hyperphagia and
weight gain, and central injection of NPY antagonists or antiserum decreases food intake in the dark phase when rats normally
eat readily (Kalra et al., 1999). There is a rapid increase in NPY
before mealtimes in the PVN, and levels remain elevated as long
as food is withheld, suggesting that NPY plays a role in the central
control of meal initiation. NPY acts to stimulate feeding predominantly through activation of Y1 and Y5 receptors. NPY also
has multiple actions on the HPA, on seizure activity and on
responses to stress and anxiety, which may limit its use as a drug
target for obesity.
AgRP increases food intake through antagonism of the
melanocortin MC3 and MC4 receptors and thus blockade of the
inhibition of the anorexigenic agonist α-melanocyte-stimulating
hormone (α-MSH; see below). In contrast to the potent but relatively short-lived effects of NPY, central administration of AgRP
to rodents leads to an increase in food intake for up to 1 week (Rossi
et al., 1998). Chronic administration of AgRP to rodents causes
sustained hyperphagia and leads to obesity (Small et al., 2001).
AgRP is found exclusively in the arcuate nucleus, and virtually
all AgRP neurones co-secrete NPY (Goldstone et al., 2002).
NPY/AgRP neurones are inhibited by leptin and insulin, and
activated by ghrelin (Kalra et al., 1999; Nakazato et al., 2001).
The Y2R is a presynaptic inhibitory autoreceptor on NPY neurones. Injection of PYY3-36, the gut-derived Y2R agonist,
directly into the ARC inhibits food intake. The appetite inhibitory
effects of PYY3-36 are absent in the Y2 knockout mouse
(Batterham et al., 2002). Therefore it appears that circulating
PYY3-36 inhibits appetite by acting directly on the arcuate
© 2003 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 153 –160
Obesity and appetite regulation 157
nucleus to inhibit orexigenic NPY neurones. Thus low circulating
leptin, insulin and PYY3-36, and elevated ghrelin levels such as
in fasting or starvation lead to an increase in NPY and AgRP
neuronal activity and increased appetite, whereas the opposite in
seen postprandially (Fig. 1).
Anorectic hypothalamic neuropeptides
The melanocortins
The melanocortins are derived from the precursor molecule proopiomelanocortin (POMC) via tissue-specific post-translational
cleavage. In the anterior pituitary, POMC gives rise to ACTH,
which acts via the MC2 receptor to stimulate adrenal steroidogenesis. The melanocortin α-MSH is derived from POMC in
brain. The MC3 and MC4 receptors are biologically unique in
that there is an endogenous antagonist (AgRP) in addition to
endogenous agonists (the melanocortins).
Central ICV administration of α-MSH inhibits feeding and
reduces body weight. The stimulatory effect of AgRP is inhibited
by α-MSH (Rossi et al., 1998). Thus α-MSH and AgRP neurones
act as a dynamic system in vivo.
POMC is co-expressed in arcuate neurones with cocaine- and
amphetamine-regulated transcript (CART), and these neurones
are directly stimulated by leptin (Cowley et al., 2001). Peripheral
administration of PYY 3–36 increases POMC expression and
inhibits NPY expression (Batterham et al., 2002). These changes
in message levels may explain the long duration of action of PYY.
The MC4 receptor, in particular, is thought to be critical to
body weight regulation. The MC4 knockout mouse is hyperphagic and very obese, and insensitive to α-MSH (Huszar et al.,
1997). Functional mutations of the MC4 receptor are also a
cause of monogenic human obesity and are much more common
than leptin deficiency, being found in up to 4% of adults with
severe childhood-onset obesity (Farooqi et al., 2000). The minority with homozygous mutations tend to be more severely obese.
For the majority of obese patients who have intact melanocortin
receptors, agonists at these receptors and, in particular, the MC4
receptor could reduce appetite and food intake. The prolonged
action of the endogenous antagonist AgRP suggests that
manipulation of the melanocortin system could have longlasting effects. Melanocortin receptor agonists are currently
being developed as potential obesity treatments. Recently it
was demonstrated that intranasal administration of a fragment
of melanocortin (MSH/ACTH4−10), common to all melanocortins,
leads to modest weight reduction in humans (Fehm et al., 2001).
Serotonin
Serotonin (5-HT) is a short-acting widespread neurotransmitter
which acts on a number of receptor subtypes found at high
© 2003 Blackwell Publishing Ltd, Clinical Endocrinology, 60, 1 5 3 – 160
density in the limbic system and Raphe nuclei as well as in the
hypothalamus (Blundell, 1984). In general, agonists at the 5-HT
receptors and drugs that inhibit the re-uptake of serotonin reduce
feeding. Additionally, 5-HT stimulates noradrenaline release and
modifies behaviour and mood.
Agonists at the 5-HT2C receptor show the most consistent
inhibition of food intake, and the 5-HT2C knockout mouse is
hyperphagic and obese (Tecott et al., 1995). Additionally, this
knockout mouse has a low seizure threshold and exhibits severe
and life-threatening epilepsy. However, 5-HT2C antagonists do
not cause hyperphagia or epilepsy. This apparent dichotomy
could be explained if the phenotype of the knockout mouse had
been altered through adaptation, and illustrates the potential
limitations in the extrapolation of the function of a neuropeptide
from its knockout model.
Current treatments for obesity
The first-line treatment for obesity is food restriction and exercise. However, most people find it difficult to lose weight despite
a wide choice of diets and exercise programmes, and even more
difficult to maintain weight loss (Yanovski & Yanovski, 2002).
Current second-line treatments are the medications sibutramine
and orlistat, and surgery.
Pharmacological therapy
Sibutramine, a serotonin and noradrenaline re-uptake inhibitor,
is recommended by the National Institute of Clinical Excellence
(NICE) for the treatment of obesity in patients with a BMI of
over 30 kg/m2 or the presence of an obesity-related disease and
a BMI of over 27 kg/m2 (NICE, 2001). The earlier drugs fenfluramine and dex-fenfluramine, which acted through stimulation
of 5-HT secretion as well as inhibition of 5-HT re-uptake, were
withdrawn following the discovery of an association with their
use and cardiac valve abnormalities (Connolly et al., 1997). In
a recent European trial (James et al., 2000), following a 6-month
run-in period on sibutramine, patients who achieved a 5%
reduction in weight were randomized to either continue with
sibutramine or receive placebo. At 18 months, 69% of patients on
sibutramine compared with 42% of controls retained this modest
5% reduction. Sibutramine may cause an increase in blood pressure and pulse (acting as a sympathomimetic) and is therefore
unsuitable for hypertensive patients. In normotensive patients,
treatment with sibutramine may achieve moderate weight loss for
a limited period at least.
Orlistat acts locally in the gut by binding to gastrointestinal
lipases to inhibit fat absorption. Patients who take orlistat with
or 1 h after meals excrete approximately one-third of their
ingested dietary fat in their stools, thereby reducing calorie
intake. Consequently, they may have flatulence and offensive
158 N. M. Neary et al.
stools after a fatty meal. Trials show that orlistat can also achieve
mild weight loss of 9% at 1 years compared with 5% of placebo
and may slow the regain of weight for a second year of use
(Yanovski & Yanovski, 2002). However, orlistat is only licensed
for 2 years, and is less effective by the second year.
Surgery
Surgery is the only treatment which has been proven to achieve
weight loss in the long term. The jejuno-intestinal bypass has
been performed since the 1960s and leads to impressive weight
loss up to 15 years (Frandsen et al., 1998). However, its use has
been limited by serious complications including liver failure,
severe electrolyte imbalance, renal calculi due to impaired
oxalate absorption, osteomalacia and bypass enteritis.
The Roux-en-Y gastric bypass has now been largely superseded the jejuno-intestinal bypass. This technique involves cutting the jejunum, and joining the distal end to the body of the
stomach (the Roux-en-Y) and the proximal part to another part
of jejunum distal to the Roux-en-Y. The stomach is stapled,
leaving a 10–15 ml fundal pouch which drains directly into the
jejunum. The advantages of the gastric bypass over the jejunointestinal bypass are that there is no blind loop, the bile can drain
through the duodenum and into the jejunum and there is less
severe malabsorption. In one series, mean weight loss at 15 years
postgastric bypass surgery was 30 kg (Mitchell et al., 2001) compared with 43 kg in another study following jejuno-intestinal
surgery (Frandsen et al. 1998) but with the benefit of fewer
complications. Nonetheless, the morbidity associated with gastric bypass surgery, in addition to practical and financial constraints, usually limit this approach to severely obese patient
(BMI > 40 kg/m2).
Interestingly, the success of bypass surgery may be as much
hormonal as mechanical. Fasted rats with jejuno-intestinal
bypass ate 32% less in the first hour of re-feeding than fasted
rats given a sham procedure (Atkinson & Brent, 1982). When
plasma from the bypass group following feeding was injected
into a new group of fasting rats, the recipients ate 32% less in
the first hour than rats injected from plasma from the sham bypass
group. Thus it appeared that the reduction in appetite was hormonally driven. After intestinal resection in the rat, there is
significant elevation in the concentration of PYY (Savage et al.,
1985). With our current knowledge of the PYY 3–36 circuitry
from the gut to the ARC of the hypothalamus, it is tempting to
hypothesize that elevated circulating PYY 3–36 levels in patients
with gastric or intestinal bypass contribute to a reduction in
appetite and food intake. Gastric bypass surgery may also affect
circulating ghrelin. Plasma ghrelin concentrations were recently
measured in obese patients before and after diet-induced weight
loss, and in patients who had previously undergone gastric bypass
surgery. As predicted, circulating ghrelin increased with
diet-induced weight loss. However, ghrelin levels were 77%
lower in the gastric bypass group compared with matched BMI
controls, and the usual premeal peaks were lost (Cummings et al.,
2002). Under normal circumstances the presence of nutrients in
the stomach is believed to suppress ghrelin secretion from the
stomach. However, the observations of this study suggest that
prolonged absence of nutrients or surgical manipulation of the
stomach suppresses ghrelin secretion. Reduced circulating
ghrelin with a possible elevation of circulating PYY 3–36 could
account for the paradoxical decrease in hunger reported by most
patients, and explain the long-term weight loss usually seen
following gastric bypass surgery.
Conclusion
The current epidemic of obesity is threatening the health of
the western world. We have explored how appetite is regulated by
the circulating hormones leptin and insulin, and the gut hormones
ghrelin and PYY 3–36, and signalled to the hypothalamus. Exciting potential pharmacological targets include the receptors of
orexigenic ghrelin and anorexigenic PYY 3–36. Further understanding is required to enable us to develop more effective
treatments, not only to inhibit appetite in the obese but also to
stimulate appetite in cachectic patients. While many of the signals and circuits described in this article might be manipulated,
the real challenge is to find treatments that modify appetite and
lead to lasting weight reduction selectively without significantly
affecting other neuroendocrine systems.
Acknowledgements
MRC Programme Grant (Bloom SR, Ghatei MA and Small CJ)
number G7811974. Nicola Neary is a Wellcome Trust Clinical
Research Training Fellow.
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