Clinical Endocrinology (2004) 60, 153–160 doi: 10.1046/j.1365-2265.2003.01839.

Review
Blackwell Publishing Ltd.

Appetite regulation: from the gut to the hypothalamus

Nicola Marguerite Neary*, Anthony Peter Goldstone† regulated peripherally by adipose tissue and the gastrointestinal
and Stephen Robert Bloom* tract, and how these signals are relayed in the hypothalamus
*Department of Metabolic Medicine, Faculty of Medicine, (Fig. 1). We will discuss which of these pathways might be phar-
Imperial College of Science Technology and Medicine, macologically manipulated.
Hammersmith Campus and †Department of
Endocrinology, St Bartholomew’s Hospital, London, UK
(Received 28 July 2002; returned for revision 4 September 2002; Peripheral hormones regulating appetite
finally revised 28 March 2003; accepted 8 April 2003)
Insulin

Almost 50 years ago, Kennedy (1953) postulated that there

Introduction
was a circulating factor, related to or arising from adipose
Obesity is a serious medical condition whose prevalence is rising. tissue, that regulated the hypothalamic control of food intake
Figures from the Health Survey for England show that, in 1980, to achieve the usual long-term stability of body weight and
8% of women and 6% of men were classified as obese, as defined fat mass. Insulin was the first hormone postulated to be such a
by a body mass index (BMI) of greater than 30 kg /m2. By 2001, factor. The rise in circulating insulin in response to a glucose
these proportions had increased to 26% and 22%, respectively, load is proportional to fat mass, and insulin reaches the CNS
with 55% of women and 66% of men being overweight via receptor-mediated transport across the blood–brain barrier.
(BMI > 25 kg/m2; Health Survey for England, 2001), reflecting CNS administration of insulin to rodents, either into the third
a worldwide trend which is most marked in, but not restricted ventricle or directly into the hypothalamus, causes a reduction
to, the developed world. Most of us in affluent countries live in in food intake (Baura et al., 1993). However, patients with
a privileged land of plenty where high calorie foods are easily type II diabetes who are commenced on insulin tend to gain
available and in which we have a limited need for exercise. The rather than lose weight, probably as a result of a loss of the
rising prevalence of obesity in children is of particular concern anorexigenic effect of hyperglycaemia and the lipogenic actions
(Chinn & Rona, 2001). of insulin.
Obesity is associated with significant morbidity and mortality,
which can be attributed to increased risk of a number of medical
Leptin
conditions (Kopelman, 2000) including type II diabetes mellitus,
hypertension and coronary heart disease, the most common cause In 1994 there was a major breakthrough when the obese (ob) gene
of premature mortality in the obese population. Less well known was identified from examination of naturally occurring mutant
are the associations between obesity and several cancers includ- ob/ob mice (Zhang et al., 1994). The protein encoded by the
ing breast, endometrial, prostate and bowel cancer (Daling et al., ob gene was named leptin from the Greek leptos meaning thin,
2001). Obesity predisposes to osteoarthritis particularly in the synthesized predominantly in adipose tissue. Circulating leptin
large weight-bearing joints and to respiratory problems including levels are directly proportional to adiposity in animals and humans
obstructive sleep apnoea. Thus obesity poses an immense and and correlate better with total fat mass than with body weight
increasing public health burden. (Considine et al., 1996). Central and peripheral administration
Despite the increase in population obesity described above, it of leptin in rodents cause a profound decrease in food intake and
should not be forgotten , in individual people, energy balance is weight loss (Friedman & Halaas, 1998). However it is the central
usually very precise. Daily intake of food is highly variable and intracerebroventricular (ICV) route that is the more potent, sug-
correlates poorly with energy expenditure, whereas over longer gesting that leptin’s actions are mediated chiefly through the
periods body weight is stable in most adults (Edholm, 1977). In hypothalamus. The ob/ob mouse, completely deficient in leptin,
this article, we will explore how appetite and food intake are 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
Correspondence: Professor S. R. Bloom, Department of Metabolic
results in sustained reduction in body weight, and reduced food
Medicine, Faculty of Medicine, Imperial College of Science Technology
and Medicine, Hammersmith Campus, Du Cane Road, London W12 intake but has no effect on the db/db mouse.
ONN, UK. Tel: +44 020 8383 3242; Fax: +44 020 8383 3142. Leptin increases hours after a meal in rodents and after several
E-mail: [email protected] days of overeating in humans (Kolaczynski et al., 1996).

© 2003 Blackwell Publishing Ltd 153

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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 magni- 28 amino acid peptide with an acyl side chain which is essential
tude of these responses is disproportionate to changes in fat mass, for its biological action (Kojima et al., 1999). Interestingly, ghre-
suggesting that leptin may act to stabilize body weight before a lin is synthesized predominantly in the stomach. In addition to
major change in weight occurs. In starvation, in which leptin stimulating GH, ghrelin has been shown to increase food intake
levels are further reduced, there is activation of the hypothalamo– when administered both peripherally and centrally (Wren et al.,
pituitary axis (HPA) and suppression of reproduction, the 2000). Although there are many peptides that have orexigenic
thyroid axis and the immune system (Ahima et al., 1996; Lord actions when administered centrally, ghrelin is the only peptide
et al., 1998). When leptin is administered in the fasting state, hormone found to stimulate appetite when administered
these effects are blunted. Thus leptin plays a key role in signalling peripherally.
and survival in times of food deprivation as well as in food excess. Ghrelin is thought to signal premeal hunger and meal initia-
The importance of the leptin pathways in the control of human tion. Endogenous levels of ghrelin in man rise on fasting and fall
body weight has been demonstrated by the childhood-onset rapidly on re-feeding with sharp peaks occurring just before each
obesity and hyperphagia associated with rare congenital leptin meal (Cummings et al., 2001). Ghrelin also appears to play a role
deficiency in humans. Treatment of three leptin-deficient children in longer-term appetite regulation and energy balance. Chronic
with recombinant leptin has led to a significant reduction in administration of ghrelin in rodents leads to continuing hyper-
hyperphagia and fat mass (Farooqi et al., 2002). However, the phagia and weight gain independent of GH secretion (Tschop
vast majority of obese people have high circulating leptin con- et al., 2000). Circulating ghrelin decreases in response to chronic
centrations due to normal ob genes and reflecting their high fat overfeeding and increases in response to chronic negative energy
mass (Considine et al., 1996). Leptin treatment appears to be safe balance associated with exercise or anorexia nervosa. Whereas
and well-tolerated, but has been of limited benefit in treating obese people usually have high plasma leptin they have low
obesity in nonleptin-deficient people (Mantzoros & Flier, 2000). plasma ghrelin (Tschop et al., 2001).
It remains to be seen whether leptin may be better at maintaining Intravenous ghrelin is effective in stimulating food intake in
rather than inducing weight loss. humans. A recent study has shown a 28% increase in food intake
from a free buffet meal in healthy volunteers with a ghrelin infu-
sion compared with saline control (Wren et al., 2001). Addition-
Gastrointestinal peptides ally, there were increases in subjective hunger as measured by
visual analogue scales. Ghrelin or a synthetic analogue could be
Ghrelin
a possible therapy to increase food intake in cachexia and ano-
In 1999 ghrelin was identified as the endogenous ligand for the rexia. Conversely, an antagonist at the ghrelin GHS-R receptor
growth hormone secretagogue receptor (GHS-R). It is a small could be an obesity treatment. The challenge in any antiobesity

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Obesity and appetite regulation 155

drug is to find an agent that reduces appetite and food intake and inhibits glucagon release (Kreymann et al. 1987). Human
without affecting other endocrine systems. In the case of ghrelin, data on whether GLP-1 inhibits feeding in humans is conflicting.
one would want to block the feeding effects at the GHS-R with- A recent meta-analysis shows that GLP-1 causes a small dose-
out significantly reducing circulating GH. Circulating ghrelin dependent inhibition of food intake in both lean and overweight
achieves its orexigenic action through stimulation of hypo- subjects (Verdich et al., 2001). Reduction in the rate of gastric
thalamic neurones (Nakazato et al., 2001), and inhibitory actions emptying may contribute to the increased satiety induced by
on the gastric vagal afferent nerve (Date et al., 2002). GLP-1.
The combination of enhanced insulin release with probable
reduction of food intake makes GLP-1 an attractive treatment for
Peptide YY
patients with type II diabetes. A 6-week trial of three subcutaneous
Peptide YY (PYY) is secreted from the endocrine L cells of the GLP-1 premeal injections per day improved glycaemic control by
small and large bowel, and released into the circulation after increasing insulin levels and inhibiting glucagon compared with
meals. PYY is a member of the neuropeptide Y (NPY) family placebo control with no adverse effects (Todd et al., 1997).
with a tyrosine residue at both ends. The main form of PYY in Exendin-4, the GLP-1 receptor agonist with a longer biological
both the gut mucosal endocrine cells and the circulation, is PYY action than GLP-1, is currently undergoing phase III clinical
3–36 (Grandt et al., 1994). Peripheral administration of PYY 3– trials (Egan et al., 2002). An alternative therapeutic strategy is
36 leads to a marked inhibition in food intake. In human volun- to target the enzymes such as dipeptidyl peptidase-4 (DPP4),
teers, an exogenous infusion accurately mimicking postprandial which catalyse the breakdown of GLP-1. After 4 weeks of three
PYY 3–36 concentrations reduced food intake by 30% when subcutaneous premeal injections of the DPP4 inhibitor NVP
compared with saline control in a double-blinded cross-over DPP728, there was an improvement in glycaemic control com-
study with no adverse effects (Batterham et al., 2002). PYY3- pared with placebo, but without the additional benefit of weight
36 has a high affinity for the Y2 receptor (Y2R), a member of loss (Ahren et al., 2002).
the NPY receptor family. The pattern of c-fos neuronal activation
following peripheral administration of PYY 3–36 suggests that
Cholecystokinin
its action is via the hypothalamus, where the Y2 is located.
In contrast with the negligible effect on appetite caused by the Cholecystokinin (CCK) was the first gut hormone shown to
normal daily fluctuations in circulating leptin (Sinha et al., inhibit feeding following exogenous administration in rodents
1996), PYY 3–36 inhibits food intake in rodents and man at phys- (Gibbs et al., 1973). CCKA receptors, present on the vagus nerve
iological concentrations. Thus PYY 3–36 is likely to be important and pyloric sphincter, are bound exclusively by the sulphated
in the everyday regulation of food intake. Further work is needed forms of CCK and are active in reducing food intake (Moran,
to determine whether PYY 3–36 is effective in obese people, and 2000). Other well-known functions of CCK include the stimu-
whether the Y2 receptor could be a future drug target. lation 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
Glucagon-like-peptide-1
feeding, exerting its maximum inhibition within 30 min post-
Glucagon-like-peptide 1 (GLP-1) is co-secreted with PYY in injection (Moran, 2000) which is consistent with a role in mediat-
response to nutrients in the gut. The precursor prepro-glucagon ing satiety and meal termination. High-dose CCK may also cause
is cleaved tissue-specifically – in the pancreas it forms glucagon nausea, vomiting and taste aversion, although lower doses have
whereas in the intestinal L cells it gives rise to GLP-1. Central been shown to inhibit feeding without inducing these effects
ICV injection of GLP-1 powerfully inhibits feeding in rodents (West et al., 1987). However, tolerance is exhibited with pro-
(Turton et al., 1996). longed CCK administration after 24 h (Crawley & Beinfeld,
GLP-1 plays an additional role in enhancing insulin secretion 1983). Although meal size was persistently reduced with the
and suppressing glucagon secretion after a meal, functioning as CCK infusion, there was compensatory increase in meal number.
an incretin (Kreymann et al., 1987). The plasma insulin response There is, however, evidence that CCK may play a role in longer-
to a given rise in plasma glucose is much greater after an oral term energy regulation by synergizing the actions of leptin.
glucose load than after an intravenous glucose infusion and Central leptin administration potentiates the feeding inhibition
this difference can be attributed to the rise in circulating GLP-1 of peripheral CCK and the CCK/leptin combination results in
and gastric inhibitory polypeptide (GIP) stimulated by the oral greater weight loss over 24 h than does leptin alone (Matson
glucose. et al., 1997). This synergy may occur by CCK activating brain
GLP-1 is the most powerful incretin known in man. Infusion stem neurones that project to the hypothalamus combined with
of GLP-1 to healthy volunteers increases plasma insulin levels leptin’s direct hypothalamic actions.

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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, Orexigenic hypothalamic neuropeptides
dorsomedial hypothalamus; LH, lateral hypothalamic area; OC, optic chiasm.
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
Central appetite regulation stimulates feeding in rodents. Chronic administration of NPY
into the hypothalamic PVN leads to sustained hyperphagia and
The hypothalamus
weight gain, and central injection of NPY antagonists or anti-
The hypothalamus can be subdivided into nuclei consisting of serum decreases food intake in the dark phase when rats normally
collections of neurones with discrete functions (Fig. 2). Neuronal eat readily (Kalra et al., 1999). There is a rapid increase in NPY
projections between these nuclei and to and from other areas in before mealtimes in the PVN, and levels remain elevated as long
the brain enable the hypothalamus to integrate signals from the as food is withheld, suggesting that NPY plays a role in the central
brain, the peripheral circulation and the gastrointestinal tract to control of meal initiation. NPY acts to stimulate feeding pre-
regulate energy intake and expenditure. dominantly through activation of Y1 and Y5 receptors. NPY also
The arcuate nucleus (ARC), termed infundibular nucleus in has multiple actions on the HPA, on seizure activity and on
man, is situated at the base of the hypothalamus. This is an elon- responses to stress and anxiety, which may limit its use as a drug
gated arc-shaped collection of neuronal cell bodies which express target for obesity.
receptors for many of the hormones and neuropeptides that are AgRP increases food intake through antagonism of the
known to regulate feeding. The arcuate nucleus is a privileged melanocortin MC3 and MC4 receptors and thus blockade of the
site which can sample the peripheral circulation through semi- inhibition of the anorexigenic agonist α-melanocyte-stimulating
permeable capillaries in the underlying median eminence, and is hormone (α-MSH; see below). In contrast to the potent but rel-
thus in an ideal position to integrate hormonal signals for energy atively short-lived effects of NPY, central administration of AgRP
homeostasis. The paraventricular nucleus (PVN) is adjacent to the to rodents leads to an increase in food intake for up to 1 week (Rossi
superior part of the third ventricle in the anterior hypothalamus. et al., 1998). Chronic administration of AgRP to rodents causes
The PVN is the main site of corticotrophin-releasing hormone sustained hyperphagia and leads to obesity (Small et al., 2001).
(CRH) and TRH secretion, in addition to being richly supplied AgRP is found exclusively in the arcuate nucleus, and virtually
with neuronal projections from the ARC. Thus the PVN plays a all AgRP neurones co-secrete NPY (Goldstone et al., 2002).
role in the integration of nutritional signals with the thyroid and NPY/AgRP neurones are inhibited by leptin and insulin, and
HPA axes. activated by ghrelin (Kalra et al., 1999; Nakazato et al., 2001).
The Y2R is a presynaptic inhibitory autoreceptor on NPY neu-
rones. Injection of PYY3-36, the gut-derived Y2R agonist,
The brain stem
directly into the ARC inhibits food intake. The appetite inhibitory
One of the satiety signals following a meal is from afferent fibres effects of PYY3-36 are absent in the Y2 knockout mouse
of the vagus nerve to the brain stem (Williams et al., 2001). The (Batterham et al., 2002). Therefore it appears that circulating
hypothalamus and brain stem are linked via projections from PYY3-36 inhibits appetite by acting directly on the arcuate

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Obesity and appetite regulation 157

nucleus to inhibit orexigenic NPY neurones. Thus low circulating density in the limbic system and Raphe nuclei as well as in the
leptin, insulin and PYY3-36, and elevated ghrelin levels such as hypothalamus (Blundell, 1984). In general, agonists at the 5-HT
in fasting or starvation lead to an increase in NPY and AgRP receptors and drugs that inhibit the re-uptake of serotonin reduce
neuronal activity and increased appetite, whereas the opposite in feeding. Additionally, 5-HT stimulates noradrenaline release and
seen postprandially (Fig. 1). 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
Anorectic hypothalamic neuropeptides hyperphagic and obese (Tecott et al., 1995). Additionally, this
knockout mouse has a low seizure threshold and exhibits severe
The melanocortins
and life-threatening epilepsy. However, 5-HT2C antagonists do
The melanocortins are derived from the precursor molecule pro- not cause hyperphagia or epilepsy. This apparent dichotomy
opiomelanocortin (POMC) via tissue-specific post-translational could be explained if the phenotype of the knockout mouse had
cleavage. In the anterior pituitary, POMC gives rise to ACTH, been altered through adaptation, and illustrates the potential
which acts via the MC2 receptor to stimulate adrenal steroido- limitations in the extrapolation of the function of a neuropeptide
genesis. The melanocortin α-MSH is derived from POMC in from its knockout model.
brain. The MC3 and MC4 receptors are biologically unique in
that there is an endogenous antagonist (AgRP) in addition to
Current treatments for obesity
endogenous agonists (the melanocortins).
Central ICV administration of α-MSH inhibits feeding and The first-line treatment for obesity is food restriction and exer-
reduces body weight. The stimulatory effect of AgRP is inhibited cise. However, most people find it difficult to lose weight despite
by α-MSH (Rossi et al., 1998). Thus α-MSH and AgRP neurones a wide choice of diets and exercise programmes, and even more
act as a dynamic system in vivo. difficult to maintain weight loss (Yanovski & Yanovski, 2002).
POMC is co-expressed in arcuate neurones with cocaine- and Current second-line treatments are the medications sibutramine
amphetamine-regulated transcript (CART), and these neurones and orlistat, and surgery.
are directly stimulated by leptin (Cowley et al., 2001). Peripheral
administration of PYY 3–36 increases POMC expression and
Pharmacological therapy
inhibits NPY expression (Batterham et al., 2002). These changes
in message levels may explain the long duration of action of PYY. Sibutramine, a serotonin and noradrenaline re-uptake inhibitor,
The MC4 receptor, in particular, is thought to be critical to is recommended by the National Institute of Clinical Excellence
body weight regulation. The MC4 knockout mouse is hyper- (NICE) for the treatment of obesity in patients with a BMI of
phagic and very obese, and insensitive to α-MSH (Huszar et al., over 30 kg/m2 or the presence of an obesity-related disease and
1997). Functional mutations of the MC4 receptor are also a a BMI of over 27 kg/m2 (NICE, 2001). The earlier drugs fenflu-
cause of monogenic human obesity and are much more common ramine and dex-fenfluramine, which acted through stimulation
than leptin deficiency, being found in up to 4% of adults with of 5-HT secretion as well as inhibition of 5-HT re-uptake, were
severe childhood-onset obesity (Farooqi et al., 2000). The minor- withdrawn following the discovery of an association with their
ity with homozygous mutations tend to be more severely obese. use and cardiac valve abnormalities (Connolly et al., 1997). In
For the majority of obese patients who have intact melanocortin a recent European trial (James et al., 2000), following a 6-month
receptors, agonists at these receptors and, in particular, the MC4 run-in period on sibutramine, patients who achieved a 5%
receptor could reduce appetite and food intake. The prolonged reduction in weight were randomized to either continue with
action of the endogenous antagonist AgRP suggests that sibutramine or receive placebo. At 18 months, 69% of patients on
manipulation of the melanocortin system could have long- sibutramine compared with 42% of controls retained this modest
lasting effects. Melanocortin receptor agonists are currently 5% reduction. Sibutramine may cause an increase in blood pres-
being developed as potential obesity treatments. Recently it sure and pulse (acting as a sympathomimetic) and is therefore
was demonstrated that intranasal administration of a fragment unsuitable for hypertensive patients. In normotensive patients,
of melanocortin (MSH/ACTH4−10), common to all melanocortins, treatment with sibutramine may achieve moderate weight loss for
leads to modest weight reduction in humans (Fehm et al., 2001). 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
Serotonin
or 1 h after meals excrete approximately one-third of their
Serotonin (5-HT) is a short-acting widespread neurotransmitter ingested dietary fat in their stools, thereby reducing calorie
which acts on a number of receptor subtypes found at high intake. Consequently, they may have flatulence and offensive

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158 N. M. Neary et al.

stools after a fatty meal. Trials show that orlistat can also achieve diet-induced weight loss. However, ghrelin levels were 77%
mild weight loss of 9% at 1 years compared with 5% of placebo lower in the gastric bypass group compared with matched BMI
and may slow the regain of weight for a second year of use controls, and the usual premeal peaks were lost (Cummings et al.,
(Yanovski & Yanovski, 2002). However, orlistat is only licensed 2002). Under normal circumstances the presence of nutrients in
for 2 years, and is less effective by the second year. 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
Surgery
stomach suppresses ghrelin secretion. Reduced circulating
Surgery is the only treatment which has been proven to achieve ghrelin with a possible elevation of circulating PYY 3–36 could
weight loss in the long term. The jejuno-intestinal bypass has account for the paradoxical decrease in hunger reported by most
been performed since the 1960s and leads to impressive weight patients, and explain the long-term weight loss usually seen
loss up to 15 years (Frandsen et al., 1998). However, its use has following gastric bypass surgery.
been limited by serious complications including liver failure,
severe electrolyte imbalance, renal calculi due to impaired
Conclusion
oxalate absorption, osteomalacia and bypass enteritis.
The Roux-en-Y gastric bypass has now been largely super- The current epidemic of obesity is threatening the health of
seded the jejuno-intestinal bypass. This technique involves cut- the western world. We have explored how appetite is regulated by
ting the jejunum, and joining the distal end to the body of the the circulating hormones leptin and insulin, and the gut hormones
stomach (the Roux-en-Y) and the proximal part to another part ghrelin and PYY 3–36, and signalled to the hypothalamus. Excit-
of jejunum distal to the Roux-en-Y. The stomach is stapled, ing potential pharmacological targets include the receptors of
leaving a 10–15 ml fundal pouch which drains directly into the orexigenic ghrelin and anorexigenic PYY 3–36. Further under-
jejunum. The advantages of the gastric bypass over the jejuno- standing is required to enable us to develop more effective
intestinal bypass are that there is no blind loop, the bile can drain treatments, not only to inhibit appetite in the obese but also to
through the duodenum and into the jejunum and there is less stimulate appetite in cachectic patients. While many of the sig-
severe malabsorption. In one series, mean weight loss at 15 years nals and circuits described in this article might be manipulated,
postgastric bypass surgery was 30 kg (Mitchell et al., 2001) com- the real challenge is to find treatments that modify appetite and
pared with 43 kg in another study following jejuno-intestinal lead to lasting weight reduction selectively without significantly
surgery (Frandsen et al. 1998) but with the benefit of fewer affecting other neuroendocrine systems.
complications. Nonetheless, the morbidity associated with gas-
tric bypass surgery, in addition to practical and financial con-
straints, usually limit this approach to severely obese patient Acknowledgements
(BMI > 40 kg/m2). MRC Programme Grant (Bloom SR, Ghatei MA and Small CJ)
Interestingly, the success of bypass surgery may be as much number G7811974. Nicola Neary is a Wellcome Trust Clinical
hormonal as mechanical. Fasted rats with jejuno-intestinal Research Training Fellow.
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 References
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