Appetite regulation: from the gut to the hypothalamus

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 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. Circulating gastrointestinal and adipocyte hormones and neuronal circuits involved in energy homeostasis. Solid lines represent net stimulatory effect, dashed lines represent net inhibitory effect. 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. 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). 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. 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 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 (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). PYY3-36 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 (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 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 dose-dependent 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 (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 longer-term 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. 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. 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. 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 signals for energy homeostasis. The paraventricular nucleus is to the of the third ventricle in the hypothalamus. The is the main site of hormone and in addition to being with neuronal projections from the Thus the plays a role in the of signals with the thyroid and of the satiety signals following a meal is from afferent of the vagus nerve to the brain stem et al., 2001). The hypothalamus and brain stem are via projections from neurones to the and lateral hypothalamus, such as GLP-1 and projections of neurones of the nuclei to the arcuate The role of the brain stem in appetite and feeding regulation has been in which between the brain stem and are & The were to for changes in the of individual to However, when with a reduction in meal number from three to per by increasing their food intake at each meal, but the to their meal Thus the brain stem plays a role in individual meal the hypothalamus is for long-term energy balance and appetite NPY is a amino acid neuropeptide which is one of the most orexigenic A ICV injection feeding in Chronic administration of NPY into the hypothalamic leads to sustained hyperphagia and weight and central injection of NPY or decreases food intake in the phase when et al., 1999). There is a rapid increase in NPY before in the PVN, and levels as as food is suggesting that NPY plays a role in the central control of meal initiation. NPY to stimulate feeding predominantly through activation of and receptors. NPY also has actions on the on and on responses to and which may its as a drug target for increases food intake through of the and receptors and thus of the inhibition of the anorexigenic agonist hormone In contrast to the but relatively short-lived effects of central administration of to rodents leads to an increase in food intake for to 1 et al., 1998). Chronic administration of to rodents causes sustained hyperphagia and leads to obesity et al., 2001). is found exclusively in the arcuate and neurones NPY et al., 2002). neurones are by leptin and and by ghrelin et al., et al., 2001). The is a inhibitory on NPY of the directly into the inhibits food intake. The appetite inhibitory effects of PYY3-36 are in the Y2 mouse (Batterham et al., 2002). it appears that circulating PYY3-36 inhibits appetite by directly on the arcuate nucleus to inhibit orexigenic NPY Thus low circulating leptin, insulin and and ghrelin levels such as in fasting or to an increase in NPY and neuronal and increased whereas the in seen (Fig. 1). The are from the precursor via In the gives rise to which via the receptor to stimulate The is from in The and receptors are in that there is an endogenous antagonist in addition to endogenous Central ICV administration of inhibits feeding and reduces body The stimulatory effect of is by et al., 1998). Thus and neurones act as a system in is in arcuate neurones with and and these neurones are directly stimulated by leptin et al., 2001). Peripheral administration of PYY 3–36 increases and inhibits NPY (Batterham et al., 2002). changes in levels may the of action of The in is thought to be to body weight The mouse is and very obese, and to et al., 1997). of the receptor are also a cause of human obesity and are much more common than leptin being found in to of adults with childhood-onset obesity (Farooqi et al., 2000). The with tend to be more the majority of obese patients who have receptors, at these receptors in the receptor could appetite and food intake. The prolonged action of the endogenous antagonist suggests that of the system could have receptor are currently being developed as obesity it was demonstrated that administration of a of common to leads to weight reduction in humans et al., 2001). is a which on a number of receptor found at high in the system and nuclei as well as in the hypothalamus In at the receptors and that inhibit the of feeding. 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However, ghrelin levels were lower in the gastric compared with and the usual premeal peaks were (Cummings et al., 2002). normal the of nutrients in the is to ghrelin secretion from the stomach. However, the of this study that prolonged of nutrients or of the ghrelin circulating ghrelin with a possible of circulating PYY 3–36 could for the decrease in hunger by most and the long-term weight loss usually seen following gastric The of obesity is the health of the world. We have how appetite is regulated by the circulating hormones leptin and and the gut hormones ghrelin and PYY and to the hypothalamus. include the receptors of orexigenic ghrelin and anorexigenic PYY Further is to enable us to more effective not only to inhibit appetite in the obese but also to stimulate appetite in many of the signals and circuits described in this might be the challenge is to find that appetite and to weight reduction without significantly affecting other systems. and number is a