The increase in hunger before a meal and the reduction following it cannot be explained by the small changes in plasma leptin. Similarly, the acute postprandial rise in insulin does not appear to reduce appetite directly (Chapman et al. 1998). There is evidence that the hypothalamus may sense nutrients and adjust food intake accordingly (Levin et al. 1999; Obici et al. 2002), but mimicking the postprandial rise in circulating nutrients by exogenous infusion has little effect on appetite (Opara et al. 1996; Stratton & Elia, 1999).
Postprandial satiety might be explained by a gut sensor system, signalling from the gut to the appetite centres in the brain. Both neural and endocrine afferent signalling appear to be involved. The presence of food in the stomach stimulates both mechanical and chemical receptors to transmit signals to the brainstem via vagal afferent fibres (Fraser et al. 1995; Willing & Berthoud, 1997; Mathis et al. 1998). Gastric loading volume-dependently decreases short-term food intake, independent of nutrient content. This suggests that stomach distension is more important than content in the neural suppression of food intake (Phillips & Powley, 1996). Nutrient content plays a larger role in the small intestine, stimulating vagal pathways that may contribute to satiety (Schwartz, 2000).
Cholecystokinin The role of cholecystokinin (CCK) in pancreatic secretion and gallbladder contraction was already well established when it was demonstrated that CCK also reduced meal size in a dose-dependent manner in rats (Gibbs et al. 1973). CCK was the first gut hormone implicated in the control of appetite. The anorectic effects of CCK have since been confirmed in rodent and human studies (Kissileff et al. 1981; Muurahainenn et al. 1988; Moran & Schwartz, 1994). The presence of digestive products in the intestinal lumen stimulates the release of CCK from the proximal small intestine. The anorectic effects of CCK appear to be mediated by the CCKA receptor via the vagal nerve, and are abolished by vagotomy (Smith et al. 1981). Preprandial administration of CCKA antagonists increases meal size in humans and other species (Hewson et al. 1988; Reidelberger & O'Rourke, 1989; Beglinger et al. 2001). Otsuka Long Evans Tokushima Fatty rats, which lack CCKA receptors, are obese and fail to reduce their appetite in response to CCK (Moran, 2000).
However, though the CCKA receptor knockout mouse is also insensitive to the anorectic action of CCK, it has normal food intake and body weight. In addition, tolerance rapidly develops to continuously infused CCK (Crawley & Beinfeld, 1983). Though administering CCK intermittently to rats preserves its anorectic effect, there is little change in daily food intake or body weight because of compensatory eating between injections (West et al. 1984). Therefore, despite its anorectic pedigree, CCK may prove difficult to exploit in the design of antiobesity agents.
Ghrelin Ghrelin is the only peripherally active appetite-stimulating hormone so far discovered. Ghrelin potently stimulates food intake and growth hormone secretion following peripheral administration in man and rats (Tschop et al. 2000; Wren et al. 2000, 2001a). Plasma ghrelin levels are inversely correlated with body weight and rise following weight loss in humans (Cummings et al. 2002). The major source of circulating ghrelin is the stomach, though ghrelin mRNA and immunoreactivity are also found in other regions of the gastrointestinal tract (Date et al. 2000). Ghrelin is composed of 28 amino acids with an acyl sidechain attached to the serine residue at position 3. This acyl group is crucial to ghrelin's orexigenic and growth hormone-releasing actions, which are mediated through the growth hormone secretagogue receptor (GHS-R; Kojima et al. 1999). The GHS-R is highly expressed in the hypothalamus, including the ARC, but also found in the brainstem, pituitary, gastrointestinal tract, adipose tissue and other peripheral tissues (Petersenn, 2002). It has been suggested that des-acylated ghrelin has other biological functions mediated by separate GHS-R subtypes (Baldanzi et al. 2002).
Circulating ghrelin concentrations rise during fasting and fall rapidly after a meal. Ghrelin may therefore be involved in meal initiation (Cummings et al. 2001), though recent work has shown that circulating ghrelin levels do not predict intermeal interval in humans (Callahan et al. 2004). Though calorie intake appears to be the primary regulator of plasma ghrelin levels (Tschop et al. 2000), the exact mechanisms mediating ghrelin release are unknown. There is some suggestion that glucose and/or insulin suppress ghrelin release (Yoshihara et al. 2002), though another study has shown that physiological levels of either appear to have little effect on plasma ghrelin concentrations (Schaller et al. 2003). Circulating ghrelin levels are lower in obese individuals, perhaps reflecting a feedback mechanism to reduce appetite (Tschop et al. 2001).
The orexigenic effects of peripheral ghrelin are mediated via the CNS. Peripheral administration of ghrelin activates neurones in the ARC and the PVN (Ruter et al. 2003) and i.c.v. administration of ghrelin increases appetite (Wren et al. 2000). Infusing anti-ghrelin antibodies into the rat brain inhibits fasting-induced feeding. The orexigenic effects of ghrelin may be mediated via NPY and AgRP. Central injection of ghrelin activates NPY/AgRP neurones and increases hypothalamic NPY mRNA expression. NPY and AgRP antagonists and antibodies block ghrelin-induced increases in feeding (Nakazato et al. 2001). In addition, in NPY and AgRP double knockout mice, the orexigenic action of ghrelin is abolished (Chen et al. 2004). Recently, ghrelin has been found to be expressed in a previously uncharacterized neuronal population adjacent to the third ventricle (Cowley et al. 2003). These hypothalamic ghrelin neurones may be involved in another hypothalamic appetite circuit, though the relationship between central and peripheral ghrelin signalling is currently unknown. It is interesting to note that the patterns of neuronal activation following peripheral and central ghrelin administration differ (Lawrence et al. 2002; Ruter et al. 2003).
Chronic peripheral ghrelin administration causes hyperphagia and obesity in rats (Tschop et al. 2000; Wren et al. 2001b). The ghrelin system therefore offers a potential target for long-term antiobesity therapy. Though there is little change in body weight or food intake in ghrelin or GHS-R knockout animal models, this may be due to compensatory developmental changes in other appetite regulatory systems (Sun et al. 2003, 2004). Further work is required to investigate whether ghrelin antagonists might be viable antiobesity drugs.
Pancreatic polypeptide and peptide YY Pancreatic polypeptide (PP) and peptide YY (PYY) are anorectic gut hormones belonging to the PP fold peptide family, of which NPY is also a member. All three peptides are 36 amino acids long, with primary structures incorporating a number of tyrosine residues. The PP fold is a tertiary structural motif common to all members and important in the binding and activation of the six G protein-coupled receptor subtypes – Y1, Y2, Y3, Y4, Y5 and Y6 –that mediate the overlapping physiological actions of the family (Keire et al. 2000).
PP binds with greatest affinity to Y4 and Y5 receptors. It is found predominantly in the endocrine pancreas, and its release is stimulated by food intake. Postprandial plasma levels are proportional to caloric intake, though other factors, including gastric distension, vagal tone, blood glucose levels and other gastrointestinal hormones, also influence its release. PP inhibits pancreatic exocrine secretion and gallbladder contraction and modulates gastric acid secretion and gastrointestinal motility.
Peripheral administration of PP suppresses food intake and gastric emptying in rodents (Asakawa et al. 2003). In contrast, central administration of PP increases food intake and gastric emptying. It has been suggested that the effect of PP on food intake may therefore be secondary to the effects on gastric emptying (Katsuura et al. 2002). However, intravenous infusion of PP has also been shown to reduce food intake in humans without affecting gastric emptying (Batterham et al. 2003b). The inimical effects of central and peripheral PP may represent the activation of different receptor subtypes. Peripheral PP administration activates neurones in the area postrema, an area where the Y4 receptor is highly expressed (Whitcomb et al. 1997). Central PP may mediate its orexigenic effects through the Y5 receptor, as Y5 knockout mice show a reduced PP-induced increase in food intake (Kanatani et al. 2000). However, Y5 receptor antisense oligonucleotides do not affect this response, suggesting that another receptor may be involved (Flynn et al. 1999).
Peripheral PP increases hypothalamic NPY expression and also increases oxygen consumption and stimulates the sympathetic nervous system, suggesting that it may increase energy expenditure (Asakawa et al. 2003). Chronic administration of PP to ob/ob mice lowers body weight gain, and transgenic mice over-expressing peripheral PP have lower food intake and body weight than controls (Ueno et al. 1999). PP may therefore represent a potential long-term obesity therapy.
PYY is produced by gut endocrine cells and is released into the circulation postprandially (Adrian et al. 1985). Peripheral administration of full-length PYY increases fluid and electrolyte absorption from the ileum and inhibits gut motility, meal-induced pancreatic and gastric secretion and gallbladder and gastric emptying. It also acts as a vasoconstrictor. These effects are thought to be mediated both directly in the periphery and centrally via the area postrema and the nucleus of the solitary tract.
Full-length PYY binds with high affinity to all Y receptors. However, the majority of PYY found stored in cells and present in the circulation is in the form PYY3-36, a truncated 34 amino acid peptide generated by the cleavage of two amino acids from the N terminus. PYY3-36 has high affinity for the Y2, and a lesser affinity for Y1 and Y5 receptors. Peripheral administration of PYY3-36 at doses mimicking postprandial levels activates neurones in the ARC and markedly inhibits food intake in rodents and man. Direct intra-ARC injection also reduces food intake in rats. Food intake and body weight are reduced in rodents chronically treated with peripheral PYY3-36 (Batterham et al. 2002).
However, i.c.v. injection of either PYY or PYY3-36 increases food intake in rats. The actions of peripheral PYY3-36 on satiety appear to be mediated by a direct action on the arcuate Y2 receptor, a presynaptic inhibitory receptor of NPY neurones. This inhibition reduces ARC NPY expression and release, and also results in increased POMC neurone activity. The anorectic effect of peripheral PYY3-36 is abolished in Y2 knockout mice and reduced by a selective Y2 agonist. Though PYY does not have a high affinity for the Y1 and Y5 receptors, they may mediate its central orexigenic action, since PYY3-36-stimulated food intake is reduced in Y1 knockout mice and Y5 knockout mice (Kanatani et al. 2000).
Glucagon-like peptide 1 and oxyntomodulin Glucagon-like peptide-1(7–36) amide (GLP-1) and oxyntomodulin (Oxm) are produced by posttranslational processing of the preproglucagon gene in the CNS and the intestine and colon. Both peptides are released into the circulation in response to nutrient intake and appear to function as satiety signals.
Physiological actions of GLP-1 include stimulation of insulin release, suppression of gastric acid secretion and slowing of gastric emptying. GLP-1 receptors are found in the brainstem, ARC and PVN, in addition to various peripheral tissues. Central administration of GLP-1 to rats inhibits food intake and activates ARC and PVN neurones (Turton et al. 1996). Peripheral administration to rats and humans also inhibits food intake, and activates neurones in the brainstem of rats (Verdich et al. 2001a; Yamamoto et al. 2003).
Like GLP-1, Oxm also inhibits gastric acid secretion and reduces food intake when administered centrally or peripherally (Dakin et al. 2002, 2004). As with GLP-1, these anorectic effects can be blocked by the GLP-1 receptor antagonist, exendin(9–39) (Tang-Christensen et al. 2001), suggesting that Oxm also signals via the GLP-1 receptor. However, Oxm and GLP-1 are equally efficacious at reducing food intake, yet the affinity of Oxm for the GLP-1 receptor is much lower than that of GLP-1 (Fehmann et al. 1994). It is possible that another as yet unknown Oxm receptor exists. Such a receptor must have similarities to the GLP-1 receptor, since it is antagonized by exendin(9–39). Peripheral administration of Oxm activates neurones in the ARC, and intra-ARC administration of exendin(9–39) blocks the anorectic actions of peripheral Oxm but not GLP-1, suggesting that Oxm and GLP-1 may reduce food intake by different pathways (Dakin et al. 2004). Peripheral Oxm may reduce food intake via the ARC, while GLP-1 may act on appetite through the area postrema in the brainstem (Yamamoto et al. 2003).
Chronic central administration of GLP-1 and central or peripheral administration of Oxm cause a reduction in weight gain (Meeran et al. 1999; Dakin et al. 2002, 2004). A reduction in food intake appears to be responsible in GLP-1-treated animals; however, Oxm-treated animals lost more weight than pair-fed controls, suggesting that Oxm may also increase energy expenditure.
While intravenous infusion of GLP-1 in man has a significant effect on appetite at physiological concentrations, only pathophysiological levels of circulating Oxm have been demonstrated to reduce calorie intake (Verdich et al. 2001a; Cohen et al. 2003). Further work is required to elucidate the physiological significance of Oxm in human appetite. Interestingly, Oxm infusion reduces plasma ghrelin levels in humans, which might be responsible for the observed reduction in appetite (Cohen et al. 2003).