Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY(3-36) (PYY(3-36)), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain. PYY(3-36) also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY(3-36) inhibits food intake. PYY(3-36) also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY(3-36) may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.

Ghrelin is a recently identified endogenous ligand for the growth hormone secretagogue receptor. It is synthesized predominantly in the stomach and found in the circulation of healthy humans. Ghrelin has been shown to promote increased food intake, weight gain and adiposity in rodents. The effect of ghrelin on appetite and food intake in man has not been determined. We investigated the effects of intravenous ghrelin (5.0 pmol/kg/min) or saline infusion on appetite and food intake in a randomised double-blind cross-over study in nine healthy volunteers. There was a clear-cut increase in energy consumed by every individual from a free-choice buffet (mean increase 28 ± 3.9%, p<0.001) during ghrelin compared with saline infusion. Visual analogue scores for appetite were greater during ghrelin compared to saline infusion. Ghrelin had no effect on gastric emptying as assessed by the paracetamol absorption test. Ghrelin is the first circulating hormone demonstrated to stimulate food intake in man. Endogenous ghrelin is a potentially important new regulator of the complex systems controlling food intake and body weight. _____________________________________________________________________________________________________

Ghrelin is a recently identified endogenous ligand for the growth hormone secretagogue receptor. It is synthesized predominantly in the stomach and found in the circulation of healthy humans. Ghrelin has been shown to promote increased food intake, weight gain and adiposity in rodents. The effect of ghrelin on appetite and food intake in man has not been determined. We investigated the effects of intravenous ghrelin (5.0 pmol/kg/min) or saline infusion on appetite and food intake in a randomised double-blind cross-over study in nine healthy volunteers. There was a clear-cut increase in energy consumed by every individual from a free-choice buffet (mean increase 28 +/- 3.9%, p<0.001) during ghrelin compared with saline infusion. Visual analogue scores for appetite were greater during ghrelin compared to saline infusion. Ghrelin had no effect on gastric emptying as assessed by the paracetamol absorption test. Ghrelin is the first circulating hormone demonstrated to stimulate food intake in man. Endogenous ghrelin is a potentially important new regulator of the complex systems controlling food intake and body weight.

Ghrelin, a circulating growth hormone-releasing peptide derived from the stomach, stimulates food intake. The lowest systemically effective orexigenic dose of ghrelin was investigated and the resulting plasma ghrelin concentration was compared with that during fasting. The lowest dose of ghrelin that produced a significant stimulation of feeding after intraperitoneal injection was 1 nmol. The plasma ghrelin concentration after intraperitoneal injection of 1 nmol of ghrelin (2.83 ؎ 0.13 pmol/ml at 60 min postinjection) was not significantly different from that occurring after a 24-h fast (2.79 ؎ 0.32 pmol/ml). After microinjection into defined hypothalamic sites, ghrelin (30 pmol) stimulated food intake most markedly in the arcuate nucleus (Arc) (0 -1 h food intake, 427 ؎ 43% of control; P < 0.001 vs. control, P < 0.01 vs. all other nuclei), which is potentially accessible to the circulation. After chronic systemic or intracerebroventricular (ICV) administration of ghrelin for 7 days, cumulative food intake was increased (intraperitoneal ghrelin 13.6 ؎ 3.4 g greater than saline-treated, P < 0.01; ICV ghrelin 19.6 ؎ 5.5 g greater than saline-treated, P < 0.05). This was associated with excess weight gain (intraperitoneal ghrelin 21.7 ؎ 1.4 g vs. saline 10.6 ؎ 1.9 g, P < 0.001; ICV ghrelin 15.3 ؎ 4.3 g vs. saline 2.2 ؎ 3.8 g, P < 0.05) and adiposity. These data provide evidence that ghrelin is important in long-term control of food intake and body weight and that circulating ghrelin at fasting concentrations may stimulate food intake.

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after i.c.v. administration was sustained for 24 hours. Following i.c.v. administration of 3 nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5 nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following i.c.v. administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.

Ghrelin, a novel 28 amino acid peptide found in hypothalamus and stomach, was recently identified as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). We have now found that both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of ghrelin in freely feeding rats stimulated food intake. The onset of increased feeding was rapid and after i.c.v. administration was sustained for 24 hours. Following i.c.v. administration of 3 nmol ghrelin, the duration and magnitude of the feeding stimulation was similar to that following 5 nmol neuropeptide Y (NPY). Plasma growth hormone (GH) concentration increased following both i.c.v. and i.p. administration of ghrelin. Release of adrenocorticotrophic hormone (ACTH) was stimulated and thyroid stimulating hormone (TSH) inhibited following i.c.v. administration of ghrelin. These data suggest a possible role for the newly identified endogenous hypothalamic peptide, ghrelin, in stimulation of feeding and growth hormone secretion.

There is a pressing need for more effective appetite-stimulatory therapies for many patient groups including those with cancer. We have previously demonstrated that the gastric hormone ghrelin potently enhances appetite in healthy volunteers. Here, we performed an acute, randomized, placebo-controlled, cross-over clinical trial to determine whether ghrelin stimulates appetite in cancer patients with anorexia. Seven cancer patients who reported loss of appetite were recruited from oncology clinics at Charing Cross Hospital. The main outcome measures were energy intake from a buffet meal during ghrelin or saline infusion and meal appreciation as assessed by visual analog scale. A marked increase in energy intake (31 +/- 7%; P = 0.005) was observed with ghrelin infusion compared with saline control, and every patient ate more. The meal appreciation score was greater by 28 +/- 8% (P = 0.02) with ghrelin treatment. No side effects were observed. The stimulatory effects of ghrelin on food intake and meal appreciation seen in this preliminary study suggest that ghrelin could be an effective treatment for cancer anorexia and possibly for appetite loss in other patient groups.

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