The sequence of glucagon-like peptide-1 (7-36) amide (GLP-1) is completely conserved in all mammalian species studied, implying that it plays a critical physiological role. We have shown that GLP-1 and its specific receptors are present in the hypothalamus. No physiological role for central GLP-1 has been established. We report here that intracerebroventricular (ICV) GLP-1 powerfully inhibits feeding in fasted rats. ICV injection of the specific GLP-1-receptor antagonist, exendin (9-39), blocked the inhibitory effect of GLP-1 on food intake. Exendin (9-39) alone had no influence on fast-induced feeding but more than doubled food intake in satiated rats, and augmented the feeding response to the appetite stimulant, neuropeptide Y. Induction of c-fos is a marker of neuronal activation. Following ICV GLP-1 injection, c-fos appeared exclusively in the paraventricular nucleus of the hypothalamus and central nucleus of the amygdala, and this was inhibited by prior administration of exendin (9-39). Both of these regions of the brain are of primary importance in the regulation of feeding. These findings suggest that central GLP-1 is a new physiological mediator of satiety.

Melanin-concentrating hormone (MCH) has recently been proposed as both a central stimulator and an inhibitor of food intake. To clarify its role, we investigated the effects of MCH and the prepro-MCH-derived peptide neuropeptide E-I injected intracerebroventricularly (icv) in rats. MCH (0.15-15 micrograms) was injected icv at the beginning of the light phase. Food intake at 2 h showed a dose-dependent increase from 325 +/- 7% of the control value (1.5-microgram dose; P < 0.05) to 462 +/- 30% of the control value (15-microgram dose; P < 0.005). When 10 ng, 100 ng, and 5 micrograms MCH were injected icv at the beginning of the dark phase, only 5 micrograms stimulated feeding (166 +/- 16% of the control value; P < 0.05). At no dose did MCH inhibit feeding. Twice daily icv injections of MCH (5 micrograms) caused an average 197 +/- 9% increase in 2-h food intake for the first 5 days. Injections from days 6-8 did not stimulate feeding. Food intake and body weight at 24 h remained unchanged. Intracerebroventricular neuropeptide E-I had no effect on food intake alone and did not alter MCH-induced feeding. These studies show a dose-dependent stimulation of feeding by acute central administration of MCH. Tolerance is seen with chronic administration. These findings support a role for MCH in the immediate regulation of food intake, but not in body weight control.

No abstract