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.

Oxyntomodulin is derived from proglucagon processing in the intestine and the central nervous system. To date, no role in the central nervous system has been demonstrated. We report here that oxyntomodulin inhibits refeeding when injected intracerebroventricularly and into the hypothalamic paraventricular nucleus of 24-h fasted rats [intracerebroventricularly and into the paraventricular nucleus, 1 h, oxyntomodulin (1 nmol), 3.1 ؎ 0.5 g; saline, 6.2 ؎ 0.4 g; P < 0.005]. In addition, oxyntomodulin inhibits food intake in nonfasted rats injected at the onset of the dark phase (intracerebroventricularly, 1 h: oxyntomodulin, 3 nmol, 1.1 ؎ 0.19 g vs. saline, 2.3 ؎ 0.2 g; P < 0.05). This effect of oxyntomodulin on feeding is of a similar time course and magnitude as that of an equimolar dose of glucagon-like peptide-1. Other proglucagonderived products investigated [glucagon, glicentin (intracerebroventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol), and spacer peptide-1 (intracerebroventricularly and into the paraventricular nucleus, 3 nmol)] had no effect on feeding at any time point examined. The anorectic effect of oxyntomodulin (intracerebroventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol) was blocked when it was coadministered with the glucagon-like peptide-1 receptor antagonist, exendin-(9 -39) (intracerebroventricularly, 100 nmol; into the paraventricular nucleus, 10 nmol). However, oxyntomodulin has a lower affinity for the glucagon-like peptide-1 receptor compared with glucagon-like peptide-1 (IC 50 : oxyntomodulin, 8.2 nM; glucagon-like peptide-1, 0.16 nM). One explanation for this is that there might be an oxyntomodulin receptor to which exendin-(9 -39) can also bind and act as an antagonist. (Endocrinology 142: 4244 -4250, 2001)

The adipose tissue hormone, leptin, and the neuropeptide glucagon-like peptide-1 (7-36) amide (GLP-1) both reduce food intake and body weight in rodents. Using dual in situ hybridization, long isoform leptin receptor (OB-Rb) was localized to GLP-1 neurons originating in the nucleus of the solitary tract. ICV injection of the specific GLP-1 receptor antagonist, exendin(9-39), at the onset of dark phase, did not affect feeding in saline pre-treated controls, but blocked the reduction in food intake and body weight of leptin pro-treated rats. These findings suggest that GLP-1 neurons are a potential target for leptin in its control of feeding.

There are now six recognized neuropeptide Y (NPY) receptor subtypes (Y1-Y4 and two recently cloned distinct receptors labeled Y5), of which Y1 and one of the Y5's have been suggested could mediate the effect of NPY on feeding. The fragments NPY(2-36) and NPY(3-36), which bind Y1 only poorly, were injected intracerebroventricularly (icv) and found to have similar dose-response relationships to NPY in the stimulation of feeding. However NPY (13-36), which stimulates both Y2 and Y5, caused no increase in food intake, even at high doses. Maximal stimulation with the classical Y1 agonist [Pro34]-NPY produced only 50% of the maximum effect of NPY itself despite fully inhibiting adenylyl cyclase activity in vitro in a Y1 system. The novel fragment [Pro34]-NPY(3-36) is as effective at stimulating food intake as the classical Y1 analogue [Pro34]-NPY but bound to the Y1 receptor with only 1/20th of the affinity of NPY and failed to inhibit adenylyl cyclase through this receptor. [Pro34]-NPY(3-36) is therefore a relatively appetite-selective ligand. Coadministration of high dose NPY(13-36) and [Pro34]NPY did not enhance feeding compared with [Pro34]-NPY alone. In addition, the NPY Y1 receptor antagonist BIBP-3226, which does not bind Y2, Y4, or Y5 receptors, significantly reduced NPY induced feeding. These results indicate that the feeding effect of icv NPY involves a novel receptor and that it is functionally distinct from the recognized receptor subtypes.

Hypothalamic neuropeptide Y (NPY) is thought to be important in the regulation of feeding and also in the release of Adrenocorticotrophic hormone (ACTH). Intracerebroventricular administration of NPY to male rats significantly increased plasma ACTH 10 min after injection and stimulated 2-h food intake. Neuropeptide Y (NPY) is a 36-amino acid peptide of the pancreatic polypeptide family, with homology to pancreatic polypeptide (PP, Ϸ50%) and peptide YY (PYY, Ϸ70%) (1). NPY is one of the most abundant neuropeptides in the central and peripheral nervous system of many mammals, including humans (2). NPY immunoreactivity is present throughout the brain, particularly in the hypothalamus (2). Within the hypothalamus NPY is implicated in the activation of the hypothalamic pituitary adrenal (HPA) axis (3), the regulation of growth, and sexual function (4), and is the most potent stimulant of feeding yet reported (5, 6).Several NPY receptor subtypes have been identified and characterized by their ability to bind NPY, PYY, and PP fragments and analogues. The NPY Y1 receptor binds with high affinity full-length NPY or analogues, such as [Pro 34 ]NPY or [Leu 31 Pro 34 ]NPY (7). The Y1 receptor has a reduced affinity for C-terminal fragments such as NPY(2-36), NPY(3-36), and NPY(13-36) (8). This receptor has been cloned from the human (9) and rat (10) central nervous system and is expressed in the human neuroblastoma cell line, SK-N-MC (9). The Y2 receptor has a high affinity for C-terminal fragments such as NPY(13-36) and NPY(3-36) (8) but a low affinity for [Pro 34 ]NPY, and has been cloned from human hippocampus (11) and from the human neuroblastoma cell line, SMS-KAN (12). Human neuroblastoma cell lines are considered the de facto standards for the characterization of ligands for Y1 and Y2 receptors. PYY binds with high affinity to both the Y1 and Y2 receptor subtypes, whereas human and rat PP bind with very low affinities (9,11,13). A group of receptors with disparate pharmacological profiles have been labeled Y3 and are characterized by a low affinity for PYY in comparison to NPY (14-16). Hypotension, bradycardia, and inhibition of glutamate effects in response to unilateral injection of NPY into the nucleus tractus solitarius of the rat are associated with Y3 receptor activation in the central nervous system (17, 18). The Y4 receptor is characterized by a very high affinity for PP compared with NPY and NPY(13-36) (13, 19). The Y4 receptor has been cloned and its mRNA is expressed in the human brain, coronary artery, and ileum (19). An NPY receptor designated Y6 has been cloned from mouse (20), human, chimpanzee, gorilla, and rabbit (21) but is inactivated in primates by a frame-shift mutation. The Y6 receptor has a high affinity for NPY and PYY and a low affinity for human PP (20,21).NPY has been proposed to activate a hypothalamic ''feeding'' receptor (Y FEEDING ) distinct from previously cloned NPY receptors (22,23). This receptor was initially suggested to be Y1-like because [Pro 34 ]NPY mediates a pot...