NEUROPEPTIDE Y AND ITS ROLE IN CONGENITAL OBESITY

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When injected into the cerebral ventricular or paraventricular nucleus (PVN), Neuropeptide Y (NPY) is the most potent stimulant of food intake known. It also stimulates the release of corticotropin releasing hormone (CRH), ACTH and cortisol. This latter action is dose dependent and shared by the structurally related peptide, pancreatic polypeptide (PP). NPY nerves that influence the PVN arise from the Nucleus Tractus Solitarius in the dorsal vagal comples and the amygdala. Bilateral destruction of the amygdala results in anorexia and weight loss in experimental animals. We propose 1) to compare NPY contents and NPY mRNA levels in that amygdala and PVN of obese and lean rats, 2) examine NPY binding in the hippocampus and PVN of obese and lean rats and mice, 3) examine structure-function requirements fro binding to these regions of the brain, 4) crosslink and characterize these receptor populations in obese and lean animals, 5) contrast NPY's ability to stimulate the release of CRH in obese and lean animals. These studies will be performed in male and female rats. Adrenalectomy abolishes the ability of NPY to stimulate food intake suggesting a relationship between the NPY's ability to stimulate food intake and the HPA axis. Congenital obese rodents, particularly males, exhiit a hyperactive hypothalamic- pituitary-adrenal axis (HPA) and adrenalectomy reverse the obesity in congenitally obese rodents. We will determine the effects of adrenalectomy and steroid supplementation on NPY contents in the amygdala and PVN and NPY binding to the hippocampus and PVN in Sprague Dawley rats. Similar studies will be repeated in obese rats. In prior studies we have established that ob/ob mice fail to release PP in response to a meal, a characteristic thay share with Prader-Willi children. Treatment with bovine PP is the only other treatment, other than adrenalectomy, that reverse the obesity and diabetes seen in these animals . Using autoradiography will have identified novel PP receptor populations in the brain (NTS) and adrenal that may mediate these beneficial effects. We will contrast bbinding of PP to the NTS in bese and lean rats and mice. We will also characterize the PP receptor population in the Zona Fasiculata and determine if PP inhibits corticosterone release. NPY and PP are structurally related peptides that are capable of modifying feeding behaviors and/or the HPA axis. These studies will clarify how these structurally related brain-gut peptides interact to control body weight.