THE PANCREATIC POLYPEPTIDE FAMILY IN OBESITY

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Pancreatic Polypeptide, Neuropeptide Y and Peptide YY are the third family of structurally related peptides to be extracted from the brain-gut axis. The objectives of the present proposal are to clarify the mechanisms by which these peptides control nutrient intake and utilization and to determine their role in the pathogenesis of obesity. We will examine the effects of isologous pancreatic polypeptide upon glucose metabolism using the glucose clamp technique and upon lipolysis using isolated rat adipocytes. Other studies will determine the effects of intracisternal injections of Neuropeptide Y on food intake, gastric emptying, thermoregulation, insulin secretion and splanchnic blood flow using the labelled microsphere technique. We will also determine if Peptide YY released by fat bathing the ileal mucosa engages the ileal-brake which increases absorption of nutrients by slowing intestinal transit. In these studies we will examine the effects of Peptide YY on gastric emptying, intestinal transit and jejunal fluxes of water, electrolytes and nutrients. Preliminary studies demonstrate that pancreatic amylase and DNA contents are reduced by chronic treatment with peptide YY. Full dose-response studies will be performed and the effects of this peptide on intestinal growth determined. Following these experiments in rat, we will investigate the cause and significance of the defect in pancreatic polypeptide release recently decribed in congenitally obese mice. We will examine the ultrastructural relationships between the pancreated polypeptide cell and other endocrine cells within the hypertrophic islet of the obese mouse and determine the effects of insulin hypoglycemia and adrenalectomy on pancreated polypeptide release in this animal model. Other studies will determine whether pancreatic polypeptide reverses congenital obesity by inducing malabsorption through inhibition of bile and pancreatic flow. Finally we will expand our investigations on the abnormal brain content of the neuropeptide observed in obese mice. In particular we will compare the distribution of neuropeptide Y in obese and lean mice emphasizing the regional distribution of neuropeptide Y in brain. These studies will determine the mechanisms by which this family controls nutrient intake and utilization and could provide the experimental basis for the future use of pancreatic polypeptide in the treatment of obesity.