More than 64% of US adults are overweight or obese, with nearly 31% (over 61 million) meeting criteria for obesity. There is a clear link between obesity and the development of diabetes, heart disease, many cancers, and depression. Defining the physiological mechanisms that control food intake thus provides direction in the search for pathogenic mechanisms of obesity and strategies for prevention and treatment of obesity-related diseases. Peptide YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP) comprise a family of structurally related brain-gut peptides with diverse actions mediated by four known receptors (Y1, Y2, Y4, Y5). Endocrine cells of the distal gut provide a major source of PYY. Food intake releases at least two forms of PYY into the circulation: PYY(1-36) and PYY(3-36); other predicted/detected isoforms include PYY(1-36)-Gly, PYY(3-36)-Gly, [Ser13PO3]PYY(1-36), and [Ser13P03]PYY(3-36). Systemic administration of PYY(3-36) potently inhibits food intake in rodents and humans; PYY(1-36) is 10-fold less potent in rats. Obese humans appear to have a blunted plasma PYY response to food intake; yet, low doses of PYY(3-36) decrease food intake similarly in lean and obese humans. Together, these results suggest that PYY(3-36) may act physiologically to reduce food intake and body adiposity, and that insufficient production of PYY(3-36) may promote obesity. Studies will test the hypothesis that PYY(3-36) secreted by the gut in response to a meal acts as a hormonal signal to the brain to produce satiety and regulate energy reserves. Rats with indwelling jugular vein, abdominal aortic, and/or gastric cannulae will be used to address the following specific aims: 1) Determine whether PYY(3-36), when infused iv, is the most potent and efficacious PYY isoform for reducing food intake. 2) Use selective Y-receptor agonists and antagonists to identify the Y-receptor subtype(s) that mediate anorexic responses to exogenous PYY isoform(s). 3) Determine whether anorexigenic PYY isoform(s) act synergistically with other putative satiety and body energy regulatory signals (CCK, amylin, GLP-1, leptin) to reduce food intake. 4) Determine whether body adiposity is reduced by daily, intermittent iv infusions of anorexigenic PYY isoform(s) when given alone and in combination with other PYY isoform(s), satiety peptides, and leptin. 5) Use novel proteomic methods to determine whether postprandial increases in plasma levels of PYY isoform(s), when reproduced by iv infusion, are sufficient to reduce food intake and body adiposity. 6) Determine whether circulating PYY isoform(s) act as essential blood-borne signals to the brain to reduce food intake, by investigating whether immuneutralization of circulating PYY increases food intake. 7) Use antagonists of PYY action (receptor antagonists and PYY antibodies) and abdominal vagal denervation to determine whether anorexigenic PYY isoform(s) act through control of vagal signaling to the brain to reduce food intake. ? ?
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