PEPTIDE YY--COLONIC GASTRIC AND PANCREATIC INHIBITION

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Peptide YY (PYY) is released from endocrine cells in the distal gut to exert effects on upper gut function i.e., to inhibit pancreatic and exocrine secretion. Evidence exists to show that PYY may be both the "enterogastrone" and "anti-CCK' hormone described by others. PPY may also mediate the "ileal brake" phenomenon whereby gut motility is slowed in the face of malabsorption. In the present study we will extend these observations by 1) contrasting the ability of different intraluminal nutrients to inhibit acid secretion with their ability to release PYY and 2) delineating the relative importance of the large and small intestine in these phenomena. Other studies will determine if there is a role for PYY in feedback control of the pancreas. These observations in the whole animal will be extended by delineating at the cellular level, the mechanisms of PYY's release and action. We will study the role of adrenergic agonists and antagonists and peptide hormones in the release of PYY using an isolated cultured PYY cell preparation we developed. The second messenger that mediates these effects will also be delineated. In other experiments we will contrast the binding and structural characteristics of the intestinal PYY receptor with the generic NPY-PYY receptor we recently isolated and characterized in the brain. We will attempt to purify the receptor in a series of steps culminating in affinity chromatography. Other experiments will determine if the intestinal receptor is, like the central receptor, linked through an inhibitory G protein to adenyl cyclase. Finally, we will test the hypothesis that PYY acts centrally to inhibit vagal tone on the stomach. We speculate that circulating PYY is exposed to a subpopulation of central NPY-PYY receptors after it passes through the Area Postrema, an area of the blood-brain barrier that is known to be leaky. These studies should define the physiologically importance of PYY and they may delineate a unique mechanism and route of action for this gut hormone.