CHOLECYSTOKININ MECHANISMS IN CONTROL OF FOOD INTAKE

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DESCRIPTION (adapted from the Abstract): This is a new application seeking three years of support to identify the actions through which endogenous CCK affects food intake. Cholecystokinin (CCK) is a peptide that is found throughout the brain and in neurons and endocrine cells of the gut. Recent studies demonstrating that devazepide, a CCK-A receptor antagonist that penetrates the blood/brain barrier, stimulates feeding in a variety of species provide compelling evidence that CCK is an important satiety factor. However, whether CCK is acting peripherally, within the brain, or at multiple peripheral and central sites to produce satiety remains to be determined. Recent work demonstrating the existence of CCK-A receptors on vagal afferent neurons, activation of vagal afferent neurons by exogenous CCK, and attenuation of exogenous CCK and duodenal nutrient induced inhibition of feeding by vagal neural lesions has led to the following hypothesis of endogenous CCK's action which is to be tested by the proposed studies: CCK secreted from the upper intestine in response to duodenal delivery of nutrients acts through paracrine or neurocrine stimulation of intestinal vagal sensory neurons to produce satiety. In the proposed research the Principal Investigator and his colleagues will use a sham feeding rat model (ingested food drains from a gastric cannula) to test this hypothesis. The specific aims are: (1) to use receptor subtype and site specific CCK antagonist (devazepide, A70104, CCK monoclonal antibody, JMV-180) to determine the relative contribution and site of endogenous CCK action in mediating the satiety produced by duodenal delivery of various nutrients; (2) to use region-specific lesions of vagal afferent neurons (truncal vagal rizotomy, perivagal capsaicin, celiac vagal rizotomy) to assess the role of intestinal vagal sensory neurons in mediating the satiety produced by duodenal delivery of various nutrients; and (3) to evaluate the role of intestinal CCK in mediating the activation of vagal sensory neurons by duodenal delivery of various nutrients. In this project, the researchers will examine whether peripheral CCK receptor blockade attenuates duodenal nutrient-induced activation of brain stem neurons in the dorsal vagal complex as evidenced by immunohistochemical detection of c-fos expression. These studies should advance our understanding of the mechanisms of CCK actions and the physiological controls of food intake. They should also provide direction in the search for pathogenic mechanisms of eating disorders and strategies for their treatment.