The long term goal of this laboratory is to understand the mechanisms which produce obesity and to use this insight as the basis for designing new treatment for this major public health problem. The hypothesis for this specific set of studies is that there are identifiable hypothalamic systems which control the intake of individual macronutrients. This grant proposal will focus on fat intake which is stimulated by the injection of galanin into the paraventricular nucleus. Galanin is a 29 amino acid peptide which stimulates primarily the intake of fat. This effect is blocked by galanin, a peptide antagonists. The existing data suggest that there is a population of galanin containing neurons which release galanin in the parventricular nucleus and that neurons responsive to this galanin are involved in the physiological modulation of fat intake. The first part of this proposal will ask how the galanin system is modulated by peripheral signals of fat depletion and fat repletion. Dietary fat will be varied in one of two ways. Fat intake will be """"""""clamped"""""""" by giving animals a single high or low fat diet to eat, or the animals will be allowed a """"""""choice"""""""" of diets consisting of the 3 separate macronutrients or of 2 complete diets differing in their percentage of fat. Both acute responses to galanin and its antagonist will be determined using dose-response curves to galanin given into the ventricle or into the PVN. In addition the response to galanin will be tested in animals whose food intake has been manipulated by infusing oleate into the duodenum, by giving injections of 3-hydroxy-butyrate intraperitoneally or into the lateral ventricle, and by giving injections of mercaptoacetate which blocks fatty acid oxidation in the liver. The second set of experiments will examine the interface between injections of galanin or a galanin antagonist and the gustatory signals associated with initial ingestion of macronutrients. The third part of the proposed research will examine how the galanin system is integrated into the neural substate which regulates food intake. A series of neuroanatomical and neurochemical identification procedures will be used to characterize these connections. These studies will provide significant new insights into the anatomic organization and physiology of fat intake. The ability to selectively modulate fat intake has important implications not only for obesity, but for heart disease and cancer as well.
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