It is proposed to investigate four interrelated areas concerning cyclo-(His-Pro) (C(HP)) and appetite regulation. The long range goal is to understand how C(HP) causes appetite suppression and to achieve long-term appetite suppression in the rat and primate. 1. To characterize how and where C(HP) exerts its appetite suppressive actions in the hypothalamus, its effects upon fasting- and refeeding-associated alterations in the content and turnover of catecholamines will be investigated by HPLC. Stereospecific receptors for 3H-C(HP) in the hypothalamus will be sought and their relevance to appetite control examined. To understand the mechanism of the acute elevations in hypothalamic C(HP) concentrations, transcription rates of the preproTRH (preproC(HP)) genome will be studied using a 32P-cDNA probe for pro-TRH. The ultrastructural co-localization of C(HP) in hypothalamic nuclei will be studied with light and electron microscopic immunocytochemistry. 2. Potential mechanisms underlying the fluctuations in small bowel C(HP) concentrations with fasting and feeding will be examined by studying the synthesis, secretion, and turnover rate of C(HP) in relation to nutrient status. The ultrastructural features of the small bowel C(HP) will be characterized to determine whether C(HP) is in neural or endocrine structures. 3. The potential role of C(HP) in the pathophysiology of experimental obesity will be investigated in rodent models of acquired and hereditary obesity. 4. Long-term appetite suppression and weight loss in both rats and primates will be accomplished by administration of C(HP) either intraventricularly, subcutaneously, or orally.
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