Three interrelated area pertaining to the novel implications of cyclo (His-Pro) in appetite regulation in health and disease will be explored. 1. The potential role of cyclo (His-Pro) as a physiologic modulator of normal appetite regulation will be studied through, a) measurements of cyclo (His-Pro) concentrations in micropunch biopsies from the ventromedial hypothalamus (satiety center) during fasting and refeeding, b) antibody neutralization of endogenous cyclo (His-Pro) activity to inquire if specific anti-cyclo (His-Pro) sera can reverse satiety and stimulate hyperphagia, c) examination of the dependency of the appetite-lowering properties of cyclo (His-Pro) upon integrity of hypothalamus in ventromedial electrolytic-lesioned rats and/or the gastrointestinal (GI) tract in animals subjected to abdominal and gastric vagotomy. The role of cyclo (His-Pro) of peripheral (GI) origin will be investigated also by quantitation of cyclo (His-Pro) concentrations in peripheral blood and GI extracts in relationship to fasting and nutrient ingestion, d) examination of the ability of exogenous cyclo (His-Pro) to simulate the behavioral pattern of authentic satiety, and not non-specific anorexia, in the absence of nutrients, and e) investigation of the hypothesis that cyclo (His-Pro) produces appetite suppression in the rat by inhibition of the hypothalamic noradrenergic system. 2. The potential role of cyclo (His-Pro) in the pathophysiology of experimental obesity will be examined in a model of diet-induced obesity and 4 models of hereditary obesity. Cyclo (His-Pro) concentrations will be measured in 7 CNS region, peripheral blood, and the GI tract to determine if a deficiency in cyclo (His-Pro) synthesis and/or secretion may be contributing to the production of obesity. 3. The potential role of cyclo (His-Pro) in human appetite regulation will be explored by measurements in peripheral blood extracts during fasting and refeeding in normals, obese, and anorexia nervosa subjects. The hypothesis will be investigated that blood cyclo (His-Pro) concentrations become elevated in normal subjects and that such elevations become attenuated in obesity and exaggerated in anorexia nervosa.