This research grant proposes studies on two experimental forms of obesity. These are: 1) genetically transmitted obesity in the obese (ob/ob) mouse, the diabetes (db/db) mouse and the fatty (Zucker) rat, and 2) hypothalamic obesity. The studies on genetic forms of obesity have been framed to test thehypothesis that the alterations in the endocrine system may be the primary biochemical defect in this system. Three approaches will be used to examine the endocrine hypothesis for genetic obesity. Adrenalectomy has been shown to stop the developoment of many features of this syndrome. The possibility that the primary defect of these mice is in the pituitary-adrenal system will be tested. To explore this question the effects of adrenalectomy will be studied in vivo. In addition, Hepatic cell cultures will be employed to provide an in vitro approach to delineating this possibility more precisely. A second approach will study the concentration of neurotransmitters, especially the peptides in the hypothalamus for which radioimmunoassays are available. Among the peptides which will be examined are cholecystokinin, bombesin, neurotensin, and nerve growth factor. Studies on the development of the brain will also be initiated. The third approach will examine the function of the sympathetic nervous system during stress. Studies on hypothalamic obesity will test the hypothesis that this syndrome results from an altered balance between the sympathetic and parasympathetic components of the autonomic nervous system. The first approach will compare unilateal sympathectomy with and without unilateral hypothalamic lesions. A second approach will explore therole of transplantd pancreatic islets made before or after the introduction of hypothalamic lesions. The concentration and turnover of catecholamines will be measured under a variety of experimental conditions in animals with hypothalamic obesity.