Studies have suggested that insulin may be a regulator of food intake and body weight by acting at the central nervous system (CNS). This renewal proposal addresses the hypothesis that the ability of insulin to act as a satiety signal may change during normal growth and development, and may be abnorrnal in obesity. Studies are proposed to examine whether insulin uptake into the CNS, or insulin action-in the CNS, is altered in rats as a function of age, gender, and genetic or diet-induced obesity. Insulin uptake by brain will be assessed in vivo by measurement of steady state levels of plasma and CSF insulin during vehicle or insulin infusions. Brain capillary insulin binding sites will be measured as an in vitro estimate of specific receptor-mediated transport capacity. Regulation of these receptors has been observed by this laboratory and others and may represent a potential mechanism for regulation of insulin uptake into the CNS. Insulin action will be assessed behaviorally by measuring body weight and food intake in response to intraventricular insulin infusions. Insulin action in vitro will be assessed by measurement of insulin effects on norepinephrine uptake and post-synaptic events in the hippocampus, a brain region in which I have demonstrated insulin stimulation of phospholipid metabolism which may be mediated locally by catecholamines, as well as in the hypothalamus and olfactory bulb, two brain regions which play a major role in the regulation of food intake and body weight, and compared with changes of peripheral insulin action. Together, these studies should determine whether the effectiveness of the candidate CNS adiposity signal, insulin, is regulated by changes in its uptake and/or action in the CNS.