The increasing incidence of obesity is a major health issue facing the USA. Fortunately, in the past decade several key hormones and central nervous system (CNS) pathways controlling body weight and glucose homeostasis have been identified. Indeed, we now have a rough CNS roadmap through which key metabolic signals like ghrelin exert its effects which may lead to effective strategies to combat the incidence of obesity, diabetes and eating disorders. In the past grant period, we sought to delineate the neural substrates through which ghrelin and its receptor, the growth hormone secretagouge receptor (GHSR; ghrelin receptor) selectively regulate food intake and body weight. We created a novel GHSR null mouse and found that lack of ghrelin signaling protected mice from developing diet-induced obesity and diabetes. In the current proposal, we will extend these observations using our novel mouse model in which we can selectively reactivate GHSR expression in selected cell types. We will identify if vagal sensory neurons in the nodose ganglia are sufficient to restore the orexigenic properties of ghrelin in mice lacking GHSRs everywhere else. We will next determine is GHSR re-expression by key autonomic regulatory neurons in the brainstem is required for normal body weight and glucose homeostasis. Finally, we will also determine if reactivation of GHSRs in 2 cells in the pancreas is sufficient to restore the ability of ghrelin to suppress insulin levels in the face of diet induced obesity. PUBLIC HEALTH RELEVANCE: The experiments proposed in this study have been designed to investigate the role ghrelin plays in regulating food intake, body weight and glucose homeostasis. It is hoped that these studies will result in new targeted therapies to treat mood obesity, diabetes and eating disorders such as anorexia nervosa and bulimia nervosa.