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 leptin, insulin and serotonin exert its effects, which may lead to effective strategies to combat the incidence of obesity and diabetes. In the past grant period, we sought to delineate the neural substrates through which melanocortin 4 receptor (MC4-R) agonists exert their effects to regulate food intake, body weight, energy expenditure and glucose homeostasis. We created novel mouse models, which allow selective manipulation of MC4-R expression and found that MC4-Rs expressed by autonomic preganglionic neurons are regulators of energy expenditure and glucose production by the liver. In the current proposal, we will extend these observations using our novel mouse model in which we can selectively delete MC4-Rs. We will identify cellular mechanisms through which MC4-R agonists inhibit parasympathetic and activate sympathetic preganglionic neurons. We will next determine if deletion of MC4-Rs in autonomic preganglionic neurons alters hepatic glucose production. Finally, we will also determine if blocking glucagon action blunts the disruptions in glucose homeostasis induced by MC4-R deletion in autonomic preganglionic neurons.