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 exert their effects. This may lead to effective strategies to combat the incidence of obesity, diabetes and eating disorders. In the past grant period, we found that CNS serotonin (5-HT) systems interact with hypothalamic melanocortin neurons. We created a reactivatable 2C null mouse model, and we found that re-expression of 5-HT2CR only in pro-opiomelanocortin (POMC) neurons rescues hyperphagia, obesity and insulin resistance caused by global deletion of 5-HT2CR. However, our studies thus far have not determined if there are other physiologically important targets of serotonin receptor agonists. In the current proposal we will extend these observations using several mouse models in which we can selectively reactivate or delete the 5- HT2CR in specific subsets of neurons. We will determine if neurons in the paraventricular nucleus of hypothalamus are sufficient to restore the anorexigenic properties of 5-HT2CR in the 2C null mice. We will also determine if 5-HT2CR re-expression by key autonomic regulatory neurons in the brainstem is sufficient for normal body weight and glucose homeostasis. Finally, we will determine if autonomic preganglionic neurons expressing melanocortin 4 receptors mediate the anti-diabetic actions of serotonin receptor agonists. PUBLIC HEALTH RELEVANCE: Obesity is now recognized as global crisis due to its increasing prevalence and serious comorbidities, including insulin resistance and diabetes. Understanding the homeostatic mechanisms that maintain normal body weight and glucose balance and looking for rational targets for anti-obesity and anti-diabetic therapies are a priority in the field. The proposed research will investigate the efficacy of central serotonin system in the regulation of food intake, body weight and glucose homeostasis and will identify critical brain sites that mediate the anti-obesity and anti-diabetic effects of serotoninergic compounds. Results from these studies will advance our understanding of the serotoninergic circuits necessary to permit the design of effective treatment strategies for obesity and diabetes.