Alterations in the metabolic control of lipid and glucose homeostasis predispose an individual to develop cardiometabolic diseases, such as obesity, type 2-diabetes (T2D) and cardiovascular dysfunction. The Central Nervous System (CNS) plays a critical role in regulating cardiometabolic homeostasis. Within the CNS, the melanocortin system has been shown to be a major component in modulating cardiometabolic homeostasis. This system consists of 3 components: 1) neurons expressing Neuropeptide Y/Agouti related peptide (NPY/AgRP), 2) neurons expressing pro-opiomelanocortin (POMC) and 3) neurons expressing melanocortin receptors, including MC3R and MC4R. The POMC gene encodes several peptides that are the products of a complex post-translational process. Among these peptides, alpha-melanocyte stimulating hormone (?-MSH) has been shown to play a fundamental role in metabolism. Although its production has been largely studied, its degradation process has been unknown for a long time. In 2009, we demonstrated that prolyl carboxypeptidase (PRCP) is a peptidase responsible for the degradation of ?-MSH. We have showed that ?-MSH1-13 is indeed a substrate of PRCP, which cleaves ?-MSH1-13 to inactive ?-MSH1-12. Through anatomical, biochemical, pharmacological and genetic tools, we have demonstrated that central PRCP is an important regulator of melanocortin action. In this application, we aim to further elucidate on the role of PRCP in specific neuronal populations in the regulation of cardiometabolism and on role of neuronal activity in PRCP release and action. Four specific aims are proposed: Aim 1 will determine whether PRCP expression in NPY/AgRP neurons is necessary to modulate food intake. Aim 2 will determine whether PRCP in the hypothalamic dorsomedial nucleus (DMH) is necessary in the regulation of blood pressure and energy expenditure (EE). Aim 3 will determine whether PRCP release is promoted by neuronal activity. Because PRCP plays a pivotal role in homeostasis by regulating central melanocortin signaling, PRCP represents a potential new therapeutic target to treat cardiometabolic disorders such as obesity, type 2 diabetes and cardiovascular dysfunction. Thus, the execution of these studies will further unmask the role of central PRCP in metabolism regulation and will help us to better develop new classes of tissue-specific PRCP inhibitors needed to translate PRCP genetics and biochemistry for treatments of cardiometabolic disorders.