Project Summary/Abstract The central nervous system plays a pivotal role in metabolism, within which the ventromedial hypothalamus (VMH) is crucial for proper regulation of body weight and blood glucose level. The VMH senses nutrients and circulating hormones and integrates its metabolic information to coordinate effector responses to maintain organismal homeostasis. O-linked beta-D-N-acetylglucosamine (O-GlcNAc) modification, catalyzed by O-GlcNAc transferase (OGT), is considered a cellular sensor of nutrients and hormones. Our recent studies reveal that OGT in the VMH is required for promoting adipose tissue lipolysis and maintaining energy balance by regulating the VMH neuronal activity and sympathetic innervations to white adipose tissues. Based on these findings, we hypothesize that VMH O-GlcNAc signaling determines a body weight setpoint by means of humoral and nutritional sensing and filtering lipolytic information to white adipose tissues. To test this hypothesis, we will combine gain- and loss-of- function models with state-of-the-art neural tracing and molecular profiling tools, optogenetic and electrophysiological recordings, and comprehensive physiological assessments to delineate the mechanisms by which VMH OGT regulates adipose tissue function and constrains body weight gain. Aim 1 will determine whether O-GlcNAc signaling in VMH neurons determines the setpoint of body weight. Aim 2 will delineate the neurocircuitry by which OGT-expressing VMH neurons relay lipolytic information to white adipose tissues. Aim 3 will identify how O-GlcNAc signaling regulates hormonal and nutritional sensing of VMH neurons. A detailed understanding of body weight control by hypothalamic OGT could support the development of novel therapies for obesity and co-morbidities.