Metabolic syndrome has become a global epidemic that dramatically increases the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Brown fat plays an important role in the defense against cold and contributes to whole body energy balance. To date, the metabolic action of brown fat has been primarily attributed to its unique ability to stimulate uncoupled mitochondrial respiration. Secreted factors exert diverse effects on carbohydrate and lipid metabolism in peripheral tissues and the maintenance of systemic energy homeostasis. Adipose tissue hormones, such as leptin and adiponectin, gut-derived fibroblast growth factors, and myokines sense nutrient status and coordinate key aspects of cellular metabolism. Whether brown adipocytes engage other metabolic tissues through secreted factors to regulate nutrient and energy metabolism in the body is unknown. In preliminary studies, we identified a novel brown fat-enriched secreted factor that is highly inducible during brown adipocyte differentiation. Using gain and loss of function mouse models, we established that this brown adipokine regulates whole body glucose and lipid metabolism. In this proposal, we will test our central hypothesis that brown fat secreted factors play a central role in metabolic crosstalk. In Aim 1, we plan to define the role of brown adipokine in metabolic adaptation during thermogenesis and in obesity. In Aim 2, we will evaluate the mechanisms underlying the metabolic action of this secreted factor. In Aim 3, we will assess the extent to which elevated adipokine expression protects mice from diet-induced metabolic derangements. Our proposed work will provide insights into a previously unrecognized role of brown fat in endocrine signaling and generate critical preclinical data for future therapeutic development.