Endothelial cells interface blood and tissues for nutrient and fluid transport between organs. Therefore, endothelial cells critically provide fatty acids and other carbon fuels to meet tissue demands during periods of nutrient limitation. Despite vital interorgan communication roles for endothelial cells, we lack fundamental insight into how endothelial cells serve systemic metabolism and the responses to food and environmental challenges. Metabolic disorders such as obesity and insulin resistance reflect the combined impacts of genetic and environmental factors that alter the ways the liver and adipose tissues govern energy balance. Therefore, precise strategies must activate or repress metabolic pathways in the liver and adipose tissues to maintain the energetic needs of connected organ systems. In the previous funding cycle, we established that circulating bone morphogenetic protein-binding endothelial regulator (BMPER) promoted hepatic insulin sensitivity in multiple mouse models of diabetes. In addition, human BMPER gene variants and its protein plasma level were strongly associated with obese parameters. The subsequent experiments demonstrated BMPER abundance in blood coincides with nutrient availability. Fasting in rodents and people increased BMPER levels in blood while feeding caused a coincident reduction in bioavailable BMPER. Mechanistically, our preliminary data suggest fasting causes BMPER release from the liver, which acts on adipose tissue to liberate free fatty acids and glycerol for gluconeogenesis. Peroxisome proliferator activated receptor alpha activation heightens BMPER expression in the liver upon fasting. However, this signaling axis is likely dysregulated by high fat-diet feeding. Based on our preliminary data, we hypothesize that fasting-induced BMPER in the liver acts as an endocrine stimulator of lipolysis in adipose tissue. We will test our hypothesis by defining how BMPER influences fatty acid mobilization in adipose tissue; establishing mechanisms governing BMPER regulation of adipocyte lipolysis; and determining nutrient sensing transcription factors that regulate BMPER availability in serum. Our studies will define a new liver-to-adipose tissue circuit mediated by BMPER in the regulation of energy homeostasis and offer new insight into whether BMPER signaling can be leveraged for the treatment of obesity, diabetes and other metabolic disorders.