Metabolic homeostasis is inherently “systems physiology”. Cell-autonomous processes within each tissue and organ must be tightly coordinated to allow for the integrative control of whole-body metabolism. This integration is achieved in part by the vagal nerve system, connecting the brain to visceral organs. Tissue crosstalk in the periphery is instead largely mediated by secreted hormones. Disruption of hormonal circuits underlying these peripheral organ communications is causally linked to metabolic disorders. Yet, we lack fundamental knowledge about mechanisms underlying this hormonal regulation in both physiologic and pathologic conditions. Toward this end, our efforts to map the organ-level metabolic circuits have largely centered on understanding the function and mechanisms of action of a family of highly conserved secreted hormones—C1q/TNF-related proteins (CTRP1-15)—that we initially described. In the last decade, we have generated numerous enabling tools and mouse models that have promoted major advances in understanding CTRP biology and the critical roles they play in sugar and fat metabolism, including in disease contexts. In this competitive renewal application, we propose focused studies of CTRP2, a poorly characterized CTRP family member that is enriched in adipose tissue. Using novel mouse models, we discovered that CTRP2 is required for maintaining systemic lipid homeostasis. Our preliminary data suggest that CTRP2 is a novel anti-lipolytic hormone within the fat tissue, as well as an important regulator of hepatic triglyceride, cholesterol, and phospholipid metabolism. We propose two specific aims toward understanding the mechanisms by which CTRP2 regulates lipid metabolism in adipose tissue (Aim 1) and liver (Aim 2), its major target tissues. The completion of this project will provide critical insights into the metabolic gene circuits and signaling networks directly regulated by CTRP2 in adipocytes and hepatocytes to control local and systemic lipid metabolism. Our studies have the potential to provide fundamental insights that ultimately inform innovative strategies to mitigate metabolic disease outcomes in clinical settings.