ABSTRACT A major long-term goal of our laboratory is to delineate regulatory mechanisms that control adipocyte development and systemic physiology. This proposal will address a new regulatory pathway involved in adipocyte nutrient sensing, adipose tissue physiology, and adipose depot-specific energy expenditure. The proposed studies are focused on understanding how dynamic regulation adipocyte membrane composition contributes to the control of whole-body metabolic homeostasis in living animals. Preliminary data implicates the phospholipid remodeling enzyme Lpcat3 as novel mechanistic link between dietary fatty acid intake, adipose tissue homeostasis, and susceptibility to obesity. This proposal builds upon our preliminary discoveries to address important questions regarding the relationship of membrane lipid composition to adipose tissue function and systemic physiology and energy balance. We have previously shown that the enzyme Lpcat3 is uniquely required for the incorporation of the 6 polyunsaturated fatty acids into phospholipids. Our preliminary data reveal that adipose Lpcat3 expression is induced in the setting of cold exposure or diet-induced obesity. Moreover, initial characterization of mice lacking Lpcat3 selectively in adipose tissues has revealed two distinct phenotypes: one traced to white adipose tissue (WAT) and one traced to brown adipose tissue (BAT). Adipose Lpcat3 KO mice fed a high-fat diet develop a lipodystrophic phenotype are unable to appropriately expand their WAT, leading to ectopic hepatic lipid accumulation and the compensatory upregulation of fatty acid oxidation in WAT. At the same time, BAT Lpcat3 KO mice show an abnormal response to cold challenge, characterized by marked ER stress. A striking commonality between these WAT and BAT KO models is the compensatory production of FGF21 in an apparent effort to maintain energy homeostasis. We hypothesize that the fine tuning of adipose tissue membrane composition by Lpcat3 is a critical adaptive response to cold and dietary challenge that permits optimal lipid storage and catabolic function in a range of environments. We will address these hypotheses with the following specific aims. Specific Aim 1 is to elucidate the role of membrane phospholipid remodeling in nutrient sensing and healthy adipose tissue expansion. Specific Aim 2 is to determine the role of phospholipid remodeling in BAT function and response to thermal stress.