mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia

Abstract Objective Pharmacological agents targeting the mTOR complexes are used clinically as immunosuppressants and anticancer agents, and can extend lifespan in model organisms. An undesirable side effect of these drugs is hyperlipidemia. Despite multiple roles that have been described for mTOR complex 1 (mTORC1) in lipid metabolism, the etiology of hyperlipidemia remains incompletely understood. The objective of this study was to determine the influence of adipocyte mTORC1 signaling in systemic lipid homeostasis in vivo. Methods We characterized systemic lipid metabolism in mice lacking the mTORC1 subunit raptor (RaptoraKO), the key lipolytic enzyme ATGL (ATGLaKO), or both (ATGL-RaptoraKO) in adipocytes. Results Mice lacking mTORC1 activity in adipocytes failed to completely suppress lipolysis in the fed state and displayed prominent hypertriglyceridemia and hypercholesterolemia. Blocking lipolysis in adipose tissue restored normal levels of triglycerides and cholesterol in the fed state, as well as the ability to clear triglycerides in an oral fat tolerance test. Conclusions Unsuppressed adipose lipolysis in the fed state interferes with triglyceride clearance and contributes to hyperlipidemia. Adipose tissue mTORC1 activity is necessary for appropriate suppression of lipolysis and for the maintenance of systemic lipid homeostasis.