Abnormal lipid storage and partitioning is one of the top global health problems because it represents a major (or the major) causative factor of insulin resistance, type 2 diabetes, hypertension, heart and liver disease, etc. In a healthy non-obese organism, lipids are, for the most part, stored in adipose tissue as triglycerides (TG). Redistribution of TG from adipocytes to non-adipose tissues, such as skeletal muscle, heart, liver and pancreas triggers a number of pathological effects collectively known as lipotoxicity that causes and aggravates insulin resistance, type 2 diabetes, and other metabolic disease. Mammalian target of rapamycin complex 1 (mTORC1) has been established as the central controller of protein biosynthesis and cell growth. In addition, mTORC1 is now emerging as an important regulator of lipid metabolism. In particular, we have recently found that mTORC1 suppresses lipolysis by inhibiting expression of the rate-limiting lipolytic enzyme, adipose triglyceride lipase thus rendering lipolysis responsive to regulation by insulin and nutrients. Using a genetic screen in S.cerevisiae, we have determined that the effect of mTORC1 on the expression of ATGL is mediated by the primary early growth response transcription factor Egr1. However, we still do not know how exactly mTORC1 activates expression of Egr1 in mammalian cells. Therefore, in Specific Aim 1, we will explore the molecular mechanism of Egr1 regulation by mTORC1 in adipocytes.
In Specific Aim 2, we will test the hypothesis that FSP27 (a.k.a. CIDEC) plays a dual role in fat metabolism as a lipid droplet protein and a co-factor of Egr1 that regulates ATGL transcription.
In Specific Aim 3, we will use a newly developed model of conditional fat-specific constitutively active Rheb transgenic mouse in order to test the hypothesis that mTORC1 in adipocytes is responsible for lipid partitioning and metabolic fitness in vivo.
In this application, we propose to explore novel roles of mTORC1, transcription factor Egr1, and a lipid droplet protein FSP27 in regulation of lipolysis, lipid partitioning, and metabolic fitness in vivo and in vitro.
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