Impaired lipolysis and dysregulated levels of circulating free fatty acids represent important causative factors for the development of insulin resistance, type 2 diabetes, cardiovascular disease and other hazardous metabolic conditions that rapidly advance and pose especially serious health risk in the elderly. Restraining metabolic diseases in the aging population will improve life quality as well as life expectancy and radically reduce health care costs. We have recently found that activation of mTORC1 inhibits expression of the rate-limiting lipolytic enzyme, ATGL, suppresses basal and cAMP-stimulated lipolysis, and causes marked accumulation of triglycerides in fat and muscle cells. Inhibition of mTORC1 has the opposite effect. In order to determine the molecular mechanism of mTORC1 action, we have conducted a screen in S. cerevisiae. Results of this screen suggest that mTORC1 inhibits ATGL expression via transcription factors of the early growth response (Egr) family. Thus, in Specific Aim 1 we propose to mechanistically establish the role of Egr1/2 in mTORC1- mediated transcription of ATGL and lipolysis, and in Specific Aim 2 we will investigate the role of the mTORC1/Egr1/2 axis in the metabolic disease and aging. We believe that our work will help to establish the mTORC1-mediated pathway as a central controller of FFA homeostasis and dysregulation of this pathway - as a major etiological factor of metabolic disease that limit healthspan and lifespan of the US population.
Dysregulation of lipolysis in fat tissue represents a major causative factor for the development of cardiovascular disease, insulin resistance, and other age-related hazardous metabolic conditions. We have recently found that the mTORC1-mediated pathway controls lipolysis in adipocytes, and we propose to determine the molecular mechanism and the physiological significance of our observations.
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