Rapamycin, which is FDA approved as an anti-rejection agent, has been extensively shown to extend lifespan and delay the onset of age related diseases across several model organisms. However, patients treated with rapamycin develop several metabolic abnormalities, including glucose intolerance, insulin insensitivity and hyperlipidemia, preventing the therapeutic use as an anti-ageing agent. Rapamycin is an allosteric inhibitor of mTOR (mechanistic target of rapamycin), a serine/threonine protein kinase that functions as a master regulator of cellular growth and metabolism. mTOR plays an important role in metabolic tissues, such as the liver, skeletal muscle and adipose tissue. Tissue specific disruption of mTORC1 or mTORC2 has revealed that each complex has different effects on whole body glucose and lipid homeostasis in different organs. It is known that mTOR signaling regulates lipid homeostasis and that rapamycin blocks expression of genes involved in lipogenesis and impairs the nuclear accumulation of SREBPs. Preliminary data suggest that mTOR loss in the liver is not responsible for the elevated serum cholesterol and triglyceride levels seen with rapamycin treatment. Many groups have shown that mTOR signaling in adipose tissue regulates lipid synthesis through various effectors, but the mechanisms are not fully understood. To understand how mTOR signaling in adipose tissue and rapamycin affects metabolism, specifically on lipid homeostasis, I will use genetic mTOR adipose specific knockout mouse models and wildtype mice treated with rapamycin. These mice will be used for turnover studies with HDL and VLDL labeled with tracers, and phosphoproteomics. Together, this proposal will provide an improved understanding on mTOR and rapamycin which will aid in the therapeutic uses of rapamycin by avoiding such side effects as hyperlipidemia.
Rapamycin, which is FDA approved, has been extensively shown to extend lifespan and delay the onset of age related diseases across several model organisms. However, patients treated with rapamycin develop hyperlipidemia, but the mechanism is not known. An improved understanding of the side effects of rapamycin will aid in the therapeutic uses to delay aging or to treat metabolic disorders and cancer.
