Obesity is now a pandemic that will have significant impact on our current health care system. A common theme in obese individuals that progress towards diabetes is insulin resistance. A critical question in the field asks how obesity impairs insulin sensitivity as a first step in progression to type 2 diabetes mellitus. The mammalian Target of Rapamycin Complexes (mTORC1) and 2 are multisubunit kinase complexes responsible for integrating multiple aspects of nutrient and growth factor signaling to regulate cellular anabolic processes such as cell growth, and translation. We have found that during catecholamine-induced lipolysis in fat cells the mTOR complexes are dissociated and thereby inhibited. While investigating the mechanism by which this occurs we made the novel discovery of a new class of oxidized neutral lipids that are responsible. While oxidized phospholipids have been implicated as component of lipoproteins responsible for initiating cardiovascular disease, our findings suggest that oxidized neutral lipids may analogously be responsible for adipocyte dysfunction. Completion of these aims will: 1.) define oxidized neutral lipids as novel inputs regulating mTOR complex activity, 2.) discover new strategies for inhibiting both mTOR complexes, 3.) describe the mechanism whereby catecholamines inhibit glucose uptake by adipocytes.
This proposal investigates oxidized triacylglycerols and the regulation of the mTOR complexes. mTOR integrates cellular nutrient status to control growth, proliferation, and life span. Our studies suggest that oxidized neutral lipids play an important role in cellular physiology and can contribute to insulin resistance.