Role of Oxidized neutral lipids in adipocyte function

描述（由申请人提供）：肥胖现在是一种流行病，将对我们目前的医疗保健系统产生重大影响。肥胖个体发展为糖尿病的一个共同主题是胰岛素抵抗。该领域的一个关键问题是肥胖如何损害胰岛素敏感性，这是发展为2型糖尿病的第一步。哺乳动物雷帕霉素靶标复合物（mTORC 1）和2是多亚基激酶复合物，负责整合营养和生长因子信号传导的多个方面，以调节细胞合成代谢过程，如细胞生长和翻译。我们已经发现，在脂肪细胞中的儿茶酚胺诱导的脂解过程中，mTOR复合物被解离，从而被抑制。在研究这种情况发生的机制时，我们发现了一类新的氧化中性脂质。虽然氧化磷脂被认为是引发心血管疾病的脂蛋白的组成部分，但我们的研究结果表明，氧化中性脂质可能类似地导致脂肪细胞功能障碍。实现这些目标将：（1）将氧化中性脂质定义为调节mTOR复合物活性的新输入，2.）发现抑制两种mTOR复合物的新策略，3.）描述了儿茶酚胺抑制脂肪细胞摄取葡萄糖的机制。

DESCRIPTION (provided by applicant): 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.