Role of Oxidized neutral lipids in adipocyte function

氧化中性脂质在脂肪细胞功能中的作用

• 批准号: 8672812
• 负责人: Thurl E. Harris
• 金额: $ 33.87万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672812
• 关键词: 1,2-diacylglycerol; Adipocytes; Adrenergic Agents; Adrenergic Receptor; Affect; Attenuated; Biochemical; Cardiovascular Diseases; Catecholamines; Cell physiology; Complex; Data; Defect; Development; Diabetes Mellitus; Diglycerides; Dissociation; Esterification; Fatty Acids; Figs - dietary; Functional disorder; GLUT4 gene; Glycerol; Growth; Growth Factor; Healthcare Systems; Hydrolysis; Impairment; In Vitro; Individual; Insulin; Insulin Resistance; Insulin Signaling Pathway; Laboratories; Lipids; Lipolysis; Lipoproteins; Longevity; Measures; Mediating; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Phospholipids; Phosphotransferases; Play; Polyunsaturated Fatty Acids; Process; Reactive Oxygen Species; Regulation; Role; Signal Transduction; Structure; System; Techniques; Translations; Triglycerides; Vesicle; adrenergic; attenuation; blood glucose regulation; cell growth; glucose uptake; human FRAP1 protein; in vivo; insulin sensitivity; insulin signaling; mTOR inhibition; mTOR protein; novel; oxidation; oxidized lipid; pandemic disease; particle; public health relevance; response; trafficking

Project Summary/Abstract 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.

项目总结/摘要 肥胖现在是一种流行病，将对我们目前的医疗保健产生重大影响 系统一个共同的主题，在肥胖的个人，进展为糖尿病是胰岛素 阻力该领域的一个关键问题是，肥胖首先是如何损害胰岛素敏感性的。 2型糖尿病的治疗方法雷帕霉素复合物的哺乳动物靶点 （mTORC 1）和2是多亚基激酶复合物，负责整合多个方面 营养素和生长因子信号传导来调节细胞合成代谢过程， 成长与翻译我们发现，在儿茶酚胺诱导的脂肪细胞脂解过程中， mTOR复合物被解离，从而被抑制。在研究其机制时 通过这种方法，我们发现了一类新的氧化中性脂质， 都有责任虽然氧化磷脂被认为是 我们的研究结果表明，氧化型脂蛋白是引发心血管疾病的关键因素， 中性脂质可能类似地导致脂肪细胞功能障碍。完成这些 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.）的情况。发现抑制两种mTOR复合物的新策略，3.）描述机制 由此儿茶酚胺抑制脂肪细胞对葡萄糖的摄取。