Role of lipid droplets in insulin resistance

这一建议的中心假设是为了测试内皮LD周转对正常生理过程中的代谢功能至关重要这一观点。这一假设的一个推论是，在饮食诱导的胰岛素抵抗模型中，血管中LD周转的损害将增加胰岛素抵抗状态。为了验证这一假设，提出了以下目标。1.阐明ATGL在正常生理条件下和饮食诱导的胰岛素抵抗(IR)后对EC中LD的水解性和炎症反应的调节作用；2.探讨EC ATGL调节血管功能和细胞代谢的机制；3.阐明内皮DGATS在LD合成和炎症中的重要性。总而言之，我们将首次定义内皮细胞LD代谢的作用，因为它与循环甘油三酯和代谢功能的控制有关，从而可能揭示内皮功能障碍和胰岛素抵抗之间的新联系。此外，目前毛细血管内皮细胞中脂蛋白脂解甘油三酯的模型主要集中在代谢活跃的组织，如心脏和骨骼肌，这不能解释大血管内皮细胞中LD的形成，因此，我们的实验将超越教条，并可能对甘油三酯水平升高的2型糖尿病患者更高的冠心病发病率产生洞察。

The central hypothesis of this proposal is to test the idea that endothelial LD turnover is critical for metabolic function during normal physiology. A corollary to this hypothesis is that impairments in LD turnover in blood vessels will augment insulin resistant states in models of diet induced insulin resistance. To test this hypothesis, the following Aims are proposed. 1: To elucidate the role of ATGL in regulating LD hydrolysis in EC and inflammation under normal physiological conditions and after diet induced insulin resistance (IR); 2. To interrogate the mechanisms of how EC ATGL regulates vascular function and cellular metabolism; and 3: To decipher the importance of endothelial DGATs on LD synthesis and inflammation. Collectively, we will define for the first time the role of endothelial LD metabolism as it relates to the control of circulating TG and metabolic function, thus potentially uncovering a novel link between endothelial dysfunction and insulin resistance. Moreover, the current model of TG lipolysis by LPL in capillary EC is focused on metabolically active tissues such as heart and skeletal muscle and this cannot explain LD formation in large vessel EC, thus, our experiments will move beyond the dogma and perhaps yield insights into the higher incidence of coronary disease in type 2 diabetic patients with elevated TG levels.