REGULATION OF ADIPOCYTE PROTEIN SYNTHESIS BY AMINO ACIDS

描述（由申请人提供）：这些研究的长期目标是寻找治疗肥胖的新治疗策略。在之前的资助期内，我们发现亮氨酸是一种直接作用的营养信号，可以强烈刺激脂肪组织中涉及哺乳动物雷帕霉素靶点（mTOR）的基本生长刺激途径。MTOR及其调控的底物在蛋白质合成、脂肪细胞分化、瘦素、新生脂肪生成、细胞周期进程、有丝分裂后组织肥厚生长和组织形态发生的翻译调控中起着关键作用。鉴于新兴的肥胖流行病，了解亮氨酸等营养信号如何影响脂肪组织生理学是很重要的。拟开展的研究将重点关注亮氨酸对脂肪细胞中蛋白质合成和mTOR信号通路的调节。两个基本问题推动了拟议的研究。亮氨酸是如何发挥作用的？mTOR和亮氨酸信号对脂肪组织中蛋白质合成的生理作用是什么？我们将在三个具体目标中解决这些问题。(1)有人提出，线粒体亮氨酸代谢产生的信号是mTOR激活所必需的。为了解决这种可能性，将采用遗传方法来阻断脂肪组织中亮氨酸代谢的第一步，以检查亮氨酸调节蛋白质合成和mTOR信号传导的后果。(2)验证亮氨酸信号在肥胖或有肥胖遗传倾向的动物中是不同的假设；与皮下脂肪组织储存相比，内脏（腹腔内）脂肪组织储存更大，已知肥胖相关合并症的风险更大；并研究这些差异的机制。(3)将利用生化、转基因和蛋白质组学方法揭示mTOR的生理作用及其在亮氨酸信号传导中的作用。这些研究将阐明亮氨酸如何调节mTOR，以及亮氨酸刺激mTOR在脂肪组织生理和肥胖中的作用。

DESCRIPTION (provided by applicant): The long-term goal of these studies is to find new therapeutic strategies for the treatment of obesity. In the previous funding period, we showed that leucine is a direct acting nutrient signal that robustly stimulates a fundamental growth-stimulating pathway in adipose tissue involving the mammalian target of rapamycin (mTOR). MTOR and the substrates it regulates have critical roles in translational regulation of protein synthesis, adipocyte differentiation, leptin, de novo lipogenesis, cell cycle progression, hypertrophic growth of post-mitotic tissues and tissue morphogenesis. In view of the emerging obesity epidemic it is important to understand how nutrient signals such as leucine impact adipose tissue physiology. The proposed studies will focus on leucine regulation of protein synthesis and the mTOR signaling pathway in adipocytes. Two fundamental questions drive the proposed studies. How does leucine bring about its effects? What are the physiological roles of mTOR and the leucine signal to protein synthesis in adipose tissue? We will address these questions in three specific aims. (1) It has been proposed that signals arising from mitochondrial metabolism of leucine are required for mTOR activation. To address this possibility, a genetic approach will be used to block the first step in leucine metabolism selectively in adipose tissue in order to examine the consequences on leucine regulation of protein synthesis and mTOR signaling. (2) To test the hypotheses that leucine signaling is different in animals that are obese or have a genetic propensity to become obese and; greater in visceral (intraabdominal) adipose tissue depots, known to represent a greater risk for obesity-associated co-morbidities, compared to subcutaneous adipose tissue depots; and to examine the mechanism of such differences. (3) Biochemical, transgenic and proteomic approaches will be used to uncover the physiological role of mTOR and its role in leucine signaling. The proposed studies will elucidate how leucine regulates mTOR and the roles of leucine stimulation of mTOR in adipose tissue physiology and obesity.