Adiponectin and Regulation of Triglyceride Metabolism

描述(申请人提供)：高甘油三酯血症是代谢综合征的主要组成部分，也是动脉粥样硬化和冠状动脉疾病的强烈风险因素。脂联素是一种脂肪源性激素，可促进胰岛素增敏，在能量代谢中发挥重要作用。然而，在肥胖患者中，脂联素基因表达和血浆脂联素浓度却矛盾地降低。高甘油三酯血症通常伴随着肥胖。此前的人类和动物研究已经清楚地表明，循环中的脂联素蛋白水平与甘油三酯浓度呈负相关，表明脂联素调节甘油三酯代谢。然而，脂联素调节甘油三酯代谢的机制在很大程度上还不清楚。我们的长期目标是阐明肥胖引起的血脂异常的潜在机制。使用腺病毒介导的体内基因转导，我们已经证明，血浆脂联素升高降低了血清甘油三酯水平，而不显著改变肝脏极低密度脂蛋白(VLDL)-甘油三酯的产生。有趣的是，血浆脂联素升高的小鼠，肝素后血浆脂蛋白脂酶(LPL)活性以及骨骼肌脂蛋白脂酶和极低密度脂蛋白受体基因的表达显著增加。LPL是极低密度脂蛋白-甘油三酯水解的限速酶，而极低密度脂蛋白受体增强了LPL的活性。我们的研究还发现，PPAR？脂联素可显著增加骨骼肌和培养肌管中共激活物-1a(PGC-1a)的表达。PGC-1a在骨骼肌线粒体生物发生和脂肪酸氧化中起着关键作用。因此，我们假设脂联素通过增加骨骼肌中VLDL-甘油三酯的分解代谢来降低血浆甘油三酯浓度，PGC-1a通过增加LPL和VLDLr基因的表达来介导脂联素的调节作用。该项目将解决两个主要的具体目标。在特定的目标1中，我们将研究脂联素刺激极低密度脂蛋白-甘油三酯分解代谢的机制以及骨骼肌脂联素和极低密度脂蛋白受体在这一调节中的作用。这将部分使用骨骼肌组织特异性LPL缺陷或VLDLr缺陷小鼠来完成。在具体目标2中，我们将使用PGC-1a缺陷小鼠模型和分子技术来确定PGC-1a介导脂联素诱导的骨骼肌极低密度脂蛋白-甘油三酯分解代谢的机制。这项研究有望揭示脂肪衍生激素脂联素如何调节脂类和脂蛋白代谢的新机制和新概念。它还将阐明在脂蛋白代谢的背景下整合脂肪和骨骼肌组织的新机制。这些研究可能导致肥胖和代谢综合征的新的预防或治疗策略，这在世界范围内造成了严重的健康问题。这项研究有望揭示一种新的机制和概念，即脂肪衍生的激素如何 脂联素调节脂质和脂蛋白代谢。它还将揭示一种新的机制，即 在脂蛋白代谢的背景下整合脂肪和骨骼肌组织。这些研究可能 为肥胖和代谢综合征带来新的预防或治疗策略，这将迫使 世界范围内存在严重的健康问题。

DESCRIPTION (provided by applicant): Hypertriglyceridemia is a major component of the metabolic syndrome and a strong risk factor for atherosclerosis and coronary artery disease. Adiponectin is an adipose-derived hormone that promotes insulin sensitization and plays an important role in energy metabolism. However, adiponectin gene expression and plasma adiponectin concentrations are paradoxically reduced in obesity. Hypertriglyceridemia usually accompanies adiposity. Previous human and animal studies have clearly shown that circulating adiponectin protein levels correlate inversely with triglyceride concentrations, indicating that adiponectin regulates triglyceride metabolism. However, the mechanism by which adiponectin regulates triglyceride metabolism is largely unknown. Our long term goal is to elucidate the underlying mechanisms of obesity-induced dyslipidemia. Using adenovirus-mediated in vivo gene transduction, we have shown that elevated plasma adiponectin reduces serum triglyceride levels without significantly changing hepatic very low density lipoprotein (VLDL)-triglyceride production. Interestingly, postheparin plasma lipoprotein lipase (LPL) activity, as well as LPL and VLDL receptor gene expression in skeletal muscle, was significantly increased in mice with elevated plasma adiponectin. LPL is a rate-limiting enzyme for VLDL-triglyceride hydrolysis, and the VLDL receptor enhances LPL activity. Our studies have also found that the expression of PPAR? co-activator-1a (PGC-1a) was robustly increased by adiponectin in both skeletal muscle and cultured myotubes. PGC-1a plays a pivotal role in skeletal muscle mitochondrial biogenesis and fatty acids oxidation. Therefore, we hypothesize that adiponectin reduces plasma triglyceride concentration by increasing VLDL-triglyceride catabolism in skeletal muscle and that PGC-1a mediates the regulatory effects of adiponectin by increasing LPL and VLDLr gene expression. This project will address two main specific aims. In specific aim 1, we will investigate the mechanism by which adiponectin stimulates VLDL-triglyceride catabolism and the roles of skeletal muscle LPL and the VLDLr in this regulation. This will be accomplished in part using skeletal muscle tissue-specific LPL deficient or VLDLr deficient mice. In specific aim 2, we will use the PGC-1a deficient mouse model and molecular techniques to determine the mechanisms by which PGC-1a mediates adiponectin-induced VLDL-triglyceride catabolism in skeletal muscle. This study is expected to reveal a new mechanism and concept about how an adipose derived hormone adiponectin regulates lipid and lipoprotein metabolism. It will also shed light on a novel mechanism that integrates adipose and skeletal muscle tissues in the context of lipoprotein metabolism. These studies may lead to new prevention or therapeutic strategies for obesity and the metabolic syndrome, which impose a serious health problem world wide. This study is expected to reveal a new mechanism and concept about how an adipose-derived hormone adiponectin regulates lipid and lipoprotein metabolism. It will also shed light on a novel mechanism that integrates adipose and skeletal muscle tissues in the context of lipoprotein metabolism. These studies may lead to new prevention or therapeutic strategies for obesity and the metabolic syndrome, which impose a serious health problem world wide.