Glucolipotoxicity and Cardiac Dysfunction in Obesity

描述(由申请人提供)：关于肥胖蔓延的令人震惊的统计数据包括因心血管疾病过早死亡的增加。然而，过度营养对心脏的影响还不是很清楚。因此，我们建议研究肥胖在心脏中的“分子足迹”，并在动物模型中以及在接受胃旁路手术的临床肥胖症患者中确定导致心脏功能受损的机制。特别强调了葡萄糖和脂肪酸代谢紊乱导致肥胖心肌病的心肌后果，这种心肌病可能是可逆的。这项建议的主要目的是检验这样一种假设，即底物摄取和氧化失去同步性导致葡萄糖和脂肪酸代谢物异常积累，导致糖毒性，并导致心脏收缩功能障碍。第一个具体目标将确定过量燃料供应(超过脂肪细胞的储存能力)导致脂肪毒性化合物在心脏和其他器官(如骨骼肌)积聚的过程。在遗传和饮食诱导的肥胖大鼠模型中，我们将定义对过量底物供应的适应和不适应的时间进程。我们还将确定通过食物限制或手术干预(胃旁路手术)逆转肥胖引起的变化的时间进程。第二个具体目标将解决心脏和骨骼肌中糖脂毒性的潜在机制。我们将检测基因表达、PKC活性、蛋白质糖基化、蛋白质泛素化和细胞程序性死亡。这些不同途径的选择性激活可能在糖代谢毒性中发挥重要作用。第三个具体目标将应用从动物实验中获得的见解，以确定人类是否存在血糖毒性的相关因素，并测试减肥逆转接受胃旁路手术的患者的不良适应反应的假设。我们将在手术前、术后3个月和术后9个月，结合骨骼肌活组织检查，确定代谢指数(BMI、胰岛素抵抗、血压、血脂、脂肪因子水平)和心功能指数(通过超声心动图)。我们的长期质量是定义临床相关肥胖患者心脏的代谢适应和不适应，将糖毒性的概念从操作定义转变为具体的生理原理，并为更有效地治疗肥胖症合并心力衰竭建立理论基础。

DESCRIPTION (provided by applicant): Alarming statistics on the spread of obesity include an increase in premature death from cardiovascular disease. Yet, the effects of over-nutrition on the heart are not well understood. We therefore propose to examine the "molecular footprints" of obesity in the heart, and identify mechanisms leading to impaired cardiac function in animal models, as well as in clinically obese patients undergoing gastric bypass surgery. Special emphasis is placed on the myocardial consequences of deranged glucose and fatty acid metabolism leading to a cardiomyopathy of obesity that is potentially reversible. The broad objective of this proposal is to test the hypothesis that abnormal accumulation of ,qlucose and fatty acid metabolites resulting from a loss of synchronization of substrate uptake and oxidation, induces glucolipotoxicity, and leads to contractile dysfunction of the heart. The first specific aim will define the process by which excess fuel supply (beyond the storage capacity of adipocytes) results in accumulation of lipotoxic compounds in the heart and in other organs (e.g. skeletal muscle). In genetic and diet-induced rat models of obesity we shall define the time course of adaptation and maladaptation to excess substrate availability. We shall also define the time course of reversal of obesity-induced changes by food restriction or surgical intervention (gastric bypass). The second specific aim will address potential mechanisms of glucolipotoxicity in heart, as well as in skeletal muscle. We shall examine gene expression, PKC activity, protein glycosylation, protein ubiquitinization, and programmed cell death. Selective activation of these different pathways may play a significant role in glucolipotoxicity. The third specific aim will apply insights gained from animal experiments to ascertain whether correlates of glucolipotoxicity exist in humans and test the hypothesis that weight loss reverses the maladaptive response in patients undergoing gastric bypass. We will define metabolic indices (BMI, insulin resistance, blood pressure, lipid profile, adipokine levels) and indices of cardiac function (by echocardiography) in tandem with skeletal muscle biopsies before, as well as three and nine months after surgery. Our Iong-term qoals are to define metabolic adaptation and maladaptation of the heart in clinically-relevant obesity, to transform the concept of glucolipotoxicity from an operational definition to a concrete physiological principle, and to establish a rationale for more effective treatment of obese patients with heart failure.