Glucolipotoxicity and Cardiac Dysfunction in Obesity

肥胖症中的糖脂毒性和心脏功能障碍

• 批准号: 6602591
• 负责人: HEINRICH TAEGTMEYER
• 金额: $ 43.81万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6602591
• 关键词: adipocytes; biological signal transduction; cardiovascular disorder; clinical research; cytotoxicity; dietary lipid; enzyme activity; fatty acid metabolism; gene expression; glucose; histology; human subject; intracellular; laboratory rat; nutrient intake activity; nutrition related tag; obesity; polymerase chain reaction; protein kinase C; stomach /intestine bypass

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.

描述（由申请人提供）：关于肥胖蔓延的惊人统计数据包括心血管疾病导致的过早死亡的增加。然而，过度营养对心脏的影响还没有得到很好的理解。因此，我们建议研究肥胖在心脏中的“分子足迹”，并在动物模型和接受胃旁路手术的临床肥胖患者中确定导致心功能受损的机制。特别强调的是对心肌的后果紊乱的葡萄糖和脂肪酸代谢导致的心肌病的肥胖，是潜在的可逆。本提案的主要目的是验证以下假设：葡萄糖和脂肪酸代谢物的异常积累是由于底物摄取和氧化同步的丧失，引起糖脂毒性，并导致心脏收缩功能障碍。第一个具体目标将定义过量的燃料供应（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）积累的过程。在遗传和饮食诱导的肥胖大鼠模型中，我们将定义适应和不适应过量底物的时间过程。我们还将定义通过食物限制或手术干预（胃旁路）逆转肥胖引起的变化的时间过程。第二个具体目标将探讨心脏和骨骼肌中糖脂毒性的潜在机制。我们将检查基因表达、PKC活性、蛋白糖基化、蛋白泛素化和程序性细胞死亡。这些不同途径的选择性激活可能在糖脂毒性中起重要作用。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糖脂毒性的相关因素，并验证体重减轻逆转胃旁路手术患者适应不良反应的假设。我们将定义代谢指标（BMI、胰岛素抵抗、血压、血脂、脂肪因子水平）和心功能指标（通过超声心动图），并在手术前、手术后3个月和9个月进行骨骼肌活检。我们的长期目标是在临床相关肥胖中定义心脏的代谢适应和不适应，将糖脂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心力衰竭患者建立理论基础。