The role of GLP-1 in cardiac recovery after bariatric surgery in obesity-induced heart failure

项目摘要 肥胖性心肌病是一种日益流行和病态的心肌细胞疾病，引起 严重肥胖导致的心力衰竭。即使通过节食减肥并不能改善心脏 功能、肥胖的减肥手术，如袖状胃切除术(SG)，可显著改善心脏状况 功能。SG后心脏恢复的刺激机制尚不清楚。该项目将探索 心脏高血糖素样多肽-1受体(GLP-1R)信号转导导致细胞活化的新假说 核受体过氧化物酶体增殖物激活受体α(PPARα)导致心脏功能改善 功能。申请人发现，在肥胖大鼠身上进行SG显著改善了心功能， 与体重减轻无关，与血清GLP-1升高、心脏PPARα升高和降低相关 心肌细胞凋亡、纤维化和底物利用的变化。这项提案的具体目标将考验 心脏GLP-1R刺激激活PPARα导致代谢应激诱导的减少的假说 细胞凋亡、纤维化和β氧化增加是SG后心脏恢复的机制。本奖项 将对心血管病理生理学、心肌细胞内信号转导有详细的了解 申请人所需的途径、生化和心功能分析。此外，这项提议还允许 严格的培训计划，以获得成为一名成功的独立调查员所需的技能 科比特博士和咨询委员会的指导。这个有指导的职业生涯的主要目标是 发展奖是确定减肥手术后改善心功能的机制和 通过调查员发起的R01资金，进行必要的初步研究，以实现外部支持 美国国立卫生研究院。长期的科学目标是了解肥胖者之间相互作用的机制。 手术、肥胖和心力衰竭，并将这些发现转化为手术和非手术代谢 干预措施。威斯康星医学院(MCW)为翻译提供了良好的环境 心血管研究。MCW心血管中心和临床与翻译科学研究所提供 出色的核心资源和强大的协作环境，以成功开展拟议的研究 并制定强有力的独立调查路线。

Project Summary Obesity cardiomyopathy is an increasingly prevalent and morbid disease of myocyte dysfunction causing heart failure due to severe obesity. Even though weight reduction through dieting fails to improve cardiac function, obesity treatment with bariatric surgery, like a sleeve gastrectomy (SG), significantly improves cardiac function. The inciting mechanisms for cardiac recovery after SG are poorly understood. This project will explore the novel hypothesis that cardiac glucagon-like peptide-1 receptor (GLP-1R) signaling results in the activation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARα), resulting in improved cardiac function. The applicant has found that a SG performed in obese rats significantly improved cardiac function, independent of weight loss, associated with increased serum GLP-1, increased cardiac PPARα, and decreased cardiac apoptosis, fibrosis and changes in substrate utilization. The specific aims of this proposal will test the hypothesis that cardiac GLP-1R stimulation activates PPARα resulting in decreased metabolic stress-induced apoptosis, fibrosis and increased β-oxidation and is the mechanism for cardiac recovery after SG. This award will produce a detailed understanding of cardiovascular pathophysiology, myocyte intracellular signaling pathways, biochemistry, and cardiac function analysis needed by the applicant. Further, this proposal allows for a rigorous training program to acquire the skills necessary to become a successful independent investigator with the mentorship of Dr. Corbett and the advisory committee. The primary goal of this mentored career development award is to determine the mechanisms for improved cardiac function after bariatric surgery and produce the preliminary studies needed to achieve extramural support via investigator initiated R01 funding by the NIH. The long-term scientific objective is to understand the mechanisms of interaction between bariatric surgery, obesity, and heart failure and translate these findings into surgical and non-surgical metabolic interventions. The Medical College of Wisconsin (MCW) provides an excellent environment for translational cardiovascular research. MCW's Cardiovascular Center and Clinical and Translational Science Institute provide excellent core resources and a strong collaborative environment to successfully perform the proposed studies and develop strong independent lines of investigation.