Obesity, Adipocytokines, and Endothelial Dysfunction

描述(申请人提供)：肥胖症流行已经成为这个国家的一个主要公共卫生问题，个人前所未有地暴露在心血管风险之下。人们越来越迫切地需要了解肥胖相关心血管疾病的机制以及体重调整的有益影响。总体目标是调查肥胖、血管内皮功能障碍、脂肪细胞代谢和氧化应激之间的关系，以及减肥对这些参数的影响。血管内皮细胞通过合成和合成内皮源性一氧化氮(EDNO)等旁分泌因子来调节血管舒张性、血小板活性和炎症。在动脉粥样硬化及其相关危险因素中，内皮依赖性血管扩张和血小板抑制受到损害，可能是由于血管氧化应激增加和NO生物活性降低所致。正常血管内皮功能的丧失支持局部血管痉挛、血栓形成和促炎环境，并与包括心肌梗死、中风和不稳定心绞痛在内的心血管事件的病理生理学有关。越来越多的人认识到，脂肪组织的代谢活动可能通过释放促动脉粥样硬化因子，在血管功能障碍和心血管疾病的机制中发挥病理生理作用。以前没有研究过肥胖和减肥干预对脂肪细胞和血管内皮细胞功能的影响。本项目提出的具体目标1：确定超重或肥胖与血管内皮功能障碍的关系，具体目标2：确定减肥和危险因素修饰是否改善血管内皮功能以及氧化应激和炎症的标记物，以及具体目标3：研究脂肪组织在血管功能障碍中的代谢作用，并探讨减肥对脂肪细胞促动脉粥样硬化因子表达的影响。这些拟议的研究有可能为肥胖相关心血管疾病的机制提供重要的见解，并检查减肥是否通过脂肪细胞和血管内皮细胞功能的表型改变来调节其心脏保护作用。拟议的项目利用了波士顿医疗中心由NIH资助的肥胖研究中心(C.O.R.E)和一个紧密整合的营养和减肥中心。此外，研究人员带来了独特的专业知识组合，将极大地增强该项目解决这些重要临床问题的能力。

DESCRIPTION (provided by applicant): The obesity epidemic has become a major public health problem in this country with unprecedented exposure of individuals to cardiovascular risk. There is growing urgency to understand mechanisms of obesity-related cardiovascular disease and the beneficial effects of weight modification. The overall objective is to investigate the relationships between obesity, vascular endothelial dysfunction, adipocyte metabolism, and oxidative stress, and the effect of weight loss on these parameters. The vascular endothelium regulates vasomotor tone, platelet activity, and inflammation through the synthesis and elaboration of paracrine factors such as endothelium-derived nitric oxide (EDNO). Endothelium-dependent vasodilation and platelet inhibition are impaired in atherosclerosis and associated risk factors, possibly due to increased vascular oxidative stress and reduced NO bioactivity. Loss of normal vascular endothelial function supports a local vasospastic, prothrombotic, and proinflammatory milieu, and is linked to the pathophysiology of cardiovascular events including myocardial infarction, stroke, and unstable angina. There is growing recogition that metabolic activity of adipose tissue, through release of proatherogenic factors, may play a pathophysiologic role in mechanisms of vascular dysfunction and cardiovascular disease. No prior study has examined the effect of obesity and weight loss interventions on adipocyte and vascular endothelial function. This project proposes in specific aim 1: to characterize the relationship between overweight or obesity and vascular endothelial dysfunction, in specific aim 2: to determine whether weight reduction and risk factor modification improves vascular endothelial function and markers of oxidative stress and inflammation, and in specific aim 3: to examine the metabolic role of adipose tissue for vascular dysfunction, and investigate the effects of weight loss on adipocyte expression of proatherogenic factors. The proposed studies have the potential to provide important insights into mechanisms of obesity -associated cardiovascular disease and examine whether weight loss mediates its cardioprotective action via phenotypic modification of adipocyte and vascular endothelial function. The proposed project takes advantage of Boston Medical Center's NIH funded Center for Obesity Research (C.O.R.E) and a tightly integrated Nutrition and Weight Loss Center. In addition, the investigators bring a unique combination of expertise that will greatly enhance the project's ability to address these important clinical questions.