Role of Vascular Oxidative Stress in Obesity

描述（由申请人提供）：这些研究的中心焦点是研究血管活性氧（ROS）在诱导肥胖和胰岛素抵抗/代谢综合征中的机制创新作用。肥胖已经成为一种世界性的流行病。根据2001- 2004年年龄调整患病率报告，美国大约30%的男性和34%的女性肥胖（美国心脏协会）。全国肥胖的成本为1470亿美元，一个肥胖者每年在医疗保健上的花费比非肥胖者多41%。然而，目前fda批准的抗肥胖药物在降低体重和肥胖相关的心血管危险因素方面要么只是适度有效，要么无效。发展肥胖治疗的一个主要问题是对其发病机制的不完全了解。肥胖与高血压、高胆固醇血症和糖尿病等疾病有关。实验研究表明，这些疾病促进血管ROS的产生。人们一直认为肥胖通常是导致这些疾病的原因。我们认为事实恰恰相反，即血管ROS/相关内皮功能障碍通过促进炎症、脂肪生成和运动不耐受而导致肥胖。如果这是正确的，那么采取减少血管ROS的措施可能对预防肥胖、胰岛素抵抗和代谢综合征有效。在初步实验中，我们发现，当喂食高脂肪饮食时，基因改变后血管ROS产生过多的小鼠会出现过度肥胖和胰岛素抵抗/代谢综合征。清除活性氧减轻了这些小鼠的体重增加。在基线上，血管ROS生成过多的小鼠也比同龄野生型对照小鼠轻微但明显地重。相反，缺乏血管p22phox的小鼠体重没有增加，并且对高脂肪喂养的反应减少了内脏脂肪炎症。我们还发现这些动物的自发活动减少了。我们假设过多的血管ROS诱导骨骼肌氧化应激和线粒体功能障碍，导致肌肉功能受损和运动不耐受。这也会导致持续的肥胖。我们的初步数据表明这可能是真的。因此，我们的初步数据强烈暗示血管ROS在肥胖发展中的因果作用。目前的提案将通过解决以下三个目标来研究这一具有挑战性的观察结果的分子机制，每个目标包含3-4个子目标：目标1，验证一氧化氮来源的血管ROS诱导肥胖和胰岛素抵抗/代谢综合征的假设；目的2：验证由血管ROS生成增加引起的肥胖依赖于炎症的假设，特别是高脂肪喂养时脂肪组织中积累的T细胞促进体重增加和胰岛素不耐受的假设；目的3：验证由血管ROS生成增加引起的肥胖是由以骨骼肌氧化应激、炎症和线粒体功能障碍为特征的身体活动受损介导的假设。我们预计这些目标的实现将为氮氧化物来源的血管ROS是否以及如何诱导肥胖提供创新的机制见解。基于我们的发现，可以在人体中迅速开展转化研究，以测试血管ros衰减方法在治疗或预防肥胖方面的有效性。

DESCRIPTION (provided by applicant): The central focus of these studies is to examine mechanistically an innovative role of vascular reactive oxygen species (ROS) in inducing obesity and insulin resistance/metabolic syndrome. Obesity has become a worldwide epidemic. Approximately 30% of men and 34% of women in US are obese based on the age-adjusted prevalence report for 2001- 2004 (American Heart Association). The national cost of obesity was $147 billion, and that an obese person would spend 41% more per year on health care than non-obese people. However current FDA-approved anti-obesity drugs are either only modestly effective or ineffective in reducing body weight and obesity-associated cardiovascular risk factors. A major problem in developing therapy for obesity is an incomplete understanding of its pathogenesis. Obesity is associated with conditions like hypertension, hypercholesterolemia and diabetes. Experimental studies have shown that these diseases promote vascular ROS production. It has been thought that obesity is often causal in these conditions. We propose that the opposite is true - i.e. that vascular ROS/associated endothelial dysfunction cause obesity by promoting inflammation, adipogenesis and exercise intolerance. If this is correct, then measures taken to reduce vascular ROS might be effective in preventing obesity, insulin resistance and metabolic syndrome. In preliminary experiments we have found that mice genetically altered to have excessive vascular ROS production develop exaggerated obesity and insulin resistance/metabolic syndrome when fed high-fat diet. Scavenging of ROS attenuated weight gain in these mice. At baseline mice having excessive vascular ROS production are also modestly but significantly heavier than the age- matched wild-type control mice. Conversely, mice deficient in vascular p22phox gained no weight, and had reduced visceral fat inflammation in response to high-fat feeding. We have also found that spontaneous activity is decreased in these animals. We hypothesize that excessive vascular ROS induce skeletal muscle oxidative stress and mitochondrial dysfunction, resulting in impaired muscle function and exercise intolerance. This can also contribute to sustained obesity. Our preliminary data suggest this might be true. Therefore our preliminary data strongly implicate a causal role of vascular ROS in the development of obesity. The current proposal will investigate molecular mechanisms responsible for this provocative observation by addressing the following three aims, each of which contains 3-4 subaims: Aim 1, To test the hypothesis that NOX-derived vascular ROS induce obesity and insulin resistance/metabolic syndrome; Aim 2, To test the hypothesis that obesity caused by increased vascular ROS generation is dependent on inflammation, and specifically that T cells that accumulate in the adipose tissue upon high-fat feeding promote weight gain and insulin intolerance; Aim 3, To test the hypothesis that obesity caused by increased vascular ROS generation is mediated by impaired physical activity that is characterized by skeletal muscle oxidative stress, inflammation, and mitochondrial dysfunction. We anticipate that accomplishment of these aims would provide innovative mechanistic insights into whether and how NOX- derived vascular ROS induces obesity. Based on our findings translational studies can be rapidly developed in humans to test efficacies of vascular ROS-attenuating approaches in the treatment or prevention of obesity.