Role of Vascular Oxidative Stress in Obesity

血管氧化应激在肥胖中的作用

• 批准号: 8258447
• 负责人: Hua Linda Cai
• 金额: $ 49.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-24 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258447
• 关键词: Address; Adipose tissue; Age; American Heart Association; Angiotensin II; Animals; Anti-Obesity Agents; Antioxidants; Attenuated; Blood Vessels; Body Weight; Cells; Data; Development; Diabetes Mellitus; Diet; Disease; Endothelial Cells; Epidemic; Etiology; Exercise; FDA approved; Fatty acid glycerol esters; Functional disorder; Generations; Healthcare; Human; Hydrogen Peroxide; Hypertension; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interferon Type II; Interleukin-17; Lead; Measures; Mediating; Metabolic syndrome; Mitochondria; Molecular; Mus; Muscle function; Myosin Heavy Chains; NADPH Oxidase; Non obese; Obesity; Oxidative Stress; Pathogenesis; Phenotype; Physical activity; Prevalence; Production; Protein Isoforms; Public Health; Reactive Oxygen Species; Reporting; Role; Skeletal Muscle; Smooth Muscle Myocytes; Smooth Muscle Myosins; T-Lymphocyte; Tamoxifen; Testing; Vascular Smooth Muscle; Visceral; Weight; Weight Gain; Wild Type Mouse; Woman; base; cardiovascular risk factor; cost; ebselen; efficacy testing; feeding; human CYBA protein; hypercholesterolemia; innovation; insight; lipid biosynthesis; macrophage; men; mitochondrial dysfunction; new therapeutic target; obesity prevention; prevent; promoter; recombinase; research study; response; therapy development; translational study

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. PUBLIC HEALTH RELEVANCE: Obesity has become a worldwide epidemic hence a public health problem. Its etiology however has remained unclear. The current project investigates a causal role of vascular reactive oxygen species (ROS) in the development of obesity. Accomplishment of our mechanistic aims addressing this hypothesis will lead to innovative insights into pathogenesis of obesity and novel therapeutics targeting vascular ROS to prevent or regress obesity.

描述(申请人提供)：这些研究的中心焦点是从机制上检验血管活性氧物种(ROS)在诱导肥胖和胰岛素抵抗/代谢综合征中的创新作用。肥胖已经成为一种世界性的流行病。根据美国心脏协会2001年至2004年的年龄调整患病率报告，美国约有30%的男性和34%的女性肥胖。全国因肥胖造成的成本为1470亿美元，肥胖者每年在医疗保健上的支出比非肥胖者高出41%。然而，目前FDA批准的抗肥胖药物在减轻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。开发肥胖症治疗方法的一个主要问题是对其发病机制的了解不完全。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，这些疾病促进了血管ROS的产生。人们一直认为，肥胖通常是这些情况下的原因。我们认为相反的情况是正确的--即血管ROS/相关的内皮功能障碍通过促进炎症、脂肪生成和运动耐受而导致肥胖。如果这是正确的，那么减少血管ROS的措施可能在预防肥胖、胰岛素抵抗和代谢综合征方面有效。在初步实验中，我们发现，当喂食高脂饮食时，经过基因改造的血管ROS产生过多的小鼠会出现夸大肥胖和胰岛素抵抗/代谢综合征。清除ROS可以减轻这些小鼠的体重增加。在基线水平，血管ROS产生过多的小鼠也比年龄匹配的野生型对照小鼠适度但显着重。相反，缺乏血管p22Phox的小鼠没有体重增加，并且减少了对高脂肪喂养的内脏脂肪炎症。我们还发现，这些动物的自发活动减少了。我们假设，过量的血管ROS会导致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耐量不足。这也可能导致持续的肥胖。我们的初步数据表明，这可能是真的。因此，我们的初步数据有力地暗示了血管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导致这种挑衅性观察的分子机制：目标1，测试NOX衍生的血管ROS诱导肥胖和胰岛素抵抗/代谢综合征的假说；目标2，测试由血管ROS生成增加引起的肥胖依赖于炎症的假说，特别是高脂肪喂养时在脂肪组织中积聚的T细胞促进体重增加和胰岛素耐受；目标3，测试以骨骼肌氧化应激、炎症和线粒体功能障碍为特征的体力活动受损所导致的肥胖。我们预计，这些目标的实现将为研究NOX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，翻译研究可以在人类中迅速发展，以测试血管ROS减轻方法在治疗或预防肥胖症方面的有效性。 与公共卫生相关：肥胖已成为世界性流行病，因此是一个公共卫生问题。然而，其病因尚不清楚。目前的项目调查了血管活性氧物种(ROS)在肥胖发展中的因果作用。解决这一假说的机制目标的实现将导致对肥胖发病机制的创新见解，以及针对血管ROS的新疗法来预防或消退肥胖。