Role of Vascular Oxidative Stress in Obesity

血管氧化应激在肥胖中的作用

• 批准号: 8803804
• 负责人: Hua Linda Cai
• 金额: $ 46.69万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803804
• 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; 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; endothelial dysfunction; 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.

描述（由申请人提供）：这些研究的中心焦点是从机制上研究血管活性氧（ROS）在诱导肥胖和胰岛素抵抗/代谢综合征中的创新作用。肥胖已成为一种世界性的流行病。根据2001- 2004年年龄调整的患病率报告（美国心脏协会），美国约有30%的男性和34%的女性肥胖。全国的肥胖成本为1470亿美元，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是适度有效的，要么是无效的。肥胖症治疗的一个主要问题是对其发病机制的不完全理解。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，肥胖往往是因果关系，在这些条件。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导致肥胖。如果这是正确的，那么采取措施减少血管ROS可能有效地预防肥胖，胰岛素抵抗和代谢综合征。在初步实验中，我们发现，当喂食高脂肪饮食时，经遗传改变具有过量血管ROS产生的小鼠会发展成过度肥胖和胰岛素抵抗/代谢综合征。清除ROS减弱了这些小鼠的体重增加。在基线处，具有过量血管ROS产生的小鼠也适度但显著地比年龄匹配的野生型对照小鼠重。相反，缺乏血管p22 phox的小鼠体重没有增加，并且对高脂肪喂养的内脏脂肪炎症有所减少。我们还发现这些动物的自发活动减少。我们推测，过量的血管活性氧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耐受不良。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，我们的初步数据强烈暗示了血管ROS在肥胖症的发展中的因果作用。目前的建议将通过解决以下三个目标来研究负责这一挑衅性观察的分子机制，每个目标包含3-4个子目标：目标1，验证NOX衍生的血管ROS诱导肥胖和胰岛素抵抗/代谢综合征的假设;目的2，为了验证由血管ROS生成增加引起的肥胖依赖于炎症的假设，特别是在高脂肪喂养时在脂肪组织中积累的T细胞促进体重增加和胰岛素不耐受;目的3，检验由增加的血管ROS产生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受损的身体活动介导的假设。我们预期这些目标的实现将为NOX衍生的血管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，可以在人类中快速开发转化研究，以测试血管ROS衰减方法在治疗或预防肥胖中的功效。