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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-J (02))
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Mcdonald, Cheryl
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Bouhidel, Jalaleddinne Omar; Wang, Ping; Siu, Kin Lung et al. (2015) Netrin-1 improves post-injury cardiac function in vivo via DCC/NO-dependent preservation of mitochondrial integrity, while attenuating autophagy. Biochim Biophys Acta 1852:277-89
Siu, Kin Lung; Lotz, Christopher; Ping, Peipei et al. (2015) Netrin-1 abrogates ischemia/reperfusion-induced cardiac mitochondrial dysfunction via nitric oxide-dependent attenuation of NOX4 activation and recoupling of NOS. J Mol Cell Cardiol 78:174-85
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