Obesity and type 2 diabetes (T2D) are epidemics in the U.S. and abroad. A better understanding ofthe mechanisms that promote obesity and induce T2D is urgently needed to stem the tide of these epidemics and to control their cardiovascular complications. We suggest that endothelial dysfunction induced by nutrient excess is the primary cause that leads to metabolic changes resulting in an increase in adiposity and whole-body insulin resistance. Our studies show that overexpression of eNOS in mice prevents diet-induced obesity. These changes are accompanied by systemic and adipose tissue-specific changes in metabolism. Our metabolomic analyses indicate that eNOS over expression increases the abundance of circulating bile acids, which have been shown to be potent effectors of metabolism and regulators of adipose tissue phenotype. Nevertheless, we do not know how NO regulates bile acid production or which metabolic pathways triggered by bile acids are responsible for the lean phenotype of eNOS-TG mice. Therefore, we will test the hypothesis that NO exerts an anti-obesogenic effect by regulating bile acid metabolism, which promotes the development of adipocytes into a novel "lean" phenotype characterized by high mitochondrial content and fat burning capacity. To test this hypothesis, we will: (1) Examine the effects of NO on diet induced obesity;(2) Determine how NO regulates metabolism;and (3) Elucidate the mechanisms regulating adipocyte phenotype. The experimental approaches in these aims will test whether NO directly regulates obesity and whether the anti-obesity effects of NO are mediated through the ability of eNOS to increase bile acid production and to regulate adipose tissue phenotype. The results of these studies will develop a strong platform for constructing a competitive ROI application and will lead to a new understanding of the role of NO in regulating the metabolic changes that contribute to diabetes and obesity. These studies could lay the groundwork for the development of novel therapeutic interventions to prevent, manage or reverse obesity and insulin resistance.

Public Health Relevance

Obesity and diabetes are emerging epidemics in the US and Europe. In this project, we will examine the mechanisms by which nitric oxide regulates metabolism, obesity and susceptibility to diet-induced diabetes. These studies could lay the groundwork for the development of novel therapeutic interventions to prevent, manage, or reverse obesity and diabetes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1-TWD-Y (C2))
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University of Louisville
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Watson, Lewis J; Long, Bethany W; DeMartino, Angelica M et al. (2014) Cardiomyocyte Ogt is essential for postnatal viability. Am J Physiol Heart Circ Physiol 306:H142-53
Conklin, Daniel J (2014) Recent developments in vascular biology. Circ Res 115:e79-82
Deng, Qipan; Becker, Lindsey; Ma, Xiaodong et al. (2014) The dichotomy of p53 regulation by noncoding RNAs. J Mol Cell Biol 6:198-205
Cummins, Timothy D; Holden, Candice R; Sansbury, Brian E et al. (2014) Metabolic remodeling of white adipose tissue in obesity. Am J Physiol Endocrinol Metab 307:E262-77
Sansbury, Brian E; Hill, Bradford G (2014) Regulation of obesity and insulin resistance by nitric oxide. Free Radic Biol Med 73:383-99
Spite, Matthew; Claria, Joan; Serhan, Charles N (2014) Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab 19:21-36
O'Toole, Timothy E; Abplanalp, Wesley; Li, Xiaohong et al. (2014) Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a. Toxicol Sci 140:271-82
Salabei, Joshua K; Gibb, Andrew A; Hill, Bradford G (2014) Comprehensive measurement of respiratory activity in permeabilized cells using extracellular flux analysis. Nat Protoc 9:421-38
Sansbury, Brian E; Hill, Bradford G (2014) Antiobesogenic role of endothelial nitric oxide synthase. Vitam Horm 96:323-46
Hong, Kyung U; Guo, Yiru; Li, Qian-Hong et al. (2014) c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS One 9:e96725

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