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.
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.
|Barnett, Rebecca Elise; Conklin, Daniel J; Ryan, Lindsey et al. (2016) Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis. J Leukoc Biol 99:361-71|
|Khan, Abdur Rahman; Farid, Talha A; Pathan, Asif et al. (2016) Impact of Cell Therapy on Myocardial Perfusion and Cardiovascular Outcomes in Patients With Angina Refractory to Medical Therapy: A Systematic Review and Meta-Analysis. Circ Res 118:984-93|
|Salabei, Joshua K; Lorkiewicz, Pawel K; Mehra, Parul et al. (2016) Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells. J Biol Chem 291:13634-48|
|DeFilippis, Andrew P; Chernyavskiy, Ilya; Amraotkar, Alok R et al. (2016) Circulating levels of plasminogen and oxidized phospholipids bound to plasminogen distinguish between atherothrombotic and non-atherothrombotic myocardial infarction. J Thromb Thrombolysis 42:61-76|
|Conklin, Daniel J; Haberzettl, Petra; Jagatheesan, Ganapathy et al. (2016) Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein. Toxicol Appl Pharmacol :|
|Conklin, Daniel J (2016) Acute cardiopulmonary toxicity of inhaled aldehydes: role of TRPA1. Ann N Y Acad Sci 1374:59-67|
|Finch, Jordan; Conklin, Daniel J (2016) Air Pollution-Induced Vascular Dysfunction: Potential Role of Endothelin-1 (ET-1) System. Cardiovasc Toxicol 16:260-75|
|Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni et al. (2016) Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis. Am J Physiol Heart Circ Physiol 310:H1423-38|
|(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Zhang, Michael J; Sansbury, Brian E; Hellmann, Jason et al. (2016) Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation. Circulation 134:666-80|
Showing the most recent 10 out of 64 publications