Vascular Insulin Resistance in Obesity: Role of Endoplasmic Reticulum Stress

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DESCRIPTION (provided by applicant): My long-term career goal is to develop an independent, funded research program that contributes to understanding the mechanisms by which obesity and type 2 diabetes lead to impaired vascular insulin signaling and cardiovascular disease. In obesity, insulin-stimulated blood flow to skeletal muscle is limited and this attenuate glucose uptake, thus contributing to impaired glucose homeostasis. However, the mechanism by which insulin-induced vasodilation becomes impaired is largely unknown. The proposed study will test the hypothesis that endoplasmic reticulum (ER) stress mediates the impairment in insulin-stimulated vasodilation in skeletal muscle arterioles. It is reasoned that vascular ER stress and vascular insulin resistance caused by obesity is attributable to the local secretion of inflammatory cytokines by perivascular adipose tissue (PVAT). Using a well-established pig model of Western diet-induced obesity, Aim 1 will test if obesity-associated vascular ER stress underlies the imbalance between nitric oxide and endothlein-1 leading to impaired insulin- stimulated vasodilation. Aim 2 will then determine if obese skeletal muscle PVAT can cause vascular ER stress, thus contributing to impaired insulin-stimulated vasodilation. Finally, Aim 3 will examine whether in vivo genetic and chemical enhancement of ER function can restore impaired insulin-stimulated vasodilation associated with obesity. The contribution of this proposed work in pigs is significant as targeting ER stress may be a novel therapeutic strategy to correct vascular insulin resistance and ultimately prevent/treat metabolic and cardiovascular disease fueled by obesity. The University of Missouri (MU) campus has a distinguished history of research in cardiovascular science, metabolism, and exercise physiology and is the home for the Life Sciences Center, the Dalton Cardiovascular Research Center, the Health Activity Center, the Diabetes and Cardiovascular Center, the National Swine Resource & Research Center as resources for this project. These centers are filled with faculty from multiple departments and divisions that actively collaborate, providing an unparalleled research environment to pursue my independent research. Indeed, I will be interacting with a large number of senior investigators who will not only help ensure successful completion of the proposed studies, but also facilitate my career development as I progress toward becoming a successful independent investigator. James R. Sowers, MD, will be my primary mentor and Frank W. Booth, PhD will act as my co-mentor. Dr. Sowers is a clinical physician as well as a researcher with expertise in vascular insulin actions and cardiometabolic disease. Dr. Booth has expertise in adipose tissue biology and physical activity. Together, we have assembled a comprehensive research training plan and team of collaborators that will facilitate the acquisition of new molecular techniques (i.e., in vivo adenoviral transfection, proteomics) as well as techniques involving in vitro preparations of isolated intact arterioles to enhance my abilities to conduct mechanistic research. These additional skills combined with my earlier background in human vascular research will contribute to my long-term goal of establishing a research program with capabilities to conduct in vitro and in vivo mechanistic and translational research using animal models of obesity/type 2 diabetes as well as human patients. In short, the additional technical, academic, and career development afforded by my training plan will place me in an ideal position to successfully launch a productive, independent and translational research program. This NIH K01 application represents the next logical step in my career development as a young early investigator and will set the stage for my first R01 application. (End of Abstract)