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.

Public Health Relevance

STATEMENT The prevalence of obesity is increasing by alarming proportions in the United States and worldwide. A classic feature of obesity is vascular insulin resistance, which can precede overt vascular dysfunction and represent an early contributor to vascular disease. The goal of the proposed research is to increase understanding of the mechanisms by which obesity leads to impaired insulin-stimulated dilation in skeletal muscle arterioles, thus contributing to compromised glucose homeostasis. This career development award to promote faculty diversity will enable the incorporation of new experimental tools into my research to expedite my readiness for successful competition as an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL125503-03
Application #
9178082
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Wang, Wayne C
Project Start
2014-11-15
Project End
2018-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Nutrition
Type
Sch of Home Econ/Human Ecology
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Winn, Nathan C; Vieira-Potter, Victoria J; Gastecki, Michelle L et al. (2017) Loss of UCP1 exacerbates Western diet-induced glycemic dysregulation independent of changes in body weight in female mice. Am J Physiol Regul Integr Comp Physiol 312:R74-R84
Padilla, Jaume; Thorne, Pamela K; Martin, Jeffrey S et al. (2017) Transcriptomic effects of metformin in skeletal muscle arteries of obese insulin-resistant rats. Exp Biol Med (Maywood) 242:617-624
Padilla, Jaume; Fadel, Paul J (2017) Prolonged sitting leg vasculopathy: contributing factors and clinical implications. Am J Physiol Heart Circ Physiol 313:H722-H728
Winn, Nathan C; Grunewald, Zachary I; Gastecki, Michelle L et al. (2017) Deletion of UCP1 enhances ex vivo aortic vasomotor function in female but not male mice despite similar susceptibility to metabolic dysfunction. Am J Physiol Endocrinol Metab 313:E402-E412
Manrique-Acevedo, Camila; Ramirez-Perez, Francisco I; Padilla, Jaume et al. (2017) Absence of Endothelial ER? Results in Arterial Remodeling and Decreased Stiffness in Western Diet-Fed Male Mice. Endocrinology 158:1875-1885
Restaino, Robert M; Deo, Shekhar H; Parrish, Alan R et al. (2017) Increased monocyte-derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress. Exp Physiol 102:139-153
Porter, Jay W; Rowles 3rd, Joe L; Fletcher, Justin A et al. (2017) Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21. J Endocrinol 235:97-109
Teixeira, André L; Padilla, Jaume; Vianna, Lauro C (2017) Impaired popliteal artery flow-mediated dilation caused by reduced daily physical activity is prevented by increased shear stress. J Appl Physiol (1985) 123:49-54
Lastra, Guido; Manrique, Camila; Jia, Guanghong et al. (2017) Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice. Am J Physiol Regul Integr Comp Physiol 313:R67-R77
Morishima, Takuma; Restaino, Robert M; Walsh, Lauren K et al. (2017) Prior exercise and standing as strategies to circumvent sitting-induced leg endothelial dysfunction. Clin Sci (Lond) 131:1045-1053

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