The overall goal of this research program is to investigate the obesity-related changes in microvascular function that initiate the cardiovascular disease process. The growing population of obese adults is predicted to create a large public health burden in the next few decades. Skeletal muscle accounts for the majority of peripheral resistance and glucose uptake in humans. Decreased muscle vasodilation likely contributes to hypertension and sets the stage for hyperglycemia-both hallmarks of metabolic syndrome and diabetes. Thus, low muscle blood flow in obese humans may contribute to reduced exercise capacity-this in turn sets the stage for development of long-term cardiovascular diseases like diabetes. We propose to study younger obese """"""""metabolically health"""""""" adults (18-35 yrs), without confounding effects of age, metabolic syndrome, or diabetes- before the negative effects of obesity can exert their full negative impact. The general hypothesis is that obesity impairs endothelium dependent dilation (EDD) and exercise vasodilation via increased reactive oxygen species (ROS) and reductions in vasodilator signals and increased vasoconstrictor signals. Our preliminary data suggest young obese adults exhibit reduced EDD and exercise vasodilation, and acute ROS scavenging improves both. We will test our hypotheses by arterial drug infusion to test EDD mechanisms in lean and obese humans. We will use similar approaches to test vascular mechanisms controlling blood flow during dynamic exercise. Next, we will test EDD and exercise vascular responses before and after a diet and exercise intervention, where we can parcel out whether physical activity or weight loss plays a larger role in vascular improvements. Finally, we will sample artery endothelial cells from these same subjects to identify molecular pathways that change with obesity as potential therapeutic targets. These studies integrate physiologic, pharmacologic, and molecular approaches to test our hypotheses. We have several exciting preliminary findings that support our hypotheses, and have designed a complementary set of Aims the will soundly address our research questions. A multi-disciplinary, state-of-the-art approach will be used to pursue these aims, which will provide fundamental mechanistic understanding of EDD and exercise mechanisms responsible for reduced blood flow in obese humans. Our novel findings will guide the development of novel therapeutic strategies for obesity and other diseases, including obstructive sleep apnea, metabolic syndrome and diabetes.

Public Health Relevance

Obese adults exhibit poor exercise capacity which reduces quality of life and increases cardiovascular risk. The goal of this application is to understand the contribution of impaired blood vessel function to poor blood flow and increased cardiovascular risk in obese adults. The findings of how obesity changes blood vessel function and exercise responses will provide ideas on how to limit disease progression, or improve function, in an effort to restore the quality of life of obese adults-as well as other patients with obesity-related diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Reid, Diane M
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University of Wisconsin Madison
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Limberg, Jacqueline K; Malterer, Katherine R; Mikhail Kellawan, J et al. (2017) Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans. Eur J Appl Physiol 117:237-246
Limberg, Jacqueline K; Johansson, Rebecca E; Peltonen, Garrett L et al. (2016) ?-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase. Am J Physiol Heart Circ Physiol 310:H756-64
Limberg, Jacqueline K; Morgan, Barbara J; Schrage, William G (2016) Peripheral Blood Flow Regulation in Human Obesity and Metabolic Syndrome. Exerc Sport Sci Rev 44:116-22
Kellawan, J Mikhail; Johansson, Rebecca E; Harrell, John W et al. (2015) Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase. Eur J Appl Physiol 115:1735-46
Limberg, Jacqueline; Morgan, Barbara; Schrage, William (2014) Mechanical and metabolic reflex activation of the sympathetic nervous system in younger adults with metabolic syndrome. Auton Neurosci 183:100-5
Harrell, John W; Schrage, William G (2014) Cyclooxygenase-derived vasoconstriction restrains hypoxia-mediated cerebral vasodilation in young adults with metabolic syndrome. Am J Physiol Heart Circ Physiol 306:H261-9
Limberg, Jacqueline K; Kellawan, J Mikhail; Harrell, John W et al. (2014) Exercise-mediated vasodilation in human obesity and metabolic syndrome: effect of acute ascorbic acid infusion. Am J Physiol Heart Circ Physiol 307:H840-7
Limberg, Jacqueline K; Johansson, Rebecca E; McBride, Patrick E et al. (2014) Increased leg blood flow and improved femoral artery shear patterns in metabolic syndrome after a diet and exercise programme. Clin Physiol Funct Imaging 34:282-9
Limberg, Jacqueline K; Morgan, Barbara J; Sebranek, Joshua J et al. (2014) Neural control of blood flow during exercise in human metabolic syndrome. Exp Physiol 99:1191-202
Limberg, Jacqueline K; Morgan, Barbara J; Schrage, William G et al. (2013) Respiratory influences on muscle sympathetic nerve activity and vascular conductance in the steady state. Am J Physiol Heart Circ Physiol 304:H1615-23

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