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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105820-02
Application #
8323220
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Reid, Diane M
Project Start
2011-09-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$523,540
Indirect Cost
$167,080
Name
University of Wisconsin Madison
Department
Miscellaneous
Type
Schools of Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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; 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; 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; Harrell, John W; Johansson, Rebecca E et al. (2013) Microvascular function in younger adults with obesity and metabolic syndrome: role of oxidative stress. Am J Physiol Heart Circ Physiol 305:H1230-7
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