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Obesity, exercise, ROS, and local blood flow control
During exercise, increased muscle metabolism leads to arteriolar dilation in working muscles (functional vasodilation) such that the oxygen supply and consumption is tightly linked. Obese humans have an impaired functional vasodilation and exercise capacity, which hinders obese individuals from adequate exercise training. The mechanisms underlying this impaired functional vasodilation in obesity are unclear.
Obesity is characterized by insulin resistance, hyperglycemia, and resultant increase in reactive oxygen species (ROS), with these abnormalities leading to impaired vascular smooth muscle cell (VSMC) and endothelium function. We have shown that obese Zucker rats (OZR), a model of obesity, exhibit an impaired functional vasodilation along with decreased exercise capacity, consistent with clinical observations in obese humans. Reduction of ROS reverses the impaired functional vasodilation in the OZR. Our current study is focusing on the mechanism by which the elevated ROS impair functional vasodilation in obesity has not been thoroughly determined.
Prostacyclin (PGI2) release from endothelium and subsequent activation of KATP channels in VSMCs play important roles in mediating functional vasodilation. We have shown that PGI2 receptor (IP) sensitivity and KATP channel activity are reduced in the OZR. In addition, we also showed that PGI2 synthesis is impaired in OZR. My preliminary data show that inhibiting ROS in OZR increases functional vasodilation due to increased KATP channel activity. These results suggest that ROS impair functional vasodilation in OZR due to decreased PGI2 production/responses and/or impaired KATP channel activity.
Exercise training is an important non-pharmacological treatment for obesity. Our recent published study shows that exercise training improves functional vasodilation in non-exercising muscle (cremaster) of OZR but not of lean Zucker rats (LZR). In addition, this study shows that exercise training increases functional vasodilation in OZR associated with improved metabolic factor(s) that is present in obesity. We currently is working on whether this beneficial effect of exercise training in obesity is due to decreased ROS and resultant enhancement of the PGI2/KATP pathway.
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