Exercise Regulation of Mitochondrial Function and Insulin Resistance in Obesity

초록

The development of insulin resistance (IR), particularly in skeletal muscle (a major organ of insulin-mediated glucose disposal), is closely associated with obesity and type II diabetes. Mitochondria are involved in energy metabolism and apoptosis regulation, and mitochondrial dysfunction is central to the pathogenesis of multiple diseases, including obesity, diabetes, aging, and cancer. Mitochondrial reactive oxygen species (ROS), a byproduct of mitochondrial oxidative phosphorylation, has been also implicated in insulin resistance in skeletal muscle. We found that high fat diet (HFD)-induced mitochondrial H2O2 emission was a primary factor linking excess fat intake to the development of IR in skeletal muscle. Mitochondrial ROS production is favored when cellular substrate supply (e.g., HFD) is high and energy demand (e.g., exercise) is low, and vice versa. Mitigating HFD-induced H2O2 emission may be a potential strategy to treat and/or prevent IR in obesity. The objective of this study was to determine if a daily mild increase in energy expenditure by exercise is sufficient to prevent the increase in skeletal muscle mitochondrial H2O2 emitting potential, and the decrease in insulin sensitivity induced by HFD in rodents. Young male Sprague-Dawley rats (3groups, n=10/ group) were fed a standard chow or high fat diet (60% of total calorie from fat) for seven weeks. The animals given HFD were also administered by low intensity exercise (treadmill, 15m/min, 0grade, 2h/d, 7d/wk, 7wks). Insulin resistance by oral glucose tolerance test (2g/kg) was elevated in HFD-fed rats. However, exercise preserved whole body insulin sensitivity. The mitochondrial respiratory capacity in permeabilized skeletal muscle fibers was not affected by HFD and exercise. Exercise attenuated HFD-induced mitochondrial H2O2 emitting potential challenged by succinate (complex II substrate) and multiple substrates in permeabilized skeletal muscle fibers. These data demonstrate that a dai