Lipid handling in human skeletal muscle in relation to insulin sensitivity - effects of physical activity and fatty acids

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A sedentary lifestyle combined with increased consumption of high energy food plays a pivotal role in development of obesity, a major risk factor to develop type 2 diabetes. On the other side, regular exercise training effectively prevents the development of obesity, insulin resistance and type 2 diabetes. Interestingly, increased amounts of lipid droplets are found in skeletal muscle of both insulin resistant obese subjects and insulin sensitive endurance-trained athletes compared to lean sedentary subjects. This so called "athlete's paradox" may be explained by differential effects of physical activity and obesity on lipid handling in skeletal muscle; however the underlying mechanism is not completely understood. Using a unique human exercise intervention study (MyoGlu) as a platform, this project aims to investigate the role of SCD1 and Cidec as potential players in skeletal muscle lipid handling with a direct effect on insulin sensitivity. These targets have been identified as promising candidates because conflicting data with regard to the role of SCD1 in skeletal muscle lipid handling and insulin sensitivity have been reported, and nearly nothing is known about the role of Cidec in skeletal muscle. We will study the regulation of SCD1 and Cidec expression in different metabolic states (insulin sensitive vs. insulin resistant), and by exercise and fatty acids. For this purpose, skeletal muscle biopsies taken before and after intervention and skeletal muscle cells raised from satellite cells, that were isolated from these biopsies, will be used. For the in vitro experiments, myotubes will be subjected to electrical pulse stimulation (EPS) to induce contraction as a model of exercise and to treatment with mono-, polyunsaturated and saturated fatty acids. Furthermore, we want to compare the lipid composition of lipid droplets isolated from myotubes obtained before vs. after intervention which will provide important information on the effect of exercise on SCD1 activity. To clarify the physiological impact of SCD1 and Cidec we plan to knockdown both targets in human myotubes. Subsequently, these cells will be subjected to EPS in combination with fatty acid treatment followed by analyses of insulin sensitivity and substrate utilization. The results of this project may yield novel insights to explain why trained subjects are insulin sensitive despite high levels of intramyocellular lipids and hence may open new ways to improved preventive as well as therapeutic approaches to treat insulin resistance.