Acute and chronic effects of AMPK activation on skeletal muscle fatty acid and carbohydrate metabolism
AMP-activated protein kinase (AMPK) has been proposed to be an important energy-sensing enzyme, responding to increases in the AMP:ATP and Cr:PCr ratio. However, AMPK regulation of fatty acid (FA) metabolism and glucose oxidation is not completely understood. There is controversy regarding the effects of AMPK activation on fat-carbohydrate substrate selection and the role that AMPK plays in regulating the use of endogenous triacylglycerol (TAG) stores. It was hypothesized that an AICAR-induced decrease in glucose oxidation would be secondary to stimulation of FA oxidation occurring with adequate FA availability, and therefore inhibit TAG hydrolysis. In order to gain further insight into the role of AMPK in the regulation of substrate use during contraction, the second set of acute studies examined the regulatory role that AICAR activation of AMPK may be playing with tetanic contraction, specifically whether AICAR would increase AMPK activation above the threshold set by high intensity tetanic contraction and therefore see further increased rates of substrate oxidation. Acute AICAR treatment in isolated skeletal muscle activated AMPK[alpha]2 and simultaneously increased FA and glucose oxidation, while having no effects on intramuscular TAG metabolism, regardless of FA availability. Pyruvate dehydrogenase was also activated by AICAR, supporting the effects on glucose oxidation. AMPK[alpha]2 was activated by contraction and was further activated by the combination of AICAR and contraction. This led to further stimulation of FA oxidation, but inhibited TAG hydrolysis, suggesting that FA metabolism is very sensitive to AMPK activation. The already maximal rates of glucose oxidation were not further increased by AICAR. Based on the above results, we hypothesized that 8 weeks of metformin and/or exercise (AMPK activators) would have insulin-sensitizing effects and prevent the progression of diabetes in the high-fat fed female Zucker diabetic fatty (ZDF) rat, an inducible model of diabetes. Metformin and exercise prevented the progression of diabetes, primarily by reducing plasma membrane-associated fatty acid translocase expression (FAT/CD36) and reducing the content of reactive lipid intermediates (DAG, ceramide) postulated to interfere with the insulin-signaling pathway in skeletal muscle. FA oxidation was unaffected by these treatments. Therefore, increasing FA oxidation in skeletal muscle may not be necessary and reducing FA transporters and reactive lipid species may be an important contributor in preventing diabetes.