Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR

Previous studies have shown that 5-aminoimidazole-4-carboxamide ribonucleos ide (AICAR), a cell-permeable activator of AMP-activated protein kinase, in creases the rate of fatty acid oxidation in skeletal muscle of fed rats. Th e present study investigated the mechanism by which this occurs and, in par ticular, whether changes in the activity of malonyl-CoA decarboxylase (MCD) and the beta -isoform of acetyl-CoA carboxylase (ACC beta) are involved. I n addition, the relationship between changes in fatty acid oxidation induce d by AICAR and its effects on glucose uptake and metabolism was examined. I n incubated soleus muscles isolated from fed rats, AICAR (2 mM) increased f atty acid oxidation (90%) and decreased ACC beta activity (40%) and malonyl -CoA concentration (50%); however, MCD activity was not significantly alter ed. In soleus muscles from overnight-fasted rats, AICAR decreased ACC beta activity (40%), as it did in fed rats; however, it had no effect on the alr eady high rate of fatty acid oxidation or the low malonyl-CoA concentration . In keeping with its effect on fatty acid oxidation, AICAR decreased gluco se oxidation by 44% in fed rats but did not decrease glucose oxidation in f asted rats. It had no effect on glucose oxidation when fatty acid oxidation was inhibited by 2-bromopalmitate. Surprisingly, AICAR did not significant ly increase glucose uptake or assayable AMP-activated protein kinase activi ty in incubated soleus muscles from fed or fasted rats. These results indic ate that, in incubated rat soleus muscle, 1) AICAR does not activate MCD or stimulate glucose uptake as it does in extensor digitorum longus and epitr ochlearis muscles, 2) the ability of AICAR to increase fatty acid oxidation and diminish glucose oxidation and malonyl-CoA concentration is dependent on the nutritional status of the rat, and 3) the ability of AICAR to dimini sh assayable ACC activity is independent of nutritional state.