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Glucose uptake and fatty acid oxidation by isolated skeletal muscle cells are known to be regulated, at least in part, by the AMP kinase (AMPK). We have confirmed that both glucose uptake and fatty acid oxidation by L6 cells were stimulated by the AMP analog, AICAR. These processes were also stimulated in these cells by adiponectin, believed to act in a slightly different way to AICAR in that the adiponectin need not directly alter AMP concentrations. We observed no additivity between AICAR and adiponectin. Two other tests of allosteric alteration of AMPK were examined: the deletion of adenylate kinase (known to prevent contraction-induced AMPK activation), and the addition of creatine (reported to activate AMPK presumably through alteration in creatine, creatine phosphate, or AMP). Knockdown of adenylate kinase by siRNA did not affect the ability of adiponectin to stimulate glucose transport. Addition of creatine affected neither glucose transport nor fatty acid oxidation, but did decrease the formation of lactate. Moreover, creatine supplementation did not affect the phosphorylation state of AMPK. We conclude that AMPK can be regulated separately by either increases in AMP levels, or by direct phosphorylation by an AMPK kinase. In contrast, the evidence suggests that creatine phosphate levels may not be regulators of AMP kinase in intact cells. [ABSTRACT FROM AUTHOR]