Abstract
The 5′‐AMP‐activated protein kinase (AMPK) is a key regulator of energy homeostasis. Pharmacologic activation of AMPK is beneficial in treating metabolic disorders and improving exercise endurance. We previously identified small molecule AMPK activators that improved glucose tolerance and running endurance. These compounds reduced cellular oxygen consumption and increased AMP/ATP and ADP/ATP ratios, demonstrating that AMPK activation is due to a change in energy status which results from altered mitochondrial respiration. Further biochemical studies showed that the target appeared to be mitochondrial complex I. In vivo metabolite profiling indicated that there was an up‐regulation of fatty acid oxidation, ketogenesis and catabolism of branched chain amino acids in the compound‐treated mice. The up‐regulation in fatty acid catabolism was supported by a clear reduction of fat pads in treated mice. Furthermore, UCP1 protein expression was increased in the white adipose tissues. Taken together, our results demonstrate beneficial outcomes by AMPK activation through mitochondrial regulation. These studies should help to provide a molecular understanding for the physiological effects of AMPK activation and for the therapeutic applications of AMPK activators.
Published Version
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