Pathologies including diabetes and conditions such as exercise place an unusual demand on liver energy metabolism, and this demand induces a state of energy discharge. Hepatic AMP-activated protein kinase (AMPK) has been proposed to inhibit anabolic processes such as gluconeogenesis in response to cellular energy stress. However, both AMPK activation and glucose release from the liver are increased during exercise. Here, we sought to test the role of hepatic AMPK in the regulation of in vivo glucose-producing and citric acid cycle–related fluxes during an acute bout of muscular work. We used 2H/13C metabolic flux analysis to quantify intermediary metabolism fluxes in both sedentary and treadmill-running mice. Additionally, liver-specific AMPK 1 and 2 subunit KO and WT mice were utilized. Exercise caused an increase in endogenous glucose production, glycogenolysis, and gluconeogenesis from phosphoenolpyruvate. Citric acid cycle fluxes, pyruvate cycling, anaplerosis, and cataplerosis were also elevated during this exercise. Sedentary nutrient fluxes in the postabsorptive state were comparable for the WT and KO mice. However, the increment in the endogenous rate of glucose appearance during exercise was blunted in the KO mice because of a diminished glycogenolytic flux. This lower rate of glycogenolysis was associated with lower hepatic glycogen content before the onset of exercise and prompted a reduction in arterial glucose during exercise. These results indicate that liver AMPK12 is required for maintaining glucose homeostasis during an acute bout of exercise.
Bibliographical noteFunding Information:
This work was supported by NIDDK, National Institutes of Health Grants DK050277 (to D. H. W.), DK054902 (to D. H. W.), and DK106348 (to J. D. Y.) and a Diabetes Canada Postdoctoral Fellowship (to C. C. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Acknowledgments—We thank the Vanderbilt University Mouse Metabolic Phenotyping Center for core services (supported by NIDDK, National Institutes of Health, Grant DK059637). We acknowledge the Vanderbilt Diabetes Research and Training Center (supported by NIDDK, National Institutes of Health, Grant DK020593).