Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis but not gluconeogenic fluxes in exercising mice

Curtis C. Hughey, Freyja D. James, Deanna P. Bracy, E. Patrick Donahue, Jamey D. Young, Benoit Viollet, Marc Foretz, David H. Wasserman

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)20125-20140
Number of pages16
JournalJournal of Biological Chemistry
Volume292
Issue number49
DOIs
StatePublished - Dec 8 2017

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Hughey, C. C., James, F. D., Bracy, D. P., Patrick Donahue, E., Young, J. D., Viollet, B., Foretz, M., & Wasserman, D. H. (2017). Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis but not gluconeogenic fluxes in exercising mice. Journal of Biological Chemistry, 292(49), 20125-20140. https://doi.org/10.1074/jbc.M117.811547