Loss of hepatic AMP-activated protein kinase impedes the rate of glycogenolysis
but not gluconeogenic fluxes in exercising mice.
Authors Hughey CC, James FD, Bracy DP, Donahue EP, Young JD, Viollet B, Foretz M,
Wasserman DH
Submitted By Submitted Externally on 1/3/2018
Status Published
Journal The Journal of biological chemistry
Year 2017
Date Published 12/1/2017
Volume : Pages 292 : 20125 - 20140
PubMed Reference 29038293
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 a1 and a2 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 AMPKa1a2 is required for maintaining glucose homeostasis
during an acute bout of exercise.