AMPK is an energy sensor that protects cellular energy state by attenuating anabolic and promoting catabolic processes. AMPK signaling is purported to regulate hepatic gluconeogenesis and substrate oxidation; coordination of these processes is vital during nutrient deprivation or pathogenic during overnutrition. Here we directly test hepatic AMPK function in regulating metabolic fluxes that converge to produce glucose and energy in vivo. Flux analysis was applied in mice with a liver-specific deletion of AMPK (L-KO) or floxed control litter-mates to assess rates of hepatic glucose producing and citric acid cycle (CAC) fluxes. Fluxes were assessed in short and long term fasted mice; the latter condition is a nutrient stressor that increases liver AMP/ATP. The flux circuit connecting anaplerosis with gluconeogenesis from the CAC was unaffected by hepatic AMPK deletion in short and long term fasting. Nevertheless, depletion of hepatic ATP was exacerbated in L-KO mice, corresponding to a relative elevation in citrate synthase flux and accumulation of branched-chain amino acid-related metabolites. L-KO mice also had a physiological reduction in flux from glycogen to G6P. These results demonstrate AMPK is unnecessary for maintaining gluconeogenic flux from the CAC yet is critical for stabilizing liver energy state during nutrient deprivation.
Bibliographical noteFunding Information:
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases through grant numbers DK050277, DK059637, DK07563 and DK020593. This work was also supported by the Canadian Diabetes Association through grant PF-3-14-4687-CH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2017 Hasenour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.