title: Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation.
abstract: 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 littermates 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Clinton M
authors.initials: CM
authors.lastname: Hasenour
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: D Emerson
authors.initials: DE
authors.lastname: Ridley
authors.affiliation: Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Hughey
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: E Patrick
authors.initials: EP
authors.lastname: Donahue
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR 8104, Paris, France.|Université Paris Descartes, Sorborne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR 8104, Paris, France.|Université Paris Descartes, Sorborne Paris Cité, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.|Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Young
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.|Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005943:Gluconeogenesis; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases