title: Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin.
abstract: The obesity epidemic has led to an increased incidence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. AMP-activated protein kinase (Ampk) regulates energy homeostasis and is activated by cellular stress, hormones and the widely prescribed type 2 diabetes drug metformin. Ampk phosphorylates mouse acetyl-CoA carboxylase 1 (Acc1; refs. 3,4) at Ser79 and Acc2 at Ser212, inhibiting the conversion of acetyl-CoA to malonyl-CoA. The latter metabolite is a precursor in fatty acid synthesis and an allosteric inhibitor of fatty acid transport into mitochondria for oxidation. To test the physiological impact of these phosphorylation events, we generated mice with alanine knock-in mutations in both Acc1 (at Ser79) and Acc2 (at Ser212) (Acc double knock-in, AccDKI). Compared to wild-type mice, these mice have elevated lipogenesis and lower fatty acid oxidation, which contribute to the progression of insulin resistance, glucose intolerance and NAFLD, but not obesity. Notably, AccDKI mice made obese by high-fat feeding are refractory to the lipid-lowering and insulin-sensitizing effects of metformin. These findings establish that inhibitory phosphorylation of Acc by Ampk is essential for the control of lipid metabolism and, in the setting of obesity, for metformin-induced improvements in insulin action.
authors.affiliation: 1] Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, Ontario, Canada. [2] Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. [3].
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Fullerton
authors.forename: Sandra
authors.initials: S
authors.lastname: Galic
authors.forename: Katarina
authors.initials: K
authors.lastname: Marcinko
authors.forename: Sarah
authors.initials: S
authors.lastname: Sikkema
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Chen
authors.forename: Hayley M
authors.initials: HM
authors.lastname: O'Neill
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.forename: Rengasamy
authors.initials: R
authors.lastname: Palanivel
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Brien
authors.forename: D Grahame
authors.initials: DG
authors.lastname: Hardie
authors.forename: S Lance
authors.initials: SL
authors.lastname: Macaulay
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schertzer
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.forename: Bryce J
authors.initials: BJ
authors.lastname: van Denderen
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000502:physiology
chemical_list: D007328:Insulin; D008687:Metformin; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; D055372:AMP-Activated Protein Kinases; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase