Department of Medicine, University of Melbourne, Fitzroy, Australia; St. Vincent’s Institute of Medical Research, Melbourne, Australia
Kim Loh
Department of Medicine, University of Melbourne, Fitzroy, Australia; St. Vincent’s Institute of Medical Research, Melbourne, Australia
Lisa Murray-Segal
Department of Medicine, University of Melbourne, Fitzroy, Australia; St. Vincent’s Institute of Medical Research, Melbourne, Australia
Gregory R Steinberg
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia; Department of Physiology, Monash University, Clayton, Australia; Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia
Department of Medicine, University of Melbourne, Fitzroy, Australia; St. Vincent’s Institute of Medical Research, Melbourne, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, Australia
AMP-activated protein kinase (AMPK) is a known regulator of whole-body energy homeostasis, but the downstream AMPK substrates mediating these effects are not entirely clear. AMPK inhibits fatty acid synthesis and promotes fatty acid oxidation by phosphorylation of acetyl-CoA carboxylase (ACC) 1 at Ser79 and ACC2 at Ser212. Using mice with Ser79Ala/Ser212Ala knock-in mutations (ACC DKI) we find that inhibition of ACC phosphorylation leads to reduced appetite in response to fasting or cold exposure. At sub-thermoneutral temperatures, ACC DKI mice maintain normal energy expenditure and thermogenesis, but fail to increase appetite and lose weight. We demonstrate that the ACC DKI phenotype can be mimicked in wild type mice using a ghrelin receptor antagonist and that ACC DKI mice have impaired orexigenic responses to ghrelin, indicating ACC DKI mice have a ghrelin signaling defect. These data suggest that therapeutic strategies aimed at inhibiting ACC phosphorylation may suppress appetite following metabolic stress.
