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Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin

Nature Medicine volume 19, pages 1649–1654 (2013)Cite this article

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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 metformin1,2. 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 synthesis5 and an allosteric inhibitor of fatty acid transport into mitochondria for oxidation6. 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.

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Figure 1: Acc1 Ser79 and Acc2 Ser212 are essential for inhibiting enzyme activity and regulating liver fatty acid metabolism.
Figure 2: AccDKI mice fed a control diet are glucose intolerant and have hepatic insulin resistance.
Figure 3: Metformin improves hepatic lipid metabolism via inhibition of Acc.
Figure 4: HFD-fed AccDKI mice are insensitive to metformin-induced improvements in liver insulin sensitivity.

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Acknowledgements

We thank C. Saab from the McMaster Centre for Translational Imaging for completing the computed tomography analysis and S. Stypa and E. Day for technical assistance. This study was supported by grants and fellowships from the Australian Research Council and the Commonwealth Scientific and Industrial Research Organisation (B.E.K.), the Australian National Health and Medical Research Council (B.E.K., B.J.v.D. and G.R.S.), the Canadian Diabetes Association (G.R.S., J.R.B.D. and J.D.S.) and the Canadian Institutes of Health Research (CIHR) (G.R.S. and J.R.B.D.) and was supported in part by the Victorian Government Operational Infrastructure Support Program (B.E.K.) and the Canadian Foundation for Innovation (G.R.S.). M.D.F. is supported by a CIHR Banting Postdoctoral Fellowship, J.D.S. is supported by a Canadian Diabetes Association Scholar Award and G.R.S. holds a Canada Research Chair in Metabolism and Obesity.

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Author notes

  1. Morgan D Fullerton and Sandra Galic: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, Ontario, Canada

    Morgan D Fullerton, Katarina Marcinko, Sarah Sikkema, Hayley M O'Neill, Rebecca J Ford, Rengasamy Palanivel, Jonathan D Schertzer & Gregory R Steinberg

  2. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Morgan D Fullerton, Katarina Marcinko, Sarah Sikkema, Hayley M O'Neill, Rebecca J Ford, Rengasamy Palanivel, Jonathan D Schertzer & Gregory R Steinberg

  3. St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia

    Sandra Galic, Zhi-Ping Chen, Hayley M O'Neill, Matthew O'Brien, Bryce J van Denderen, Bruce E Kemp & Gregory R Steinberg

  4. Department of Pediatrics, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada

    Thomas Pulinilkunnil & Jason R B Dyck

  5. Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia

    Hayley M O'Neill, Matthew O'Brien & Bruce E Kemp

  6. Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, Scotland, UK

    D Grahame Hardie

  7. Commonwealth Scientific and Industrial Research Organisation Preventative Health Flagship, Materials Science and Engineering, Parkville, Victoria, Australia

    S Lance Macaulay

  8. Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada

    Jonathan D Schertzer

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Contributions

M.D.F., S.G., B.E.K. and G.R.S. designed the study. M.D.F., S.G., K.M., S.S., R.J.F. and R.P. performed in vivo experiments. M.D.F., S.G. and J.D.S. performed primary hepatocyte experiments. S.G., Z.-P.C. performed Acc activity assays and M.O. performed mass spectrometry experiments. H.M.O. performed fatty acid oxidation in isolated skeletal muscle. T.P. and J.R.B.D. measured tissue malonyl-CoA content. D.G.H. contributed Acc antibodies for activity assays and helpful comments regarding the manuscript. B.J.v.D., S.L.M., B.E.K. and G.R.S. were involved in generating the knock-in mice. M.D.F. and G.R.S. wrote the manuscript.

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Correspondence to Gregory R Steinberg.

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Fullerton, M., Galic, S., Marcinko, K. et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 19, 1649–1654 (2013). https://doi.org/10.1038/nm.3372

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