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

Morgan D Fullerton, Sandra Galic, Katarina Marcinko, Sarah Sikkema, Thomas Pulinilkunnil, Zhi-Ping Chen, Hayley M O'Neill, Rebecca J Ford, Rengasamy Palanivel, Matthew O'Brien, D Grahame Hardie, S Lance Macaulay, Jonathan D Schertzer, Jason R B Dyck, Bryce J van Denderen, Bruce E Kemp, Gregory R Steinberg

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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 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.

Original languageEnglish
Pages (from-to)1649-54
Number of pages6
JournalNature Medicine
Volume19
Issue number12
DOIs
Publication statusPublished - Dec 2013
Externally publishedYes

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Phosphorylation
AMP-Activated Protein Kinases
Metformin
Homeostasis
Insulin
Medical problems
Lipids
Liver
Fatty Acid Synthesis Inhibitors
Obesity
Fatty Acids
Type 2 Diabetes Mellitus
Malonyl Coenzyme A
Acetyl-CoA Carboxylase
Oxidation
Acetyl Coenzyme A
Mitochondria
Metabolites
Obese Mice
Alanine

Cite this

Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z-P., ... Steinberg, G. R. (2013). Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nature Medicine, 19(12), 1649-54. https://doi.org/10.1038/nm.3372
Fullerton, Morgan D ; Galic, Sandra ; Marcinko, Katarina ; Sikkema, Sarah ; Pulinilkunnil, Thomas ; Chen, Zhi-Ping ; O'Neill, Hayley M ; Ford, Rebecca J ; Palanivel, Rengasamy ; O'Brien, Matthew ; Hardie, D Grahame ; Macaulay, S Lance ; Schertzer, Jonathan D ; Dyck, Jason R B ; van Denderen, Bryce J ; Kemp, Bruce E ; Steinberg, Gregory R. / Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. In: Nature Medicine. 2013 ; Vol. 19, No. 12. pp. 1649-54.
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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 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.",
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Fullerton, MD, Galic, S, Marcinko, K, Sikkema, S, Pulinilkunnil, T, Chen, Z-P, O'Neill, HM, Ford, RJ, Palanivel, R, O'Brien, M, Hardie, DG, Macaulay, SL, Schertzer, JD, Dyck, JRB, van Denderen, BJ, Kemp, BE & Steinberg, GR 2013, 'Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin' Nature Medicine, vol. 19, no. 12, pp. 1649-54. https://doi.org/10.1038/nm.3372

Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. / Fullerton, Morgan D; Galic, Sandra; Marcinko, Katarina; Sikkema, Sarah; Pulinilkunnil, Thomas; Chen, Zhi-Ping; O'Neill, Hayley M; Ford, Rebecca J; Palanivel, Rengasamy; O'Brien, Matthew; Hardie, D Grahame; Macaulay, S Lance; Schertzer, Jonathan D; Dyck, Jason R B; van Denderen, Bryce J; Kemp, Bruce E; Steinberg, Gregory R.

In: Nature Medicine, Vol. 19, No. 12, 12.2013, p. 1649-54.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Galic, Sandra

AU - Marcinko, Katarina

AU - Sikkema, Sarah

AU - Pulinilkunnil, Thomas

AU - Chen, Zhi-Ping

AU - O'Neill, Hayley M

AU - Ford, Rebecca J

AU - Palanivel, Rengasamy

AU - O'Brien, Matthew

AU - Hardie, D Grahame

AU - Macaulay, S Lance

AU - Schertzer, Jonathan D

AU - Dyck, Jason R B

AU - van Denderen, Bryce J

AU - Kemp, Bruce E

AU - Steinberg, Gregory R

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