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

doi:10.1038/nm.3372

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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Résumé

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.

Langue d'origine	English
Pages (de-à)	1649-1654
Nombre de pages	6
Journal	Nature Medicine
Volume	19
Numéro de publication	12
DOI	https://doi.org/10.1038/nm.3372
Statut de publication	Published - déc. 2013
Publié à l'externe	Oui

Note bibliographique

Funding Information:
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.

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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Cette action contribue à la réalisation des objectifs de développement durable suivants

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10.1038/nm.3372

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Fullerton, M. D., Galic, S., Marcinko, K., Sikkema, S., Pulinilkunnil, T., Chen, Z. P., O'Neill, H. M., Ford, R. J., Palanivel, R., O'Brien, M., Hardie, D. G., MacAulay, S. L., Schertzer, J. D., Dyck, J. R. B., Van Denderen, B. J., Kemp, B. E., & 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), 1649-1654. https://doi.org/10.1038/nm.3372

Fullerton, MD, Galic, S, Marcinko, K, Sikkema, S, Pulinilkunnil, T, Chen, ZP, 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, n° 12, pp. 1649-1654. https://doi.org/10.1038/nm.3372

@article{5b7280516add4c7ea6cdb197dee78a7d,

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.",

author = "Fullerton, {Morgan D.} and Sandra Galic and Katarina Marcinko and Sarah Sikkema and Thomas Pulinilkunnil and Chen, {Zhi Ping} and O'Neill, {Hayley M.} and Ford, {Rebecca J.} and Rengasamy Palanivel and Matthew O'Brien and Hardie, {D. Grahame} and MacAulay, {S. Lance} and Schertzer, {Jonathan D.} and Dyck, {Jason R.B.} and {Van Denderen}, {Bryce J.} and Kemp, {Bruce E.} and Steinberg, {Gregory R.}",

note = "Funding Information: 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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month = dec,

doi = "10.1038/nm.3372",

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volume = "19",

pages = "1649--1654",

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T1 - Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin

AU - Fullerton, Morgan D.

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.

N1 - Funding Information: 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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AB - 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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Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin

Résumé

Note bibliographique

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODD de l’ONU

Accès au document

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