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Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin
Fullerton, Morgan Galic, Sandra Marcinko, Katarina Sikkema, Sarah Pulinilkunnil, Thomas Chen, Zhi-Ping O'Neill, Hayley Ford, Rebecca Palanivel, Rengasamy O'Brien, Matthew
Fullerton, Morgan
Galic, Sandra
Marcinko, Katarina
Sikkema, Sarah
Pulinilkunnil, Thomas
Chen, Zhi-Ping
O'Neill, Hayley
Ford, Rebecca
Palanivel, Rengasamy
O'Brien, Matthew
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.
Keywords
Date
2013
Type
Journal article
Journal
Nature Medicine
Book
Volume
19
Issue
12
Page Range
1649-1654
Article Number
ACU Department
Faculty of Health Sciences
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DOI
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Open Access Status
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Controlled