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

By M. Fullerton, S. Galic, K. Marcinko, S. Sikkema, T. Pulinilkunnil, Zhi-ping Chen, H. O'Neill, R. Ford, R. Palanivel, Matthew L. O'Brien and 7 more. Nature Medicine, 2013

858 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/f3a3e7a25f95e8747b1d67189542ad2642ea17ff

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Citations in the corpus

• Role of Dietary Fructose and Hepatic de novo Lipogenesis in Fatty Liver Disease (2016, background): “Furthermore, citrate is an allosteric activator of cytoplasmic acetyl-CoA carboxylase (ACC), whose action is to convert acetyl-CoA to malonyl-CoA, thus initiating DNL [25, 26].”
• The mechanisms of action of metformin (2017, background): “However, while the metabolic measures of the high-fat fed control mice substantially improved after 6 weeks of treatment with metformin, those of the knock-in mice were unaffected [34].”
• Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug (2017, methodology): “coli were inoculated anaerobically in a Coy chamber (5% hydrogen, 10% carbon dioxide, and 85% nitrogen) as single colonies in 7 ml of brain-heart infusion (BHI) medium containing (in g/liter) yeast extract (5), cellobiose (1), maltose (1), cysteine (0.”
• Metformin promotes antitumor immunity via endoplasmic reticulum-associated degradation of PD-L1 (2018, background): “CoA carboxylase (ACC), a known AMPK substrate (Fullerton et al., 2013) (Figure 2D).”
• Metformin: from mechanisms of action to therapies. (2014, background): “Furthermore, Fullerton and colleagues recently showed that metformin-induced improvements in insulin action operate through alterations in hepatic lipid homeostasis via the inhibitory phosphorylation of acetyl CoA carboxylase (ACC) by AMPK (Fullerton et al., 2013).”