Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin
Open accessAbstract
Metformin is one of the most widely prescribed therapeutics for type 2 diabetes. But exactly how it works is still unclear. Gregory Steinberg and colleagues now show that it does so by activation of the enzyme AMP-activated protein kinase (Ampk) and Ampk's obligate targeting of two key enzymes involved in lipid homeostasis. 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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Mice overexpressing both ACC1 and ACC2 show increased hepatic de novo lipogenesis and spontaneously develop MASH-like symptoms.
“Mice overexpressing both ACC1 and ACC2 display increased de novo lipogenesis in the liver and spontaneously develop MASH-like symptoms (189).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [189]
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- Authors
- 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.
- Affiliations
- McMaster University (CA)
- University of Alberta (CA)
- University of Dundee (GB)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- The University of Melbourne (AU)
- St Vincents Institute of Medical Research (AU)
- Corresponding author
- Steinberg, Gregory R
- ORCID
- Venue
- Nature Medicine
- Published
- 2013-11-03
- Volume
- 19
- Issue
- 12
- Pages
- 1649-1654
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4965268
- OpenAlex
- W2037918682
- Cited by
- 893
- References
- 48
- Citations by year
- 2026: 60 · 2025: 68 · 2024: 64 · 2023: 81 · 2022: 95 · 2021: 92 · 2020: 103 · 2019: 62 · 2018: 61 · 2017: 55 · 2016: 50 · 2015: 53 · 2014: 45 · 2013: 2 · 2012: 1
- FWCI
- 22.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Medicine (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Bank (Australian Catholic University) (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- Wellcome Trust (097726)
- Canadian Institutes of Health Research (125980_1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- metformin, AMPK, acetyl-CoA carboxylase 1, acetyl-CoA carboxylase 2, lipid homeostasis, non-alcoholic fatty liver disease, type 2 diabetes, insulin sensitivity, lipogenesis, fatty acid oxidation, malonyl-CoA, obesity, high-fat diet
- MeSH terms
- Acetyl-CoA Carboxylase, Acetyltransferases, Animals, Cells, Cultured, Drug Synergism, Homeostasis, Insulin, Insulin Resistance, Male, Metformin, Mice, Inbred C57BL, Phosphorylation, Lipid Metabolism, Mice, AMP-Activated Protein Kinases
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