AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice

Springer Science and Business Media LLC - Tập 57 - Trang 1693-1702 - 2014
Hayley M. O’Neill1,2, James S. Lally1, Sandra Galic2, Melissa Thomas3, Paymon D. Azizi1, Morgan D. Fullerton1, Brennan K. Smith1,4, Thomas Pulinilkunnil5, Zhiping Chen2, M. Constantine Samaan6, Sebastian B. Jorgensen2,7, Jason R. B. Dyck5, Graham P. Holloway4, Thomas J. Hawke3, Bryce J. van Denderen2, Bruce E. Kemp2, Gregory R. Steinberg1,2
1Division of Endocrinology and Metabolism, Department of Medicine, HSC 4N63, McMaster University, Hamilton, Canada
2St Vincent’s Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Australia
3Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
4Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada
5Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
6Department of Paediatrics, McMaster University, Hamilton, Canada
7Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark

Tóm tắt

Obesity is characterised by lipid accumulation in skeletal muscle, which increases the risk of developing insulin resistance and type 2 diabetes. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status and is activated in skeletal muscle by exercise, hormones (leptin, adiponectin, IL-6) and pharmacological agents (5-amino-4-imidazolecarboxamide ribonucleoside [AICAR] and metformin). Phosphorylation of acetyl-CoA carboxylase 2 (ACC2) at S221 (S212 in mice) by AMPK reduces ACC activity and malonyl-CoA content but the importance of the AMPK–ACC2–malonyl-CoA pathway in controlling fatty acid metabolism and insulin sensitivity is not understood; therefore, we characterised Acc2 S212A knock-in (ACC2 KI) mice. Whole-body and skeletal muscle fatty acid oxidation and insulin sensitivity were assessed in ACC2 KI mice and wild-type littermates. ACC2 KI mice were resistant to increases in skeletal muscle fatty acid oxidation elicited by AICAR. These mice had normal adiposity and liver lipids but elevated contents of triacylglycerol and ceramide in skeletal muscle, which were associated with hyperinsulinaemia, glucose intolerance and skeletal muscle insulin resistance. These findings indicate that the phosphorylation of ACC2 S212 is required for the maintenance of skeletal muscle lipid and glucose homeostasis.

Tài liệu tham khảo

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