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

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2014

Diabetologia 2014 Aug;57(8):1693-702. doi: 10.1007/s00125-014-3273-1. Epub 2014 Jun 10.

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

HM O'Neill;JS Lally;S Galic;M Thomas;PD Azizi;MD Fullerton;BK Smith;T Pulinilkunnil;Z Chen;MC Samaan;SB Jorgensen;JR Dyck;GP Holloway;TJ Hawke;BJ van Denderen;BE Kemp;GR Steinberg

Division of Endocrinology and Metabolism, Department of Medicine, HSC 4N63, McMaster University, 1280 Main St West, Hamilton, ON, Canada, L8N 3Z5.

Service type: Knock-in mice

Abstract

AIMS/HYPOTHESIS: 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. METHODS: Whole-body and skeletal muscle fatty acid oxidation and insulin sensitivity were assessed in ACC2 KI mice and wild-type littermates. RESULTS: 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. CONCLUSIONS/INTERPRETATION: These findings indicate that the phosphorylation of ACC2 S212 is required for the maintenance of skeletal muscle lipid and glucose homeostasis.

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