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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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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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Abbreviations

2DG:

2-Deoxyglucose

ACC:

Acetyl-CoA carboxylase

ACC DKI:

Acc double knock-in mice

ACC2 KI:

Acc2 S212A KI

AMPK β1β2 M-KO:

Skeletal muscle-specific Ampk β1β2 KO

AICAR:

5-Amino-4-imidazolecarboxamide ribonucleoside

AMPK:

AMP-activated protein kinase

CPT-I:

Carnitine palmitoyl transferase

Cyt:

Cytochrome

DKI:

Double KI

EDL:

Extensor digitorum longus

GDR:

Glucose disposal rate

HFD:

High-fat diet

KI:

Knock-in

KO:

Knockout

OXPHOS:

Proteins involved in oxidative phosphorylation

RQ:

Respiratory quotient

TAG:

Triacylglycerol

TBC1D 1 and 4:

tre-2/USP6, BUB2, cdc16 domain family member 1 and 4

\( \overset{\cdot }{V}{\mathrm{CO}}_2 \) :

Rate of CO2 production

\( \overset{\cdot }{V}{\mathrm{O}}_2 \) :

Rate of O2 consumption

WT:

Wild-type

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Funding

These studies were supported by grants and fellowships from the Australian Research Council and CSIRO (BEK), National Health and Medical Research Council (BEK, GRS, BJvD), the Canadian Diabetes Association (JRBD, GRS) and the Canadian Institutes of Health Research (CIHR) (JRBD, GRS). Support in part was received from the Victorian Government’s OIS Program (BEK) and Canadian Foundation for Innovation (GRS). MDF is a CIHR Banting Postdoctoral Fellow and GRS holds a Canada Research Chair in Metabolism and Obesity.

Contribution statement

HMO and GRS designed experiments and wrote manuscript. GRS, BEK and SBJ provided funding for the project and revised the manuscript. HMO performed the majority of experiments. JSL, SG, MT, PDA, MDF, BKS, TP, ZC, BJvD, MCS, SBJ, JRBD, GPH and TJH designed and performed experiments and revised the manuscript. All authors approved the final version of the manuscript. GRS is responsible for the integrity of the work as a whole.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Author information

Authors and Affiliations

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

    Hayley M. O’Neill, James S. Lally, Paymon D. Azizi, Morgan D. Fullerton, Brennan K. Smith & Gregory R. Steinberg

  2. St Vincent’s Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, VIC, Australia

    Hayley M. O’Neill, Sandra Galic, Zhiping Chen, Sebastian B. Jorgensen, Bryce J. van Denderen, Bruce E. Kemp & Gregory R. Steinberg

  3. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

    Melissa Thomas & Thomas J. Hawke

  4. Department of Paediatrics, McMaster University, Hamilton, ON, Canada

    M. Constantine Samaan

  5. Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada

    Brennan K. Smith & Graham P. Holloway

  6. Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Thomas Pulinilkunnil & Jason R. B. Dyck

  7. Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark

    Sebastian B. Jorgensen

Authors
  1. Hayley M. O’Neill
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  2. James S. Lally
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  3. Sandra Galic
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  4. Melissa Thomas
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  5. Paymon D. Azizi
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  6. Morgan D. Fullerton
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  7. Brennan K. Smith
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  8. Thomas Pulinilkunnil
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  9. Zhiping Chen
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  10. M. Constantine Samaan
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  11. Sebastian B. Jorgensen
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  12. Jason R. B. Dyck
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  13. Graham P. Holloway
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  14. Thomas J. Hawke
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  15. Bryce J. van Denderen
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  16. Bruce E. Kemp
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  17. Gregory R. Steinberg
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Corresponding author

Correspondence to Gregory R. Steinberg.

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O’Neill, H.M., Lally, J.S., Galic, S. et al. AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia 57, 1693–1702 (2014). https://doi.org/10.1007/s00125-014-3273-1

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