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

Hayley M. O'Neill; James S. Lally; Sandra Galic; Melissa Thomas; Paymon D. Azizi; Morgan D. Fullerton; Brennan K. Smith; Thomas Pulinilkunnil; Zhiping Chen; M. Constantine Samaan; Sebastian B. Jorgensen; Jason R.B. Dyck; Graham P. Holloway; Thomas J. Hawke; Bryce J. Van Denderen; Bruce E. Kemp; Gregory R. Steinberg

doi:10.1007/s00125-014-3273-1

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

Hayley M. O'Neill, James S. Lally, Sandra Galic, Melissa Thomas, Paymon D. Azizi, Morgan D. Fullerton, Brennan K. Smith, Thomas Pulinilkunnil, Zhiping Chen, M. Constantine Samaan, Sebastian B. Jorgensen, Jason R.B. Dyck, Graham P. Holloway, Thomas J. Hawke, Bryce J. Van Denderen, Bruce E. Kemp, Gregory R. Steinberg

Résultat de recherche: Article › examen par les pairs

110 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Pages (de-à)	1693-1702
Nombre de pages	10
Journal	Diabetologia
Volume	57
Numéro de publication	8
DOI	https://doi.org/10.1007/s00125-014-3273-1
Statut de publication	Published - août 2014
Publié à l'externe	Oui

Note bibliographique

Funding Information:
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.

ASJC Scopus Subject Areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

ODD de l’ONU

Cette action contribue à la réalisation des objectifs de développement durable suivants

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10.1007/s00125-014-3273-1

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O'Neill, H. M., Lally, J. S., Galic, S., Thomas, M., Azizi, P. D., Fullerton, M. D., Smith, B. K., Pulinilkunnil, T., Chen, Z., Samaan, M. C., Jorgensen, S. B., Dyck, J. R. B., Holloway, G. P., Hawke, T. J., Van Denderen, B. J., Kemp, B. E., & Steinberg, G. R. (2014). AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia, 57(8), 1693-1702. https://doi.org/10.1007/s00125-014-3273-1

O'Neill, HM, Lally, JS, Galic, S, Thomas, M, Azizi, PD, Fullerton, MD, Smith, BK, Pulinilkunnil, T, Chen, Z, Samaan, MC, Jorgensen, SB, Dyck, JRB, Holloway, GP, Hawke, TJ, Van Denderen, BJ, Kemp, BE & Steinberg, GR 2014, 'AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice', Diabetologia, vol. 57, n° 8, pp. 1693-1702. https://doi.org/10.1007/s00125-014-3273-1

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title = "AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity 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.",

author = "O'Neill, {Hayley M.} and Lally, {James S.} and Sandra Galic and Melissa Thomas and Azizi, {Paymon D.} and Fullerton, {Morgan D.} and Smith, {Brennan K.} and Thomas Pulinilkunnil and Zhiping Chen and Samaan, {M. Constantine} and Jorgensen, {Sebastian B.} and Dyck, {Jason R.B.} and Holloway, {Graham P.} and Hawke, {Thomas J.} and {Van Denderen}, {Bryce J.} and Kemp, {Bruce E.} and Steinberg, {Gregory R.}",

note = "Funding Information: 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{\textquoteright}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.",

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doi = "10.1007/s00125-014-3273-1",

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T1 - AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice

AU - O'Neill, Hayley M.

AU - Lally, James S.

AU - Galic, Sandra

AU - Thomas, Melissa

AU - Azizi, Paymon D.

AU - Fullerton, Morgan D.

AU - Smith, Brennan K.

AU - Pulinilkunnil, Thomas

AU - Chen, Zhiping

AU - Samaan, M. Constantine

AU - Jorgensen, Sebastian B.

AU - Dyck, Jason R.B.

AU - Holloway, Graham P.

AU - Hawke, Thomas J.

AU - Van Denderen, Bryce J.

AU - Kemp, Bruce E.

AU - Steinberg, Gregory R.

N1 - Funding Information: 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.

PY - 2014/8

Y1 - 2014/8

N2 - 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.

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

Résumé

Note bibliographique

ASJC Scopus Subject Areas

ODD de l’ONU

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