Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction

Simon Schenk, Carrie E. McCurdy, Andrew Philp, Mark Z. Chen, Michael J. Holliday, Gautum K. Bandyopadhyay, Olivia Osborn, Keith Baar, Jerrold M. Olefsky

Research output: Contribution to journalArticle

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Abstract

Skeletal muscle insulin resistance is a key component of the etiology of type 2 diabetes. Caloric restriction (CR) enhances the sensitivity of skeletal muscle to insulin. However, the molecular signals within skeletal muscle linking CR to improved insulin action remain largely unknown. Recently, the mammalian ortholog of Sir2, sirtuin 1 (Sirt1), has been identified as a potential transducer of perturbations in cellular energy flux into subsequent metabolic adaptations, including modulation of skeletal muscle insulin action. Here, we have demonstrated that CR increases Sirt1 deacetylase activity in skeletal muscle in mice, in parallel with enhanced insulin-stimulated phosphoinositide 3-kinase (PI3K) signaling and glucose uptake. These adaptations in skeletal muscle insulin action were completely abrogated in mice lacking Sirt1 deacetylase activity. Mechanistically, Sirt1 was found to be required for the deacetylation and inactivation of the transcription factor Stat3 during CR, which resulted in decreased gene and protein expression of the p55α/p50α subunits of PI3K, thereby promoting more efficient PI3K signaling during insulin stimulation. Thus, these data demonstrate that Sirt1 is an integral signaling node in skeletal muscle linking CR to improved insulin action, primarily via modulation of PI3K signaling.

Original languageEnglish (US)
Pages (from-to)4281-4288
Number of pages8
JournalJournal of Clinical Investigation
Volume121
Issue number11
DOIs
StatePublished - Nov 1 2011

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Sirtuin 1
Caloric Restriction
Insulin Resistance
Skeletal Muscle
Insulin
1-Phosphatidylinositol 4-Kinase
Transducers
Type 2 Diabetes Mellitus
Transcription Factors
Gene Expression
Glucose

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Schenk, S., McCurdy, C. E., Philp, A., Chen, M. Z., Holliday, M. J., Bandyopadhyay, G. K., ... Olefsky, J. M. (2011). Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. Journal of Clinical Investigation, 121(11), 4281-4288. https://doi.org/10.1172/JCI58554

Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. / Schenk, Simon; McCurdy, Carrie E.; Philp, Andrew; Chen, Mark Z.; Holliday, Michael J.; Bandyopadhyay, Gautum K.; Osborn, Olivia; Baar, Keith; Olefsky, Jerrold M.

In: Journal of Clinical Investigation, Vol. 121, No. 11, 01.11.2011, p. 4281-4288.

Research output: Contribution to journalArticle

Schenk, S, McCurdy, CE, Philp, A, Chen, MZ, Holliday, MJ, Bandyopadhyay, GK, Osborn, O, Baar, K & Olefsky, JM 2011, 'Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction', Journal of Clinical Investigation, vol. 121, no. 11, pp. 4281-4288. https://doi.org/10.1172/JCI58554
Schenk S, McCurdy CE, Philp A, Chen MZ, Holliday MJ, Bandyopadhyay GK et al. Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. Journal of Clinical Investigation. 2011 Nov 1;121(11):4281-4288. https://doi.org/10.1172/JCI58554
Schenk, Simon ; McCurdy, Carrie E. ; Philp, Andrew ; Chen, Mark Z. ; Holliday, Michael J. ; Bandyopadhyay, Gautum K. ; Osborn, Olivia ; Baar, Keith ; Olefsky, Jerrold M. / Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 11. pp. 4281-4288.
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