Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction
Simon Schenk, … , Keith Baar, Jerrold M. Olefsky
Simon Schenk, … , Keith Baar, Jerrold M. Olefsky
Published October 10, 2011
Citation Information: J Clin Invest. 2011;121(11):4281-4288. https://doi.org/10.1172/JCI58554.
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Research Article Metabolism

Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction

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.

Authors

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

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Figure 3

CR reduces the expression of the p55α/p50α regulatory subunits of PI3K and enhances insulin-stimulated PI3K activation in skeletal muscle via Sirt1-mediated Stat3 deacetylation.

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CR reduces the expression of the p55α/p50α regulatory subunits of PI3K a...
(A) Protein expression of the p85α/β, p55α, and p50α regulatory subunits of PI3K and Gapdh in soleus muscle. n = 5–6/group. (B) Basal and insulin-stimulated phosphotyrosine-associated (pY-associated) PI3K activity (n = 6–7/group) in soleus muscles. Note that in this image phosphoinositol 3-phopshate [PI(3)P] levels for insulin-stimulated KO AL muscle are less than those in the insulin-stimulated WT AL muscle. However, when the data are averaged across all samples and statistical analysis is performed, the data are as presented. (C) Acetylated Stat3 (n = 5/group), (D) Stat3 binding to a nonspecific region of the p85a gene upstream of the p50α start site (background) and the p55α and p50α promoters in the p85a gene, as measured by ChIP (n = 4/group), (E) input DNA for ChIP analysis, and (F) mRNA levels of p85a, p55a, and p50a (n = 6–7/group) in skeletal muscle. A 2-way ANOVA for main effects of diet and genotype was used for statistical analysis, with a Tukey post-hoc test. For PI3K activity, statistical analysis was conducted within the basal group only or within the insulin group only. *P < 0.05, within same genotype; #P < 0.05, within same diet group. Data are presented as mean ± SEM.