title: 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: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673, USA.
authors: Simon
authors: S
authors: Schenk
authors: Carrie E
authors: CE
authors: McCurdy
authors: Andrew
authors: A
authors: Philp
authors: Mark Z
authors: MZ
authors: Chen
authors: Michael J
authors: MJ
authors: Holliday
authors: Gautum K
authors: GK
authors: Bandyopadhyay
authors: Olivia
authors: O
authors: Osborn
authors: Keith
authors: K
authors: Baar
authors: Jerrold M
authors: JM
authors: Olefsky
mesh_terms: D000818:Animals; D001483:Base Sequence; D031204:Caloric Restriction; D017931:DNA Primers / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1