Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673, USA.
J Clin Invest. 2011 Nov;121(11):4281-8. doi: 10.1172/JCI58554. Epub 2011 Oct 10.
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.
骨骼肌胰岛素抵抗是 2 型糖尿病发病机制的一个关键组成部分。热量限制（CR）增强了骨骼肌对胰岛素的敏感性。然而，将 CR 与改善胰岛素作用联系起来的骨骼肌内分子信号在很大程度上仍然未知。最近，已经鉴定出哺乳动物 Sir2 的同源物，即沉默调节蛋白 1（Sirt1），作为细胞能量通量变化到随后的代谢适应的潜在转导子，包括调节骨骼肌胰岛素作用。在这里，我们已经证明 CR 增加了小鼠骨骼肌中的 Sirt1 去乙酰化酶活性，与增强的胰岛素刺激的磷酸肌醇 3-激酶（PI3K）信号和葡萄糖摄取平行。在缺乏 Sirt1 去乙酰化酶活性的小鼠中，这些骨骼肌胰岛素作用的适应性完全被消除。从机制上讲，发现 Sirt1 在 CR 期间需要去乙酰化和失活转录因子 Stat3，从而导致 PI3K 的 p55α/p50α 亚基的基因和蛋白表达减少，从而在胰岛素刺激期间促进更有效的 PI3K 信号。因此，这些数据表明 Sirt1 是将 CR 与改善胰岛素作用联系起来的骨骼肌中的一个完整信号节点，主要通过调节 PI3K 信号。
