Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
PLoS One. 2012;7(10):e47493. doi: 10.1371/journal.pone.0047493. Epub 2012 Oct 24.
Skeletal muscle resistance to the key metabolic hormones, leptin and insulin, is an early defect in obesity. Suppressor of cytokine signaling 3 (SOCS3) is a major negative regulator of both leptin and insulin signaling, thereby implicating SOCS3 in the pathogenesis of obesity and associated metabolic abnormalities. Here, we demonstrate that SOCS3 mRNA expression is increased in murine skeletal muscle in the setting of diet-induced and genetic obesity, inflammation, and hyperlipidemia. To further evaluate the contribution of muscle SOCS3 to leptin and insulin resistance in obesity, we generated transgenic mice with muscle-specific overexpression of SOCS3 (MCK/SOCS3 mice). Despite similar body weight, MCK/SOCS3 mice develop impaired systemic and muscle-specific glucose homeostasis and insulin action based on glucose and insulin tolerance tests, hyperinsulinemic-euglycemic clamps, and insulin signaling studies. With regards to leptin action, MCK/SOCS3 mice exhibit suppressed basal and leptin-stimulated activity and phosphorylation of alpha2 AMP-activated protein kinase (α2AMPK) and its downstream target, acetyl-CoA carboxylase (ACC). Muscle SOCS3 overexpression also suppresses leptin-regulated genes involved in fatty acid oxidation and mitochondrial function. These studies demonstrate that SOC3 within skeletal muscle is a critical regulator of leptin and insulin action and that increased SOCS may mediate insulin and leptin resistance in obesity.
骨骼肌对关键代谢激素瘦素和胰岛素的抗性是肥胖症的早期缺陷。细胞因子信号转导抑制因子 3（SOCS3）是瘦素和胰岛素信号的主要负调节剂，因此 SOCS3 参与了肥胖症和相关代谢异常的发病机制。在这里，我们证明 SOCS3 mRNA 的表达在饮食诱导和遗传肥胖、炎症和高脂血症的情况下在鼠类骨骼肌中增加。为了进一步评估肌肉 SOCS3 对肥胖症中瘦素和胰岛素抵抗的贡献，我们生成了肌肉特异性过表达 SOCS3 的转基因小鼠（MCK/SOCS3 小鼠）。尽管体重相似，但 MCK/SOCS3 小鼠会出现全身和肌肉特异性葡萄糖稳态和胰岛素作用受损的情况，这基于葡萄糖和胰岛素耐量试验、高胰岛素正常血糖钳夹和胰岛素信号研究。关于瘦素作用，MCK/SOCS3 小鼠表现出基础和瘦素刺激的活性以及 α2 腺苷酸活化蛋白激酶（α2AMPK）及其下游靶标乙酰辅酶 A 羧化酶（ACC）的磷酸化受到抑制。肌肉 SOCS3 过表达还抑制了涉及脂肪酸氧化和线粒体功能的瘦素调节基因。这些研究表明，骨骼肌中的 SOC3 是瘦素和胰岛素作用的关键调节剂，并且 SOCS 的增加可能介导肥胖症中的胰岛素和瘦素抵抗。
