The dual function of hepatic SOCS3 in insulin resistance in vivo
The dual function of hepatic SOCS3 in insulin resistance in vivo
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DOI：
10.1111/j.1365-2443.2007.01044.x
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发表时间：
2007-02-01
期刊：
影响因子：
2.1
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Torisu, Takehiro;Sato, Naoichi;Yoshimura, Akihiko
炎症与胰岛素抵抗有关，胰岛素抵抗使营养稳态失调并导致糖尿病。由促炎细胞因子如TNF α和IL-6诱导的细胞因子信号传导抑制因子3（SOCS 3）与肝脏和脂肪细胞中炎症介导的胰岛素抵抗有关。然而，没有提供SOCS 3参与胰岛素抵抗的遗传证据。在这里，我们产生了肝细胞特异性SOCS 3缺陷（L-SOCS 3 cKO）小鼠，并检查了胰岛素敏感性。与先前的想法一致，肝脏中SOCS 3的缺失明显改善了胰岛素敏感性。然而，出乎意料的是，L-SOCS 3 cKO小鼠随着年龄的增长表现出肥胖和全身性胰岛素抵抗。胰岛素信号在肌肉中受到抑制，这表明肝脏中SOCS 3基因的缺失调节了其他器官的胰岛素敏感性。抗炎剂水杨酸钠部分改善了老年L-SOCS 3 cKO小鼠的胰岛素抵抗，表明增强的炎症状态与这些小鼠的表型相关。在L-SOCS 3 cKO小鼠肝脏中，STAT 3被过度激活，急性期蛋白质升高，水杨酸钠处理降低。我们的结论是，肝脏SOCS 3是肝脏胰岛素抵抗的介导者;然而，肝脏中缺乏SOCS 3通过模拟慢性炎症促进全身胰岛素抵抗。
Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNF alpha and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation.