Zhang Xu, Zhuang Yuan, Qin Tian, Chang Meijia, Ji Xuetao, Wang Ning, Zhang Zhilei, Zhou Hongwen, Wang Qian, Li John Zhong
The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China.
Department of Endocrinology, The First affiliated Hospital of Nanjing Medical University, Nanijing 210029, China.
Metabolism. 2021 Sep;122:154823. doi: 10.1016/j.metabol.2021.154823. Epub 2021 Jun 29.
Hepatic gluconeogenesis plays a crucial role in maintaining blood glucose homeostasis in mammals. Globe knockout of suppressor of cytokine signalling-2 (SOCS2), a feedback inhibitor of cytokine signalling, has been shown resistant to high-fat-diet (HFD)-induced hepatic steatosis with impaired glucose tolerance in mice. However, the underlying mechanism of SOCS2 regulates hepatic glucose homeostasis still undefined. In the present study, we demonstrated that the hepatic SOCS2 expression is markedly reduced in fasted C57BL/6 J mice or db/db mice. Moreover, hepatic SOCS2 expression levels are induced by metformin treatment. Ablation of SOCS2 attenuates suppressing effects of metformin on gluconeogenesis in hepatocytes. Gain- and loss-of-function studies indicated that SOCS2 regulates hepatic gluconeogenic genes expression and glucose output by mediating JAK2/STAT5 signalling pathway in db/db mice. Mechanistically, we observed that SOCS2 inactivates STAT5 by attenuating the interaction between JAK2 and STAT5, which in turn reduces hepatic gluconeogenesis. The present study reveals a critical role of SOCS2 in regulating hepatic gluconeogenesis. The inhibitory effect of metformin on gluconeogenesis is mediated, at least in part, by upregulating SOCS2 and therefore reducing hepatic gluconeogenic genes expression. SOCS2 may represent a new therapeutic target for the treatment of diabetes.
肝脏糖异生在维持哺乳动物血糖稳态中起关键作用。细胞因子信号转导抑制因子2（SOCS2）是细胞因子信号转导的反馈抑制剂，整体敲除SOCS2的小鼠已被证明对高脂饮食（HFD）诱导的肝脂肪变性具有抗性，且糖耐量受损。然而，SOCS2调节肝脏葡萄糖稳态的潜在机制仍不明确。在本研究中，我们证明在禁食的C57BL/6 J小鼠或db/db小鼠中，肝脏SOCS2表达显著降低。此外，二甲双胍治疗可诱导肝脏SOCS2表达水平升高。敲除SOCS2可减弱二甲双胍对肝细胞糖异生的抑制作用。功能获得和功能缺失研究表明，在db/db小鼠中，SOCS2通过介导JAK2/STAT5信号通路调节肝脏糖异生基因表达和葡萄糖输出。机制上，我们观察到SOCS2通过减弱JAK2与STAT5之间的相互作用使STAT5失活，进而减少肝脏糖异生。本研究揭示了SOCS2在调节肝脏糖异生中的关键作用。二甲双胍对糖异生的抑制作用至少部分是通过上调SOCS2从而降低肝脏糖异生基因表达来介导的。SOCS2可能代表了治疗糖尿病的一个新的治疗靶点。
