Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia; the.
Diabetes. 2013 Dec;62(12):4109-21. doi: 10.2337/db12-1275. Epub 2013 Aug 12.
Signal transducer and activator of transcription (STAT) 4 is one of the seven members of the STAT family. STAT4 has a prominent role in mediating interleukin-12-induced T-helper cell type 1 lineage differentiation. T cells are key players in the maintenance of adipose tissue (AT) inflammation. The role of STAT4 in obesity and AT inflammation is unknown. We sought to determine the role of STAT4 in AT inflammation in obesity-induced insulin resistance. We studied STAT4-null mice on the C57Bl6/J background. We have found that STAT4(-/-)C57Bl6/J mice develop high-fat diet-induced obesity (DIO) similar to wild-type controls, but that they have significantly improved insulin sensitivity and better glucose tolerance. Using flow cytometry and real-time PCR, we show that STAT4(-/-) mice with DIO produce significantly reduced numbers of inflammatory cytokines and chemokines in adipocytes, have reduced numbers of CD8(+) cells, and display increased alternative (M2) macrophage polarization. CD8(+) cells, but not CD4(+) cells, from STAT4(-/-) mice displayed reduced in vitro migration. Also, we found that adipocyte inflammation is reduced and insulin signaling is improved in STAT4(-/-) mice with DIO. We have identified STAT4 as a key contributor to insulin resistance and AT inflammation in DIO. Targeting STAT4 activation could be a novel approach to reducing AT inflammation and insulin resistance in obesity.
信号转导子和转录激活子（STAT）4 是 STAT 家族的七个成员之一。STAT4 在介导白细胞介素-12 诱导的 T 辅助细胞 1 谱系分化中起着重要作用。T 细胞是维持脂肪组织（AT）炎症的关键因素。STAT4 在肥胖和 AT 炎症中的作用尚不清楚。我们试图确定 STAT4 在肥胖诱导的胰岛素抵抗中的 AT 炎症中的作用。我们研究了 C57Bl6/J 背景下的 STAT4 缺失小鼠。我们发现，STAT4(-/-)C57Bl6/J 小鼠类似于野生型对照一样发展出高脂肪饮食诱导的肥胖（DIO），但它们具有显著改善的胰岛素敏感性和更好的葡萄糖耐量。通过流式细胞术和实时 PCR，我们表明 DIO 的 STAT4(-/-) 小鼠在脂肪细胞中产生的炎症细胞因子和趋化因子数量显著减少，CD8(+)细胞数量减少，并且显示出增加的替代（M2）巨噬细胞极化。来自 STAT4(-/-) 小鼠的 CD8(+)细胞，而不是 CD4(+)细胞，显示出体外迁移减少。此外，我们发现 DIO 的 STAT4(-/-) 小鼠中脂肪细胞炎症减少和胰岛素信号改善。我们已经确定 STAT4 是 DIO 中胰岛素抵抗和 AT 炎症的关键贡献者。靶向 STAT4 激活可能是减少肥胖中 AT 炎症和胰岛素抵抗的一种新方法。
