Interleukin-6 (IL-6) can reportedly centrally affect the thermogenesis of brown fat. However, whether the peripheral IL-6 signaling regulates beiging of white fat remains largely unknown. In vitro experiments indicated IL-6-KO-derived white adipocytes exhibited lower thermogenic gene expression compared to the WT, associating with reduced phosphorylation of STAT3 at Tyr705. Mechanistically, exogenous IL-6 application increased the p-STAT3^Tyr705 level, thus the phosphorylated STAT3 bound to the promoter regions, and enhanced the transcription of Pparγ and Ucp1. The protein interaction of PGC-1α with PPARγ was increased by IL-6, which also contributed to stimulate Ucp1 expression. In vivo experiments demonstrated that IL-6 KO decreased the beiging potential of white fat with suppressed STAT3 Tyr705 phosphorylation. Accordingly, IL-6-KO mature mice were associated with disrupted glucose homeostasis and accelerated hepatic steatosis. Collectively, we identified a novel function of peripheral IL-6/STAT3 signaling which is essential for beiging of white fat, such ensuring fat and glucose homeostasis.

据报道，白细胞介素 6 (IL-6) 可以集中影响棕色脂肪的产热。然而，外周 IL-6 信号是否调节白色脂肪的褐变仍然很大程度上未知。体外实验表明，与 WT 相比，IL-6-KO 衍生的白色脂肪细胞表现出较低的产热基因表达，这与 Tyr705 处 STAT3 的磷酸化降低有关。从机制上讲，外源性 IL-6 应用增加了 p-STAT3 ^Tyr705水平，因此磷酸化的 STAT3 与启动子区域结合，并增强了Pparγ和Ucp1的转录。IL-6 增加了 PGC-1α 与 PPARγ 的蛋白质相互作用，这也有助于刺激Ucp1表达。体内实验表明，IL-6 KO 降低了白色脂肪的褐变潜力，并抑制了 STAT3 Tyr705 磷酸化。因此，IL-6-KO 成熟小鼠与葡萄糖稳态破坏和肝脂肪变性加速有关。总的来说，我们确定了外周 IL-6/STAT3 信号传导的新功能，这对于白色脂肪的形成至关重要，例如确保脂肪和葡萄糖的稳态。