In the context of obesity-induced adipose tissue (AT) inflammation, migration of macrophages and their polarization from predominantly anti-inflammatory to proinflammatory subtype is considered a pivotal event in the loss of adipose insulin sensitivity. Two major chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and Fetuin-A (FetA), have been reported to stimulate macrophage migration into inflamed AT instigating inflammation. Moreover, FetA could notably modulate macrophage polarization, yet the mechanism(s) is unknown. The present study was undertaken to elucidate the mechanistic pathway involved in the actions of FetA and MCP-1 in obese AT. We found that FetA knockdown in high fat diet (HFD) fed mice could significantly subdue the augmented MCP-1 expression and reduce adipose tissue macrophage (ATM) content thereby indicating that MCP-1 is being regulated by FetA. Additionally, knockdown of FetA in HFD mice impeded the expression of inducible nitric oxide synthase (iNOS) reverting macrophage activation from mostly proinflammatory to anti-inflammatory state. It was observed that the stimulating effect of FetA on MCP-1 and iNOS was mediated through interferon γ (IFNγ) induced activation of JAK2-STAT1-NOX4 pathway. Furthermore, we detected that the enhanced IFNγ expression was accounted by the stimulatory effect of FetA upon the activities of both cJun and JNK. Taken together, our findings revealed that obesity-induced FetA acts as a master upstream regulator of AT inflammation by regulating MCP-1 and iNOS expression through JNK-cJun-IFNγ-JAK2-STAT1 signaling pathway. This study opened a new horizon in understanding the regulation of ATM content and activation in conditions of obesity-induced insulin resistance.

中文翻译：

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Fetuin-A 通过 MCP-1 和 iNOS 调节胰岛素抵抗小鼠脂肪组织巨噬细胞含量和活化：IFNγ-JAK2-STAT1 通路的参与

在肥胖引起的脂肪组织 (AT) 炎症的背景下，巨噬细胞的迁移及其从主要抗炎亚型到促炎亚型的极化被认为是脂肪胰岛素敏感性丧失的关键事件。据报道，两种主要的化学引诱物，单核细胞化学引诱蛋白-1 (MCP-1) 和胎球蛋白-A (FetA)，可刺激巨噬细胞迁移到发炎的 AT 中，从而引发炎症。此外，FetA 可以显着调节巨噬细胞极化，但其机制尚不清楚。本研究旨在阐明参与 FetA 和 MCP-1 在肥胖 AT 中的作用的机制途径。我们发现在高脂肪饮食 (HFD) 喂养的小鼠中敲除 FetA 可以显着抑制增加的 MCP-1 表达并减少脂肪组织巨噬细胞 (ATM) 的含量，从而表明 MCP-1 受到 FetA 的调节。此外，HFD 小鼠中 FetA 的敲低阻碍了诱导型一氧化氮合酶 (iNOS) 的表达，将巨噬细胞激活从主要的促炎状态恢复为抗炎状态。观察到 FetA 对 MCP-1 和 iNOS 的刺激作用是通过干扰素 γ (IFNγ) 诱导的 JAK2-STAT1-NOX4 通路激活介导的。此外，我们检测到增强的 IFNγ 表达归因于 FetA 对 cJun 和 JNK 活性的刺激作用。综合起来，我们的研究结果表明，肥胖诱导的 FetA 通过 JNK-cJun-IFNγ-JAK2-STAT1 信号通路调节 MCP-1 和 iNOS 表达，作为 AT 炎症的主要上游调节剂。这项研究为理解肥胖引起的胰岛素抵抗条件下 ATM 含量的调节和激活开辟了新的视野。