Obesity is a strong predictor of heart disease, insulin resistance, and type II diabetes. Chronic, low-grade inflammation links obesity and insulin resistance through mitogen-activated protein kinase (MAPK) signaling pathways. Upstream kinases activate MAPK signaling, while MAPK-specific dual-specificity phosphatases (DUSPs) act as key modulators and controllers of MAPK deactivation (i.e. dephosphorylation). Using tumor necrosis factor α (TNFα) in 3 T3-L1 adipocytes as a model of inflammation, we report that TNFα-mediated induction of Dusp1, Dusp8 and Dusp16 modulated the transient regulation of MAPK (i.e., ERK, JNK, and p38) phosphorylation and subsequent inflammatory gene expression. All three MAPKs examined were phosphorylated in preadipocytes and adipocytes in response to TNFα, where signaling magnitude and duration were phenotype-specific. Moreover, TNFα increased mRNA abundance of DUSPs in preadipocytes and adipocytes in a phenotype-specific manner, concomitant with dephosphorylation of MAPKs. RNA interference (RNAi)-mediated knockdown of Dusp1, Dusp8 and Dusp16 increased signaling magnitude and duration of ERK, JNK, and p38 that subsequently resulted in significant increases in MAPK-dependent inflammatory gene expression of MCP-1, IL-6, and Cox-2 in response to TNFα. This study highlights important roles for DUSPs as integral components of MAPK signaling and adipocyte inflammatory gene expression.

中文翻译：

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双特异性磷酸酶调节脂肪细胞中的丝裂原活化蛋白激酶信号传导以响应炎症应激。

肥胖是心脏病、胰岛素抵抗和 II 型糖尿病的强预测因子。慢性、低度炎症通过丝裂原活化蛋白激酶 (MAPK) 信号通路将肥胖和胰岛素抵抗联系起来。上游激酶激活 MAPK 信号，而 MAPK 特异性双特异性磷酸酶 (DUSP) 充当 MAPK 失活（即去磷酸化）的关键调节剂和控制器。使用 3 个 T3-L1 脂肪细胞中的肿瘤坏死因子 α (TNFα) 作为炎症模型，我们报告 TNFα 介导的 Dusp1、Dusp8 和 Dusp16 诱导调节了 MAPK（即 ERK、JNK 和 p38）磷酸化的瞬时调节和随后的炎症基因表达。所检查的所有三种 MAPK 在前脂肪细胞和脂肪细胞中均响应 TNFα 磷酸化，其中信号强度和持续时间是表型特异性的。此外，TNFα 以表型特异性的方式增加了前脂肪细胞和脂肪细胞中 DUSP 的 mRNA 丰度，同时伴随着 MAPK 的去磷酸化。RNA 干扰 (RNAi) 介导的 Dusp1、Dusp8 和 Dusp16 敲低增加了 ERK、JNK 和 p38 的信号强度和持续时间，随后导致 MCP-1、IL-6 和 Cox 的 MAPK 依赖性炎症基因表达显着增加-2 响应 TNFα。本研究强调了 DUSP 作为 MAPK 信号传导和脂肪细胞炎症基因表达的组成部分的重要作用。和 p38 随后导致 MCP-1、IL-6 和 Cox-2 的 MAPK 依赖性炎症基因表达显着增加，以响应 TNFα。本研究强调了 DUSP 作为 MAPK 信号传导和脂肪细胞炎症基因表达的组成部分的重要作用。和 p38 随后导致 MCP-1、IL-6 和 Cox-2 的 MAPK 依赖性炎症基因表达显着增加，以响应 TNFα。本研究强调了 DUSP 作为 MAPK 信号传导和脂肪细胞炎症基因表达的组成部分的重要作用。