<br>DUSP5 充当脂肪细胞中 TNFα 诱导的 ERK1/2 去磷酸化和炎症基因表达的反馈调节因子。,Scientific Reports

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DUSP5 充当脂肪细胞中 TNFα 诱导的 ERK1/2 去磷酸化和炎症基因表达的反馈调节因子。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-Oct-10 , DOI: 10.1038/s41598-017-12861-y
Justine S Habibian ₁ , Mitra Jefic ₁ , Rushita A Bagchi ₂ , Robert H Lane ₃ , Robert A McKnight ₄ , Timothy A McKinsey ₂ , Ron F Morrison ₅ , Bradley S Ferguson ₁

Affiliation

脂肪组织炎症是调节肥胖介导的胰岛素抵抗和 II 型糖尿病的核心病理因素。有证据表明，细胞外信号调节激酶 (ERK 1/2) 激活（即磷酸化）将肿瘤坏死因子 α (TNFα) 与细胞核中的促炎基因表达联系起来。双特异性磷酸酶 (DUSP) 通过去磷酸化使 ERK 1/2 失活，从而抑制炎症基因表达。我们报告说，DUSP5（一种 ERK1/2 磷酸酶）在附睾白色脂肪组织 (WAT) 中被诱导，以响应饮食引起的肥胖。此外，在肥胖发展过程中，DUSP5 mRNA 表达随着 TNFα 表达的增加而增加。与体内研究结果一致，脂肪细胞中 DUSP5 mRNA 表达响应 TNFα 增加，与 ERK1/2 去磷酸化平行。 DUSP5 的遗传缺失加剧了 3T3-L1 脂肪细胞和小鼠脂肪组织中 TNFα 介导的 ERK 1/2 信号传导。此外，抑制 ERK 1/2 和 c-Jun N 末端激酶 (JNK) 信号可减弱 TNFα 诱导的 DUSP5 表达。这些数据表明，DUSP5 在响应 TNFα 的 ERK1/2 信号传导反馈抑制中发挥作用，从而导致炎症基因表达增加。因此，DUSP5 可能充当脂肪组织炎症的内源性调节因子；尽管它在肥胖介导的炎症和胰岛素信号传导中的作用仍不清楚。

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DUSP5 functions as a feedback regulator of TNFα-induced ERK1/2 dephosphorylation and inflammatory gene expression in adipocytes.

Adipose tissue inflammation is a central pathological element that regulates obesity-mediated insulin resistance and type II diabetes. Evidence demonstrates that extracellular signal-regulated kinase (ERK 1/2) activation (i.e. phosphorylation) links tumor necrosis factor α (TNFα) to pro-inflammatory gene expression in the nucleus. Dual specificity phosphatases (DUSPs) inactivate ERK 1/2 through dephosphorylation and can thus inhibit inflammatory gene expression. We report that DUSP5, an ERK1/2 phosphatase, was induced in epididymal white adipose tissue (WAT) in response to diet-induced obesity. Moreover, DUSP5 mRNA expression increased during obesity development concomitant to increases in TNFα expression. Consistent with in vivo findings, DUSP5 mRNA expression increased in adipocytes in response to TNFα, parallel with ERK1/2 dephosphorylation. Genetic loss of DUSP5 exacerbated TNFα-mediated ERK 1/2 signaling in 3T3-L1 adipocytes and in adipose tissue of mice. Furthermore, inhibition of ERK 1/2 and c-Jun N terminal kinase (JNK) signaling attenuated TNFα-induced DUSP5 expression. These data suggest that DUSP5 functions in the feedback inhibition of ERK1/2 signaling in response to TNFα, which resulted in increased inflammatory gene expression. Thus, DUSP5 potentially acts as an endogenous regulator of adipose tissue inflammation; although its role in obesity-mediated inflammation and insulin signaling remains unclear.

更新日期：2017-10-10

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