DUSP5 functions as a feedback regulator of TNFα-induced ERK1/2 dephosphorylation and inflammatory gene expression in adipocytes.
DUSP5 functions as a feedback regulator of TNFα-induced ERK1/2 dephosphorylation and inflammatory gene expression in adipocytes.
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DOI：
10.1038/s41598-017-12861-y
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发表时间：
2017-10-10
影响因子：
4.6
通讯作者：
Ferguson BS
中科院分区：
文献类型：
--
作者：
Habibian JS;Jefic M;Bagchi RA;Lane RH;McKnight RA;McKinsey TA;Morrison RF;Ferguson BS
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（DUSPs）通过去磷酸化作用抑制ERK 1/2，从而抑制炎症基因的表达。我们报告，DUSP 5，ERK 1/2磷酸酶，诱导在附睾白色脂肪组织（WAT）在饮食诱导的肥胖反应。此外，在肥胖发展过程中，DUSP 5 mRNA表达增加，同时TNFα表达增加。与体内研究结果一致，脂肪细胞中DUSP 5 mRNA表达增加，与ERK 1/2去磷酸化平行。DUSP 5的遗传缺失加剧了3 T3-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）信号转导减弱TNFα诱导的DUSP 5表达。这些数据表明，DUSP 5在响应TNFα的ERK 1/2信号传导的反馈抑制中起作用，这导致炎性基因表达增加。因此，DUSP 5可能作为脂肪组织炎症的内源性调节剂;尽管其在肥胖介导的炎症和胰岛素信号传导中的作用仍不清楚。
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.
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