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



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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.

Obesity is a global epidemic and major public health concern, in which obesity increases the risk of chronic illnesses such as; cardiovascular disease, stroke and type II diabetes1. Chronic, low-grade inflammation plays a causal role in the loss of insulin sensitivity of adipose tissue; adipose tissue inflammation and dysfunction link obesity to the pathogenesis of type II diabetes2,3. A key event in obesity is characterized by macrophage infiltration in adipose tissue, which triggers increased secretion of pro-inflammatory adipokines such as monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNFα). Secretion of MCP-1 further attracts macrophages to adipose tissue, exacerbating pro-inflammatory adipokine expression that results in chronic inflammation and systemic insulin resistance3.

Mitogen activated protein kinases (MAPKs) play a central role in the regulation of adipose tissue inflammation and insulin signaling4,5,6,7. Extracellular signal-regulated protein kinase (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 comprise the classical MAPKs and are involved in obesity-induced inflammation and insulin resistance7. For example, mice deficient in ERK1 are protected against diet-induced obesity and insulin resistance8. Substantial evidence demonstrates that TNFα perpetuates chronic inflammation leading to insulin resistance, as ablation of TNFα restores insulin sensitivity9,10,11. MAPK signaling links TNFα to cytosolic inhibition of insulin signaling via IRS-1 regulation and nuclear expression of pro-inflammatory adipokines5,7,12.

While it is well recognized that MAPKs are activated by phosphorylation of the conserved threonine and tyrosine residues within the T-X-Y motif in the activation loop by upstream MAPK kinases, less is known about their deactivation by phosphatases in the regulation of adipose inflammation6,13,14. Dual specificity phosphatases (DUSPs) constitute a subclass of protein tyrosine phosphatases that specifically dephosphorylate (i.e. deactivate) MAPKs. DUSPs are inducible protein phosphatases that have been shown to regulate cellular inflammation and more recently have been shown to play a role in obesity and insulin resistance, in particular through the regulation of MAPK deactivation14,15,16.

In this report, we show that TNFα-mediated phosphorylation of ERK1/2 and JNK stimulated expression of the ERK-specific phosphatase, dual-specificity phosphatase 5 (DUSP5) resulting in feedback inhibition of ERK signaling and ERK-dependent inflammatory gene expression in adipocytes. Consistent with…