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DUSP5 Regulation of Inflammation and Insulin Signaling
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Adipose tissue inflammation links obesity to insulin resistance and type 2 diabetes (T2D). Chronic inflammation of adipose tissue is characterized by increased expression of tumor necrosis factor ? (TNF?). TNF? stimulates signaling of mitogen-activated protein kinases (MAPKs) within adipocytes (i.e. fat cells) and muscle cells that drive systemic inflammation and insulin resistance, leading to T2D. Until recently, most studies focused on the role of upstream kinases that link TNF? to MAPK activation (i.e. phosphorylation); few studies have examined the role for downstream phosphatases in the deactivation (i.e. dephosphorylation) of this pathway. Therefore, I examined a role for the MAPK-specific dual-specificity phosphatases (DUSPs) in the deactivation of MAPK signaling in response to TNF?-mediated inflammation. We report that four of the ten DUSPs were induced during early stages of obesity development (Stage I), whereas gene expression increased for three out of ten DUSPs during late stage obesity (Stage II). Of the three DUSPs (DUSP1, 5, and 9), we show that DUSP5 regulates phosphorylation of a classical MAP kinase known as extracellular signal-regulated kinase 1/2 (ERK1/2); loss of DUSP5 function led to exacerbated ERK1/2 phosphorylation. These findings suggest that DUSP5 acts as an endogenous regulator of ERK1/2 signaling in response to obesity-mediated inflammation.