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DUSP5 Functions in a Feedback Loop to Suppress TNFα‐Induced ERK1/2 Phosphorylation and Inflammation in Adipocytes
Author(s) -
Habibian Justine S,
Jefic Mitra,
Schepps Abbie,
Bagchi Rushita A,
McKnight Robert A,
McKinsey Timothy A,
Morrsion Ron F,
Ferguson Bradley S
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.794.12
Subject(s) - dephosphorylation , phosphorylation , kinase , microbiology and biotechnology , inflammation , biology , phosphatase , tumor necrosis factor alpha , signal transduction , insulin receptor , gene knockdown , insulin resistance , endocrinology , medicine , immunology , insulin , biochemistry , gene
Adipose tissue inflammation is a central pathogenic element that links obesity to insulin resistance and type II diabetes. Evidence demonstrates that extracellular signal‐regulated kinase 1/2 (ERK1/2) acts as a key signaling molecule that can inhibit insulin signaling in the cytosol and promote pro‐inflammatory gene expression in the nucleus. Recent evidence demonstrates that dual specificity phosphatases (DUSPs) dephosphorylate (i.e. inactivate) ERK1/2, thus inhibiting inflammation and insulin resistance. In this report, we observed that the ERK1/2‐specific phosphatase, DUSP5, was induced in response to high fat diet‐induced obesity. Moreover, increased DUSP5 gene expression correlated with increased tumor necrosis factor α (TNFα) gene expression in response to high fat diet‐induced obesity over time. Based on these findings, we examined a role for DUSP5 on ERK1/2 dephosphorylation and pro‐inflammatory gene expression in 3T3‐L1 adipocytes exposed to TNFα. We demonstrate that DUSP5 functions as a negative regulator of TNFα‐mediated ERK1/2 phosphorylation leading to inflammation. We report a rapid phosphorylation and subsequent dephosphorylation of ERK1/2 in 3T3‐L1 adipocytes in response to TNFα stimulation; concomitant to ERK1/2 dephosphorylation we further observed increased DUSP5 expression in 3T3‐L1 adipocytes stimulated with TNFα, suggesting a role for DUSP5 in the regulation of ERK1/2 signaling. Consistent with this hypothesis, genetic knockdown of DUSP5 led to sustained ERK1/2 activation and enhanced inflammatory gene expression in response to TNFα. Mitogen‐activated protein kinases (MAPKs) have been reported to regulate DUSPs, thus creating a feedback inhibitory loop. Indeed, we report that inhibition of both ERK1/2 and c‐Jun N terminal kinase (JNK) attenuated TNFα‐induced DUSP5 expression. Further loss‐of‐function studies are underway to examine a role for DUSP5 on adipose tissue inflammation in vivo using DUSP5 knockout mice in response inflammatory stimuli and/or diet‐induced obesity. Collectively, these data support the postulate that DUSP5 functions in the feedback inhibition of ERK1/2 signaling in response to inflammation and that loss of DUSP5 function exacerbates the inflammatory response in adipocytes. Support or Funding Information This work is supported by the USDA National Institute of Food and Agriculture (Hatch‐NEV00727). Core facilities used for Research reported in this publication was supported by National Institute of General Medical Sciences of the National Institutes of Health (P20 GM103554).