Tpl2 Kinase Is Upregulated in Adipose Tissue in Obesity and May Mediate Interleukin-1β and Tumor Necrosis Factor-α Effects on Extracellular Signal–Regulated Kinase Activation and Lipolysis

International audienceOBJECTIVE Activation of extracellular signal–regulated kinase-(ERK)-1/2 by cytokines in adipocytes is involved in the alterations of adipose tissue functions participating in insulin resistance. This study aims at identifying proteins regulating ERK1/2 activity, specifically in response to inflammatory cytokines, to provide new insights into mechanisms leading to abnormal adipose tissue function. RESEARCH DESIGN AND METHODS Kinase activities were inhibited with pharmacological inhibitors or siRNA. Lipolysis was monitored through glycerol production. Gene expression in adipocytes and adipose tissue of obese mice and subjects was measured by real-time PCR. RESULTS IκB kinase-(IKK)-β inhibition prevented mitogen-activated protein (MAP) kinase kinase (MEK)/ERK1/2 activation in response to interleukin (IL)-1β and tumor necrosis factor (TNF)-α but not insulin in 3T3-L1 and human adipocytes, suggesting that IKKβ regulated a MAP kinase kinase kinase (MAP3K) involved in ERK1/2 activation induced by inflammatory cytokines. We show that the MAP3K8 called Tpl2 was expressed in adipocytes and that IL-1β and TNF-α activated Tpl2 and regulated its expression through an IKKβ pathway. Pharmacological inhibition or silencing of Tpl2 prevented MEK/ERK1/2 activation by these cytokines but not by insulin, demonstrating its involvement in ERK1/2 activation specifically in response to inflammatory stimuli. Importantly, Tpl2 was implicated in cytokine-induced lipolysis and in insulin receptor substrate-1 serine phosphorylation. Tpl2 mRNA expression was upregulated in adipose tissue of obese mice and patients and correlated with TNF-α expression. CONCLUSIONS Tpl2 is selectively involved in inflammatory cytokine–induced ERK1/2 activation in adipocytes and is implicated in their deleterious effects on adipocyte functions. The deregulated expression of Tpl2 in adipose tissue suggests that Tpl2 may be a new actor in adipose tissue dysfunction in obesity

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Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle

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Mitochondrial fat metabolism and genes in human muscle are down-regulated by detraining prior to changes in insulin sensitivity

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Effect of serum from IR subjects (15 min) on Akt and GSK3β phosphorylation in differentiated human myotubes.

<p>Each bar is the mean of the results with sera from 7 IR subjects. Experiments were performed in triplicate for each individual. Ctr denotes controls. <i>Panel A</i>: Basal ⁴⁷³Ser Akt phosphorylation in the presence of 100 nM insulin or of different serum concentrations (5%, 10% and 20%) from IR subjects. Blots are representative western blots of ⁹Ser Akt phosphorylation and total Akt amounts. Data (mean ± s.d.) are expressed as fold change versus control condition (no insulin nor serum) set at 1 (^*<i>P</i><0.05 vs. control). <i>Panel B</i>: Basal ⁹Ser GSK3β phosphorylation in the presence of 100 nM insulin or of different serum concentrations (5%, 10% and 20%) from IR subjects. The blot is a representative western blots of ⁹Ser GSK3β phosphorylation. Data (mean ± s.d.) are expressed as fold change versus control condition (no insulin nor serum) set at 1 (^*<i>P</i><0.05 vs. control).</p