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

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 1; pp. 61 - 70
• Main Authors: Jager, Jennifer, Grémeaux, Thierry, Gonzalez, Teresa, Bonnafous, Stéphanie, Debard, Cyrille, Laville, Martine, Vidal, Hubert, Tran, Albert, Gual, Philippe, Le Marchand-Brustel, Yannick, Cormont, Mireille, Tanti, Jean-François
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2010
• Subjects: 3T3-L1 Cells; Adipocytes; Animals; Biological and medical sciences; Cell Differentiation; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasting; Humans; I-kappa B Kinase; Interleukin-1beta; Life Sciences; Lipolysis; Male; MAP Kinase Kinase Kinases; Medical sciences; Metabolic diseases; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Obese; Mitogen-Activated Protein Kinase 3; Obesity; Obesity, Morbid; Original; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; Thinness; Tumor Necrosis Factor-alpha; Up-Regulation; Endocrinopathy; Obesity; Adipose tissue; Extracellular signal-regulated protein kinase; Enzyme; Diabetes mellitus; Cytokine; Nutrition disorder; Interleukin 1β; Nutritional status; Tumor necrosis factor α; Lipolysis
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-0470

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 Jennifer Jager 1 , 2 , Thierry Grémeaux 1 , 2 , Teresa Gonzalez 1 , 2 , Stéphanie Bonnafous 2 , 3 , 4 , Cyrille Debard 5 , Martine Laville 5 , Hubert Vidal 5 , Albert Tran 2 , 3 , 4 , Philippe Gual 2 , 3 , 4 , Yannick Le Marchand-Brustel 1 , 2 , 4 , Mireille Cormont 1 , 2 and Jean-François Tanti 1 , 2 1 Institut National de la Santé et de la Recherche Médicale (INSERM), U895, Mediterranean Center of Molecular Medicine, Team 7 “Molecular and Cellular Physiopathology of Obesity and Diabetes,” Nice, France; 2 University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France; 3 INSERM, U895, Team 8 “Hepatic Complications in Obesity,” Nice, France; 4 Centre Hospitalier Universitaire of Nice, Digestive Center, Nice, France; 5 INSERM, U870-INRA U1235, “Metabolic Regulations, Nutrition, and Diabetes,” Lyon, France. Corresponding author: Jean-François Tanti, tanti{at}unice.fr . Abstract OBJECTIVE 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received March 30, 2009. Accepted September 14, 2009. © 2010 American Diabetes Association