Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis.
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.


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
IkappaB kinase-(IKK)-beta inhibition prevented mitogen-activated protein (MAP) kinase kinase (MEK)/ERK1/2 activation in response to interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha but not insulin in 3T3-L1 and human adipocytes, suggesting that IKKbeta 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-1beta and TNF-alpha activated Tpl2 and regulated its expression through an IKKbeta 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-alpha 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.
Jager
Jennifer
J
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.
Grémeaux
Thierry
T
Gonzalez
Teresa
T
Bonnafous
Stéphanie
S
Debard
Cyrille
C
Laville
Martine
M
Vidal
Hubert
H
Tran
Albert
A
Gual
Philippe
P
Le Marchand-Brustel
Yannick
Y
Cormont
Mireille
M
Tanti
Jean-François
JF
D041721:3T3-L1 Cells / Q000166:cytology*; D017667:Adipocytes / Q000166:cytology* / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D004789:Enzyme Activation; D005215:Fasting; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D008066:Lipolysis; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D009767:Obesity, Morbid / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013851:Thinness; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D053583:Interleukin-1beta; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse