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: 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.