Article: article from journal or magazin.
Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related kinase 1/2.
OBJECTIVE: Chronic activation of the nuclear factor-kappaB (NF-kappaB) in white adipose tissue leads to increased production of pro-inflammatory cytokines, which are involved in the development of insulin resistance. It is presently unknown whether peroxisome proliferator-activated receptor (PPAR) beta/delta activation prevents inflammation in adipocytes. RESEARCH DESIGN AND METHODS AND RESULTS: First, we examined whether the PPARbeta/delta agonist GW501516 prevents lipopolysaccharide (LPS)-induced cytokine production in differentiated 3T3-L1 adipocytes. Treatment with GW501516 blocked LPS-induced IL-6 expression and secretion by adipocytes and the subsequent activation of the signal transducer and activator of transcription 3 (STAT3)-Suppressor of cytokine signaling 3 (SOCS3) pathway. This effect was associated with the capacity of GW501516 to impede LPS-induced NF-kappaB activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPARbeta/delta expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-kappaB DNA-binding activity. Furthermore, IL-6 expression and NF-kappaB DNA-binding activity was higher in white adipose tissue from PPARbeta/delta-null mice than in wild-type mice. Because mitogen-activated protein kinase-extracellular signal-related kinase (ERK)1/2 (MEK1/2) is involved in LPS-induced NF-kappaB activation in adipocytes, we explored whether PPARbeta/delta prevented NF-kappaB activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylation by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-kappaB activity, such as ZDF rats and PPARbeta/delta-null mice, also showed enhanced phospho-ERK1/2 levels. CONCLUSIONS: These findings indicate that activation of PPARbeta/delta inhibits enhanced cytokine production in adipocytes by preventing NF-kappaB activation via ERK1/2, an effect that may help prevent insulin resistance.
3T3-L1 Cells, Adipocytes/drug effects, Adipocytes/metabolism, Animals, Cytokines/biosynthesis, DNA/metabolism, Extracellular Signal-Regulated MAP Kinases/metabolism, Gene Expression/drug effects, Interleukin-6/genetics, Interleukin-6/metabolism, Lipopolysaccharides/pharmacology, Male, Mice, Mitogen-Activated Protein Kinase 3/metabolism, NF-kappa B/metabolism, PPAR delta/agonists, PPAR delta/genetics, PPAR-beta/agonists, PPAR-beta/genetics, Peroxisome Proliferator-Activated Receptors/agonists, Peroxisome Proliferator-Activated Receptors/genetics, Phosphorylation/drug effects, Protein Binding/drug effects, Protein Kinases/genetics, Protein Kinases/metabolism, Rats, Rats, Zucker, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor/metabolism, Signal Transduction/drug effects, Thiazoles/pharmacology
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