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Activation of Peroxisome Proliferator–Activated Receptor β/ Inhibits Lipopolysaccharide-Induced Cytokine Production in Adipocytes by Lowering Nuclear Factor-B Activity via Extracellular Signal–Related Kinase 1/2

¹ Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, Institut de Biomedicina de la UB (IBUB) and CIBERDEM-Instituto de Salud Carlos III, University of Barcelona, Barcelona, Spain
² Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland

Corresponding author: Manuel Vázquez-Carrera, mvazquezcarrera{at}ub.edu

OBJECTIVE—Chronic activation of the nuclear factor-B (NF-B) 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) β/ activation prevents inflammation in adipocytes.

RESEARCH DESIGN AND METHODS AND RESULTS—First, we examined whether the PPARβ/ 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-B activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPARβ/ expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-B DNA-binding activity. Furthermore, IL-6 expression and NF-B DNA-binding activity was higher in white adipose tissue from PPARβ/-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-B activation in adipocytes, we explored whether PPARβ/ prevented NF-B activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylation by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-B activity, such as ZDF rats and PPARβ/-null mice, also showed enhanced phospho-ERK1/2 levels.

CONCLUSIONS—These findings indicate that activation of PPARβ/ inhibits enhanced cytokine production in adipocytes by preventing NF-B activation via ERK1/2, an effect that may help prevent insulin resistance.

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