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Activation of Peroxisome Proliferator-Activated Receptor β/ (PPARβ/) Inhibits LPS-induced Cytokine Production in Adipocytes by Lowering NF-B Activity via ERK1/2

¹Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, IBUB (Institut de Biomedicina de la UB), and CIBERDEM-Instituto de Salud Carlos III, Diagonal 643, E-08028 Barcelona, Spain and
²Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland

Objective: Chronic activation of the nuclear factor (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: Firstly, we examined whether the PPARβ/ agonist GW501516 prevents 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 STAT3-SOCS3 pathway. This effect was associated with the capacity of GW501516 to impede LPS-induced NF-B activation. Secondly, in in vivo studies, white adipose tissue from Zucker Diabetic Fatty (ZDF) rats, compared to 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. Since mitogen-activated protein kinase (MAPK)–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. Further, 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 contribute to prevent insulin resistance.

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