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

Abstract

Objective: Chronic activation of the nuclear factor (NF)-κB 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/δ activation prevents inflammation in adipocytes.

Research Design and Methods and Results: Firstly, we examined whether the PPARβ/δ 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-κB activation. Secondly, in in vivo studies, white adipose tissue from Zucker Diabetic Fatty (ZDF) rats, compared to that of lean rats, showed reduced PPARβ/δ expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-κB DNA-binding activity. Furthermore, IL-6 expression and NF-κB DNA-binding activity was higher in white adipose tissue from PPARβ/δ-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-κB activation in adipocytes, we explored whether PPARβ/δ prevented NF-κB activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2-phosphorylation by LPS. Further, white adipose tissue from animal showing constitutively increased NF-κB activity, such as ZDF rats and PPARβ/δ-null mice, also showed enhanced phospho-ERK1/2 levels.

Conclusions: These findings indicate that activation of PPARβ/δ inhibits enhanced cytokine production in adipocytes by preventing NF-κB activation via ERK1/2, an effect that may contribute to prevent insulin resistance.