Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappa B activity via extracellular signal-related kinase 1/2

作者：Rodriguez Calvo Ricardo; Serrano Lucia; Coll Teresa; Moullan Norman; Sanchez Rosa M; Merlos Manuel; Palomer Xavier; Laguna Juan C; Michalik Liliane; Wahli Walter; Vazquez Carrera Manuel^*

来源：Diabetes, 2008, 57(8): 2149-2157.

DOI：10.2337/db08-0176

OBJECTIVE-Chronic activation of the nuclear factor-kappa B (NF-kappa 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) beta/delta activation prevents inflammation in adipocytes.
RESEARCH DESIGN AND METHODS AND RESULTS-First, we examined whether the PPAR beta/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-kappa B activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPAR beta/delta expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-kappa B DNA-binding activity. Furthermore, IL-6 expression and NF-kappa B DNA-binding activity was higher in white adipose tissue from PPAR beta/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-kappa B activation in adipocytes, we explored whether PPAR beta/delta prevented NF-kappa B activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylahon by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-kappa B activity, such as ZDF rats and PPAR beta/delta-null mice, also showed enhanced phospho-ERK1/2 levels.
CONCLUSIONS-These findings indicate that activation of PPAR beta/delta inhibits enhanced cytokine production in adipocytes by preventing NF-kappa B activation via ERK1/2, an effect that may help prevent insulin resistance.

• 出版日期2008-8