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.

Abstract

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.

• Authors: Ricardo Rodríguez-Calvo, Lucía Serrano, Teresa Coll, Norman Moullan, Rosa M Sánchez, Manuel Merlos, Xavier Palomer, Juan C Laguna, Liliane Michalik, Walter Wahli, Manuel Vázquez-Carrera
• Journal: Diabetes (Diabetes) Vol. 57 Issue 8 Pg. 2149-57 (Aug 2008) ISSN: 1939-327X [Electronic] United States
• PMID: 18443198 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• GW 501516
• Interleukin-6
• Lipopolysaccharides
• NF-kappa B
• PPAR delta
• PPAR-beta
• Peroxisome Proliferator-Activated Receptors
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Thiazoles
• DNA
• Protein Kinases
• pyruvate dehydrogenase kinase 4
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase 3

Topics

• 3T3-L1 Cells
• Adipocytes (drug effects, metabolism)
• Animals
• Cytokines (biosynthesis)
• DNA (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression (drug effects)
• Interleukin-6 (genetics, metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mitogen-Activated Protein Kinase 3 (metabolism)
• NF-kappa B (metabolism)
• PPAR delta (agonists, genetics, physiology)
• PPAR-beta (agonists, genetics, physiology)
• Peroxisome Proliferator-Activated Receptors (agonists, genetics, physiology)
• Phosphorylation (drug effects)
• Protein Binding (drug effects)
• Protein Kinases (genetics, metabolism)
• Rats
• Rats, Zucker
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Thiazoles (pharmacology)