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.
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.


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.
Rodríguez-Calvo
Ricardo
R
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.
Serrano
Lucía
L
Coll
Teresa
T
Moullan
Norman
N
Sánchez
Rosa M
RM
Merlos
Manuel
M
Palomer
Xavier
X
Laguna
Juan C
JC
Michalik
Liliane
L
Wahli
Walter
W
Vázquez-Carrera
Manuel
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000502:physiology; D048068:PPAR-beta / Q000819:agonists / Q000235:genetics / Q000502:physiology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology
D016207:Cytokines; C425931:GW 501516; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047494:PPAR delta; D048068:PPAR-beta; D047492:Peroxisome Proliferator-Activated Receptors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013844:Thiazoles; D004247:DNA; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3