serval:BIB_94587B68C0D0
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.
10.2337/db08-0176
000258134200018
18443198
Rodríguez-Calvo
R.
author
Serrano
L.
author
Coll
T.
author
Moullan
N.
author
Sánchez
R.M.
author
Merlos
M.
author
Palomer
X.
author
Laguna
J.C.
author
Michalik
L.
author
Wahli
W.
author
Vázquez-Carrera
M.
author
article
2008
Diabetes
1939-327X[electronic]
journal
57
8
2149-2157
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.
3T3-L1 Cells
Adipocytes/drug effects
Adipocytes/metabolism
Animals
Cytokines/biosynthesis
DNA/metabolism
Extracellular Signal-Regulated MAP Kinases/metabolism
Gene Expression/drug effects
Interleukin-6/genetics
Interleukin-6/metabolism
Lipopolysaccharides/pharmacology
Male
Mice
Mitogen-Activated Protein Kinase 3/metabolism
NF-kappa B/metabolism
PPAR delta/agonists
PPAR delta/genetics
PPAR-beta/agonists
PPAR-beta/genetics
Peroxisome Proliferator-Activated Receptors/agonists
Peroxisome Proliferator-Activated Receptors/genetics
Phosphorylation/drug effects
Protein Binding/drug effects
Protein Kinases/genetics
Protein Kinases/metabolism
Rats
Rats, Zucker
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor/metabolism
Signal Transduction/drug effects
Thiazoles/pharmacology
eng
60_published
true
peer-reviewed
University of Lausanne
mailto:serval_help@unil.ch
http://www.unil.ch/serval
http://serval.unil.ch/disclaimer
https://serval.unil.ch/notice/serval:BIB_94587B68C0D0