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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.
Diabetes. 2008 Aug; 57(8):2149-57.D

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18443198

Citation

Rodríguez-Calvo, Ricardo, et al. "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." Diabetes, vol. 57, no. 8, 2008, pp. 2149-57.
Rodríguez-Calvo R, Serrano L, Coll T, et al. 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. Diabetes. 2008;57(8):2149-57.
Rodríguez-Calvo, R., Serrano, L., Coll, T., Moullan, N., Sánchez, R. M., Merlos, M., Palomer, X., Laguna, J. C., Michalik, L., Wahli, W., & Vázquez-Carrera, M. (2008). 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. Diabetes, 57(8), 2149-57. https://doi.org/10.2337/db08-0176
Rodríguez-Calvo R, et al. 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. Diabetes. 2008;57(8):2149-57. PubMed PMID: 18443198.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Rodríguez-Calvo,Ricardo, AU - Serrano,Lucía, AU - Coll,Teresa, AU - Moullan,Norman, AU - Sánchez,Rosa M, AU - Merlos,Manuel, AU - Palomer,Xavier, AU - Laguna,Juan C, AU - Michalik,Liliane, AU - Wahli,Walter, AU - Vázquez-Carrera,Manuel, Y1 - 2008/04/28/ PY - 2008/4/30/pubmed PY - 2008/9/5/medline PY - 2008/4/30/entrez SP - 2149 EP - 57 JF - Diabetes JO - Diabetes VL - 57 IS - 8 N2 - 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. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/18443198/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_ DB - PRIME DP - Unbound Medicine ER -