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The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells.
Diabetologia. 2012 Mar; 55(3):743-51.D

Abstract

AIM/HYPOTHESIS

IL-6 induces insulin resistance by activating signal transducer and activator of transcription 3 (STAT3) and upregulating the transcription of its target gene SOCS3. Here we examined whether the peroxisome proliferator-activated receptor (PPAR)β/δ agonist GW501516 prevented activation of the IL-6-STAT3-suppressor of cytokine signalling 3 (SOCS3) pathway and insulin resistance in human hepatic HepG2 cells.

METHODS

Studies were conducted with human HepG2 cells and livers from mice null for Pparβ/δ (also known as Ppard) and wild-type mice.

RESULTS

GW501516 prevented IL-6-dependent reduction in insulin-stimulated v-akt murine thymoma viral oncogene homologue 1 (AKT) phosphorylation and in IRS-1 and IRS-2 protein levels. In addition, treatment with this drug abolished IL-6-induced STAT3 phosphorylation of Tyr⁷⁰⁵ and Ser⁷²⁷ and prevented the increase in SOCS3 caused by this cytokine. Moreover, GW501516 prevented IL-6-dependent induction of extracellular-related kinase 1/2 (ERK1/2), a serine-threonine protein kinase involved in serine STAT3 phosphorylation; the livers of Pparβ/δ-null mice showed increased Tyr⁷⁰⁵- and Ser⁷²⁷-STAT3 as well as phospho-ERK1/2 levels. Furthermore, drug treatment prevented the IL-6-dependent reduction in phosphorylated AMP-activated protein kinase (AMPK), a kinase reported to inhibit STAT3 phosphorylation on Tyr⁷⁰⁵. In agreement with the recovery in phospho-AMPK levels observed following GW501516 treatment, this drug increased the AMP/ATP ratio and decreased the ATP/ADP ratio.

CONCLUSIONS/INTERPRETATION

Overall, our findings show that the PPARβ/δ activator GW501516 prevents IL-6-induced STAT3 activation by inhibiting ERK1/2 phosphorylation and preventing the reduction in phospho-AMPK levels. These effects of GW501516 may contribute to the prevention of cytokine-induced insulin resistance in hepatic cells.

Authors+Show Affiliations

Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institut de Biomedicina de la UB, Diagonal 643, E-08028 Barcelona, Spain.No 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

22179221

Citation

Serrano-Marco, L, et al. "The Peroxisome Proliferator-activated Receptor (PPAR) Β/δ Agonist GW501516 Inhibits IL-6-induced Signal Transducer and Activator of Transcription 3 (STAT3) Activation and Insulin Resistance in Human Liver Cells." Diabetologia, vol. 55, no. 3, 2012, pp. 743-51.
Serrano-Marco L, Barroso E, El Kochairi I, et al. The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. Diabetologia. 2012;55(3):743-51.
Serrano-Marco, L., Barroso, E., El Kochairi, I., Palomer, X., Michalik, L., Wahli, W., & Vázquez-Carrera, M. (2012). The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. Diabetologia, 55(3), 743-51. https://doi.org/10.1007/s00125-011-2401-4
Serrano-Marco L, et al. The Peroxisome Proliferator-activated Receptor (PPAR) Β/δ Agonist GW501516 Inhibits IL-6-induced Signal Transducer and Activator of Transcription 3 (STAT3) Activation and Insulin Resistance in Human Liver Cells. Diabetologia. 2012;55(3):743-51. PubMed PMID: 22179221.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. AU - Serrano-Marco,L, AU - Barroso,E, AU - El Kochairi,I, AU - Palomer,X, AU - Michalik,L, AU - Wahli,W, AU - Vázquez-Carrera,M, Y1 - 2011/12/17/ PY - 2011/09/12/received PY - 2011/11/10/accepted PY - 2011/12/20/entrez PY - 2011/12/20/pubmed PY - 2012/7/20/medline SP - 743 EP - 51 JF - Diabetologia JO - Diabetologia VL - 55 IS - 3 N2 - AIM/HYPOTHESIS: IL-6 induces insulin resistance by activating signal transducer and activator of transcription 3 (STAT3) and upregulating the transcription of its target gene SOCS3. Here we examined whether the peroxisome proliferator-activated receptor (PPAR)β/δ agonist GW501516 prevented activation of the IL-6-STAT3-suppressor of cytokine signalling 3 (SOCS3) pathway and insulin resistance in human hepatic HepG2 cells. METHODS: Studies were conducted with human HepG2 cells and livers from mice null for Pparβ/δ (also known as Ppard) and wild-type mice. RESULTS: GW501516 prevented IL-6-dependent reduction in insulin-stimulated v-akt murine thymoma viral oncogene homologue 1 (AKT) phosphorylation and in IRS-1 and IRS-2 protein levels. In addition, treatment with this drug abolished IL-6-induced STAT3 phosphorylation of Tyr⁷⁰⁵ and Ser⁷²⁷ and prevented the increase in SOCS3 caused by this cytokine. Moreover, GW501516 prevented IL-6-dependent induction of extracellular-related kinase 1/2 (ERK1/2), a serine-threonine protein kinase involved in serine STAT3 phosphorylation; the livers of Pparβ/δ-null mice showed increased Tyr⁷⁰⁵- and Ser⁷²⁷-STAT3 as well as phospho-ERK1/2 levels. Furthermore, drug treatment prevented the IL-6-dependent reduction in phosphorylated AMP-activated protein kinase (AMPK), a kinase reported to inhibit STAT3 phosphorylation on Tyr⁷⁰⁵. In agreement with the recovery in phospho-AMPK levels observed following GW501516 treatment, this drug increased the AMP/ATP ratio and decreased the ATP/ADP ratio. CONCLUSIONS/INTERPRETATION: Overall, our findings show that the PPARβ/δ activator GW501516 prevents IL-6-induced STAT3 activation by inhibiting ERK1/2 phosphorylation and preventing the reduction in phospho-AMPK levels. These effects of GW501516 may contribute to the prevention of cytokine-induced insulin resistance in hepatic cells. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/22179221/The_peroxisome_proliferator_activated_receptor__PPAR__β/δ_agonist_GW501516_inhibits_IL_6_induced_signal_transducer_and_activator_of_transcription_3__STAT3__activation_and_insulin_resistance_in_human_liver_cells_ L2 - https://doi.org/10.1007/s00125-011-2401-4 DB - PRIME DP - Unbound Medicine ER -