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Activation of peroxisome proliferator-activated receptor-{delta} by GW501516 prevents fatty acid-induced nuclear factor-{kappa}B activation and insulin resistance in skeletal muscle cells.
Endocrinology 2010; 151(4):1560-9E

Abstract

Elevated plasma free fatty acids cause insulin resistance in skeletal muscle through the activation of a chronic inflammatory process. This process involves nuclear factor (NF)-kappaB activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase Ctheta (PKCtheta) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-delta (PPARdelta) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPARdelta agonist GW501516 prevented phosphorylation of insulin receptor substrate-1 at Ser(307) and the inhibition of insulin-stimulated Akt phosphorylation caused by exposure to the saturated fatty acid palmitate. This latter effect was reversed by the PPARdelta antagonist GSK0660. Treatment with the PPARdelta agonist enhanced the expression of two well known PPARdelta target genes involved in fatty acid oxidation, carnitine palmitoyltransferase-1 and pyruvate dehydrogenase kinase 4 and increased the phosphorylation of AMP-activated protein kinase, preventing the reduction in fatty acid oxidation caused by palmitate exposure. In agreement with these changes, GW501516 treatment reversed the increase in DAG and PKCtheta activation caused by palmitate. These effects were abolished in the presence of the carnitine palmitoyltransferase-1 inhibitor etomoxir, thereby indicating that increased fatty acid oxidation was involved in the changes observed. Consistent with these findings, PPARdelta activation by GW501516 blocked palmitate-induced NF-kappaB DNA-binding activity. Likewise, drug treatment inhibited the increase in IL-6 expression caused by palmitate in C2C12 and human skeletal muscle cells as well as the protein secretion of this cytokine. These findings indicate that PPARdelta attenuates fatty acid-induced NF-kappaB activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPARdelta activation as a pharmacological target to prevent insulin resistance.

Authors+Show Affiliations

Unitat de Farmacologia. Facultat de Farmàcia, 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

20185762

Citation

Coll, Teresa, et al. "Activation of Peroxisome Proliferator-activated Receptor-{delta} By GW501516 Prevents Fatty Acid-induced Nuclear factor-{kappa}B Activation and Insulin Resistance in Skeletal Muscle Cells." Endocrinology, vol. 151, no. 4, 2010, pp. 1560-9.
Coll T, Alvarez-Guardia D, Barroso E, et al. Activation of peroxisome proliferator-activated receptor-{delta} by GW501516 prevents fatty acid-induced nuclear factor-{kappa}B activation and insulin resistance in skeletal muscle cells. Endocrinology. 2010;151(4):1560-9.
Coll, T., Alvarez-Guardia, D., Barroso, E., Gómez-Foix, A. M., Palomer, X., Laguna, J. C., & Vázquez-Carrera, M. (2010). Activation of peroxisome proliferator-activated receptor-{delta} by GW501516 prevents fatty acid-induced nuclear factor-{kappa}B activation and insulin resistance in skeletal muscle cells. Endocrinology, 151(4), pp. 1560-9. doi:10.1210/en.2009-1211.
Coll T, et al. Activation of Peroxisome Proliferator-activated Receptor-{delta} By GW501516 Prevents Fatty Acid-induced Nuclear factor-{kappa}B Activation and Insulin Resistance in Skeletal Muscle Cells. Endocrinology. 2010;151(4):1560-9. PubMed PMID: 20185762.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of peroxisome proliferator-activated receptor-{delta} by GW501516 prevents fatty acid-induced nuclear factor-{kappa}B activation and insulin resistance in skeletal muscle cells. AU - Coll,Teresa, AU - Alvarez-Guardia,David, AU - Barroso,Emma, AU - Gómez-Foix,Anna Maria, AU - Palomer,Xavier, AU - Laguna,Juan C, AU - Vázquez-Carrera,Manuel, Y1 - 2010/02/25/ PY - 2010/2/27/entrez PY - 2010/2/27/pubmed PY - 2010/4/10/medline SP - 1560 EP - 9 JF - Endocrinology JO - Endocrinology VL - 151 IS - 4 N2 - Elevated plasma free fatty acids cause insulin resistance in skeletal muscle through the activation of a chronic inflammatory process. This process involves nuclear factor (NF)-kappaB activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase Ctheta (PKCtheta) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-delta (PPARdelta) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPARdelta agonist GW501516 prevented phosphorylation of insulin receptor substrate-1 at Ser(307) and the inhibition of insulin-stimulated Akt phosphorylation caused by exposure to the saturated fatty acid palmitate. This latter effect was reversed by the PPARdelta antagonist GSK0660. Treatment with the PPARdelta agonist enhanced the expression of two well known PPARdelta target genes involved in fatty acid oxidation, carnitine palmitoyltransferase-1 and pyruvate dehydrogenase kinase 4 and increased the phosphorylation of AMP-activated protein kinase, preventing the reduction in fatty acid oxidation caused by palmitate exposure. In agreement with these changes, GW501516 treatment reversed the increase in DAG and PKCtheta activation caused by palmitate. These effects were abolished in the presence of the carnitine palmitoyltransferase-1 inhibitor etomoxir, thereby indicating that increased fatty acid oxidation was involved in the changes observed. Consistent with these findings, PPARdelta activation by GW501516 blocked palmitate-induced NF-kappaB DNA-binding activity. Likewise, drug treatment inhibited the increase in IL-6 expression caused by palmitate in C2C12 and human skeletal muscle cells as well as the protein secretion of this cytokine. These findings indicate that PPARdelta attenuates fatty acid-induced NF-kappaB activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPARdelta activation as a pharmacological target to prevent insulin resistance. SN - 1945-7170 UR - https://www.unboundmedicine.com/medline/citation/20185762/Activation_of_peroxisome_proliferator_activated_receptor_{delta}_by_GW501516_prevents_fatty_acid_induced_nuclear_factor_{kappa}B_activation_and_insulin_resistance_in_skeletal_muscle_cells_ L2 - https://academic.oup.com/endo/article-lookup/doi/10.1210/en.2009-1211 DB - PRIME DP - Unbound Medicine ER -