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Palmitate-Mediated Downregulation of Peroxisome Proliferator–Activated Receptor- Coactivator 1 in Skeletal Muscle Cells Involves MEK1/2 and Nuclear Factor-B Activation

From the Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain

Address correspondence and reprint requests to Manuel Vázquez-Carrera, Unitat de Farmacologia, Facultat de Farmàcia, Diagonal 643, E-08028 Barcelona, Spain. E-mail: mvazquezcarrera{at}ub.edu

Abbreviations: DMEM, Dulbecco’s modified Eagle’s medium; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal–related kinase; FFA, free fatty acid; IB, inhibitor of B; IL, interleukin; MAPK, mitogen-activated protein kinase; MEK1/2, MAPK-ERK 1/2; NF-B, nuclear factor-B; PMA, phorbol myristic acid; PGC, PPAR- coactivator; PPAR, peroxisome proliferator–activated receptor; PKC, protein kinase C

The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood. Previous studies have reported that insulin-resistant states are characterized by a reduction in the expression of peroxisome proliferator–activated receptor- coactivator (PGC)-1, a transcriptional activator that promotes oxidative capacity in skeletal muscle cells. However, little is known about the factors responsible for reduced PGC-1 expression. The expression of PGC-1 mRNA levels was assessed in C2C12 skeletal muscle cells exposed to palmitate either in the presence or in the absence of several inhibitors to study the biochemical pathways involved. We report that exposure of C2C12 skeletal muscle cells to 0.75 mmol/l palmitate, but not oleate, reduced PGC-1 mRNA levels (66%; P < 0.001), whereas PGC-1ß expression was not affected. Palmitate led to mitogen-activated protein kinase (MAPK)–extracellular signal–related kinase (ERK) 1/2 (MEK1/2) activation. In addition, pharmacological inhibition of this pathway by coincubation of the palmitate-exposed cells with the MEK1/2 inhibitors PD98059 and U0126 prevented the downregulation of PGC-1. Furthermore, nuclear factor-B (NF-B) activation was also involved in palmitate-mediated PGC-1 downregulation, since the NF-B inhibitor parthenolide prevented a decrease in PGC-1 expression. These findings indicate that palmitate reduces PGC-1 expression in skeletal muscle cells through a mechanism involving MAPK-ERK and NF-B activation.

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