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J. Biol. Chem., Vol. 283, Issue 17, 11107-11116, April 25, 2008

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Oleate Reverses Palmitate-induced Insulin Resistance and Inflammation in Skeletal Muscle Cells^*

Teresa Coll^¶1, Elena Eyre^¶, Ricardo Rodríguez-Calvo^¶2, Xavier Palomer^¶1, Rosa M. Sánchez^¶, Manuel Merlos^¶, Juan Carlos Laguna^¶, and Manuel Vázquez-Carrera^¶3

From the Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, the CIBERDEM, Instituto de Salud Carlos III, and the ^¶Institut de Biomedicina de la UB, Diagonal 643, E-08028 Barcelona, Spain

Here we report that in skeletal muscle cells the contribution to insulin resistance and inflammation of two common dietary long-chain fatty acids depends on the channeling of these lipids to distinct cellular metabolic fates. Exposure of cells to the saturated fatty acid palmitate led to enhanced diacylglycerol levels and the consequent activation of the protein kinase C/nuclear factor B pathway, finally resulting in enhanced interleukin 6 secretion and down-regulation of the expression of genes involved in the control of the oxidative capacity of skeletal muscle (peroxisome proliferator-activated receptor (PPAR)-coactivator 1) and triglyceride synthesis (acyl-coenzyme A: diacylglycerol acyltransferase 2). In contrast, exposure to the monounsaturated fatty acid oleate did not lead to these changes. Interestingly, co-incubation of cells with palmitate and oleate reversed both inflammation and impairment of insulin signaling by channeling palmitate into triglycerides and by up-regulating the expression of genes involved in mitochondrial β-oxidation, thus reducing its incorporation into diacylglycerol. Our findings support a model of cellular lipid metabolism in which oleate protects against palmitate-induced inflammation and insulin resistance in skeletal muscle cells by promoting triglyceride accumulation and mitochondrial β-oxidation through PPAR- and protein kinase A-dependent mechanisms.

Received for publication, October 22, 2007 , and in revised form, February 11, 2008.

^* This work was supported in part by funds from the Fundación Ramón Areces, Spain's Ministerio de Educación y Ciencia (SAF2006-01475), ISCIII-RETIC RD06/0015/FEDER, European Union FEDER funds, and Fundació Privada Catalana de Nutriciói Lípids. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by grants from the Ministerio de Educación y Ciencia of Spain.

² Supported by a grant from the Fundación Ramón Areces.

³ To whom correspondence should be addressed: Unitat de Farmacologia, Facultat de Farmàcia, Diagonal 643, E-08028 Barcelona, Spain. Tel.: 34-93-4024531; Fax: 34-93-4035982; E-mail: mvazquezcarrera{at}ub.edu.

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