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However, the effects of PPAR-<jats:italic>\u03b4<\/jats:italic>agonism within the skeletal muscle, which plays a key role in whole-body glucose metabolism, remain unclear. This study aimed to investigate the signaling pathways activated in the gastrocnemius muscle by chronic administration of the selective PPAR-<jats:italic>\u03b4<\/jats:italic>agonist, GW0742 (1\u2009mg\/kg\/day for 16 weeks), in male C57Bl6\/J mice treated for 30 weeks with high-fructose corn syrup (HFCS), the major sweetener in foods and soft-drinks (15%\u2009wt\/vol in drinking water). Mice fed with the HFCS diet exhibited hyperlipidemia, hyperinsulinemia, hyperleptinemia, and hypoadiponectinemia. In the gastrocnemius muscle, HFCS impaired insulin and AMP-activated protein kinase signaling pathways and reduced GLUT-4 and GLUT-5 expression and membrane translocation. GW0742 administration induced PPAR-<jats:italic>\u03b4<\/jats:italic>upregulation and improvement in glucose and lipid metabolism. Diet-induced activation of nuclear factor-<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\"><mml:mrow><mml:mi>\u03ba<\/mml:mi><\/mml:mrow><\/mml:math>B and expression of inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1 were attenuated by drug treatment. These effects were accompanied by reduction in the serum concentration of interleukin-6 and increase in muscular expression of fibroblast growth factor-21. Overall, here we show that PPAR-<jats:italic>\u03b4<\/jats:italic>activation protects the skeletal muscle against the metabolic abnormalities caused by chronic HFCS exposure by affecting multiple levels of the insulin and inflammatory cascades.<\/jats:p>","DOI":"10.1155\/2013\/509502","type":"journal-article","created":{"date-parts":[[2013,6,18]],"date-time":"2013-06-18T17:01:17Z","timestamp":1371574877000},"page":"1-12","source":"Crossref","is-referenced-by-count":32,"title":["High Sugar Intake and Development of Skeletal Muscle Insulin Resistance and Inflammation in Mice: A Protective Role for PPAR-<i>\u03b4<\/i>Agonism"],"prefix":"10.1155","volume":"2013","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4481-0756","authenticated-orcid":true,"given":"Elisa","family":"Benetti","sequence":"first","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Torino, 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