title: High sugar intake and development of skeletal muscle insulin resistance and inflammation in mice: a protective role for PPAR- δ agonism.
abstract: Peroxisome Proliferator Activated Receptor (PPAR)- δ agonists may serve for treating metabolic diseases. However, the effects of PPAR- δ 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- δ agonist, GW0742 (1 mg/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% wt/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- δ upregulation and improvement in glucose and lipid metabolism. Diet-induced activation of nuclear factor-κB 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- δ activation protects the skeletal muscle against the metabolic abnormalities caused by chronic HFCS exposure by affecting multiple levels of the insulin and inflammatory cascades.
authors.affiliation: Department of Drug Science and Technology, University of Turin, Via Giuria 9, 10125 Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.forename: Mara
authors.initials: M
authors.lastname: Rogazzo
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Marco A
authors.initials: MA
authors.lastname: Minetto
mesh_terms: D000818:Animals; D002241:Carbohydrates / Q000008:administration & dosage*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D064427:Nutritive Sweeteners / Q000008:administration & dosage; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D002241:Carbohydrates; D005346:Fibroblast Growth Factors; D005947:Glucose; D007328:Insulin; D015850:Interleukin-6; D064427:Nutritive Sweeteners; D047494:PPAR delta; D013844:Thiazoles; C414620:fibroblast growth factor 21; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds