title: Chronic peroxisome proliferator-activated receptorβ/δ agonist GW0742 prevents hypertension, vascular inflammatory and oxidative status, and endothelial dysfunction in diet-induced obesity.
abstract: OBJECTIVE
  Endothelial dysfunction plays a key role in obesity-induced risk of cardiovascular disease. The aim of the present study was to analyze the effect of chronic peroxisome proliferator-activated receptor (PPAR)β/δ agonist GW0742 treatment on endothelial function in obese mice fed a high-fat diet (HFD).
  
  
  RESULTS
  Five-week-old male mice were allocated to one of the following groups: control, control-treated (GW0742, 3 mg/kg per day, by oral gavage), HFD, HFD + GW0742, HFD + GSK0660 (1 mg/kg/day, intraperitoneal) or HFD-GW0742-GSK0660 and followed for 11 or 13 weeks. GW0742 administration to mice fed HFD prevented the gain of body weight, heart and kidney hypertrophy, and fat accumulation. The increase in plasma levels of fasting glucose, glucose tolerance test, homeostatic model assessment of insulin resistance, and triglyceride found in the HFD group was suppressed by GW0742. This agonist increased plasma HDL in HFD-fed mice and restored the levels of tumor necrosis factor-α and adiponectin in fat. GW0742 prevented the impaired nitric oxide-dependent vasodilatation induced by acetylcholine in aortic rings from mice fed HFD. Moreover, GW0742 increased both aortic Akt and endothelial nitric oxide synthase phosphorylation, and inhibited the increase in caveolin-1/endothelial nitric oxide synthase interaction, ethidium fluorescence, NOX-1, Toll-like receptor 4, tumor necrosis factor-α, and interleukin-6 expression, and IκBα phosphorylation found in aortae from the HFD group. GSK0660 prevented all changes induced by GW0742.
  
  
  CONCLUSIONS
  PPARβ/δ activation prevents obesity and exerts protective effects on hypertension and on the early manifestations of atherosclerosis, that is, endothelial dysfunction and the vascular pro-oxidant and pro-inflammatory status, in HFD-fed mice.
authors.affiliation: aDepartment of Pharmacology, School of Pharmacy bCIBER-EHD, Department of Pharmacology, Center for Biomedical Research, University of Granada, Armilla, Granada cDepartment of Physiology, University of Valencia, Valencia dDepartment of Pharmacology, School of Medicine, University Complutense of Madrid, Madrid, Spain *Marta Toral and Manuel Gómez-Guzmán contributed equally to the writing of this article.
authors.forename: Marta
authors.initials: M
authors.lastname: Toral
authors.forename: Manuel
authors.initials: M
authors.lastname: Gómez-Guzmán
authors.forename: Rosario
authors.initials: R
authors.lastname: Jiménez
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.forename: María José
authors.initials: MJ
authors.lastname: Zarzuelo
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Utrilla
authors.forename: Carlos
authors.initials: C
authors.lastname: Hermenegildo
authors.forename: Ángel
authors.initials: Á
authors.lastname: Cogolludo
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.forename: Julio
authors.initials: J
authors.lastname: Gálvez
authors.forename: Juan
authors.initials: J
authors.lastname: Duarte
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects; D051242:Caveolin 1 / Q000378:metabolism; D059305:Diet, High-Fat; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006973:Hypertension / Q000503:physiopathology / Q000517:prevention & control*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000517:prevention & control*; D047494:PPAR delta / Q000819:agonists* / Q000037:antagonists & inhibitors; D048068:PPAR-beta / Q000819:agonists* / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D051242:Caveolin 1; D015850:Interleukin-6; D052250:Nitric Oxide Synthase Type III; D047494:PPAR delta; D048068:PPAR-beta; D017382:Reactive Oxygen Species; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C529769:GSK0660; C508600:IL6 protein, human; C495345:TLR4 protein, human; 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