title: New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr(-/-) mice.
abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr(-/-)) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr(-/-) mice.
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Silva
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Fernanda A
authors.initials: FA
authors.lastname: César
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Edson M
authors.initials: EM
authors.lastname: de Oliveira
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Turato
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Gustavo L
authors.initials: GL
authors.lastname: Tripodi
authors.affiliation: Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Castilho
authors.affiliation: Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Machado-Lima
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Las Heras
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, PE, Brazil.
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Rabello
authors.affiliation: Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife, PE, Brazil.
authors.forename: Marcelo Z
authors.initials: MZ
authors.lastname: Hernandes
authors.affiliation: Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil.
authors.forename: Marina G R
authors.initials: MG
authors.lastname: Pitta
authors.affiliation: Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil.
authors.forename: Ivan R
authors.initials: IR
authors.lastname: Pitta
authors.affiliation: Lipids Laboratory (LIM-10), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Marisa
authors.initials: M
authors.lastname: Passarelli
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Martina
authors.initials: M
authors.lastname: Rudnicki
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil. Electronic address: dspa@usp.br.
authors.forename: Dulcineia S P
authors.initials: DS
authors.lastname: Abdalla
mesh_terms: D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015519:Bone Density; D002460:Cell Line; D008076:Cholesterol, HDL / Q000097:blood; D005346:Fibroblast Growth Factors / Q000235:genetics; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006801:Humans; D020738:Leptin / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008958:Models, Molecular; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D008076:Cholesterol, HDL; C000612421:GQ-177; D051275:Glucose Transporter Type 4; D020738:Leptin; D047495:PPAR gamma; D011973:Receptors, LDL; C495693:Slc2a4 protein, mouse; D013450:Sulfones; D045162:Thiazolidinediones; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
keywords: Atherosclerosis; Diabetes; Obesity; PPARγ; Thiazolidinediones