New PPAR gamma partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr-/- mice

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorSILVA, Jacqueline C.
dc.contributor.authorCESAR, Fernanda A.
dc.contributor.authorOLIVEIRA, Edson M. de
dc.contributor.authorTURATO, Walter M.
dc.contributor.authorTRIPODI, Gustavo L.
dc.contributor.authorCASTILHO, Gabriela
dc.contributor.authorMACHADO-LIMA, Adriana
dc.contributor.authorHERAS, Beatriz de las
dc.contributor.authorBOSCA, Lisardo
dc.contributor.authorRABELLO, Marcelo M.
dc.contributor.authorHERNANDES, Marcelo Z.
dc.contributor.authorPITTA, Marina G. R.
dc.contributor.authorPITTA, Ivan R.
dc.contributor.authorPASSARELLI, Marisa
dc.contributor.authorRUDNICKI, Martina
dc.contributor.authorABDALLA, Dulcineia S. P.
dc.date.accessioned2016-07-04T13:51:57Z
dc.date.available2016-07-04T13:51:57Z
dc.date.issued2016
dc.description.abstractPeroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma 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 PPAR gamma 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 (20 mg/kg/day), pioglitazone (20 mg/kg/day, diet-induced obesity model) or rosiglitazone (15 mg/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 PPAR), and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPAR gamma agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr-/- mice.
dc.description.indexMEDLINE
dc.description.sponsorshipSao Paulo Research Foundation (FAPESP) [2012/51316-5]
dc.description.sponsorshipNational Council for Scientific and Technological Development (National Institute of Science and Technology for Pharmaceutical Innovation (INCT_if/CNPq)) [573663/2008-4]
dc.description.sponsorshipNational Council for Scientific and Technological Development (CNPq/MICCIN grant) [BFU2011-2476]
dc.description.sponsorshipCNPq [201602/2011-03, 151568/2013-8]
dc.description.sponsorshipFAPESP [2012/14360-6, 2009/53072-3]
dc.identifier.citationPHARMACOLOGICAL RESEARCH, v.104, p.49-60, 2016
dc.identifier.doi10.1016/j.phrs.2015.12.010
dc.identifier.issn1043-6618
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/13866
dc.language.isoeng
dc.publisherACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
dc.relation.ispartofPharmacological Research
dc.rightsrestrictedAccess
dc.rights.holderCopyright ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
dc.subjectAtherosclerosis
dc.subjectDiabetes
dc.subjectObesity
dc.subjectPPAR gamma
dc.subjectThiazolidinediones
dc.subject.otheractivated receptor-gamma
dc.subject.othercardiovascular-disease
dc.subject.otherantidiabetic actions
dc.subject.othergene-expression
dc.subject.otherrosiglitazone
dc.subject.otherpioglitazone
dc.subject.otherthiazolidinediones
dc.subject.othercholesterol
dc.subject.othermodel
dc.subject.otheradiponectin
dc.subject.wosPharmacology & Pharmacy
dc.titleNew PPAR gamma partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr-/- mice
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countryEspanha
hcfmusp.affiliation.countryisoes
hcfmusp.author.externalSILVA, Jacqueline C.:Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP, Brazil
hcfmusp.author.externalCESAR, Fernanda A.:Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP, Brazil
hcfmusp.author.externalOLIVEIRA, Edson M. de:Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP, Brazil
hcfmusp.author.externalTURATO, Walter M.:Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP, Brazil
hcfmusp.author.externalTRIPODI, Gustavo L.:Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP, Brazil
hcfmusp.author.externalCASTILHO, Gabriela:Univ Sao Paulo, Fac Med, Lipids Lab LIM 10, Sao Paulo, SP, Brazil
hcfmusp.author.externalHERAS, Beatriz de las:Univ Complutense Madrid, Dept Pharmacol, Madrid, Spain
hcfmusp.author.externalBOSCA, Lisardo:Inst Invest Biomed Alberto Sols CSIC UAM, Madrid, Spain
hcfmusp.author.externalRABELLO, Marcelo M.:Univ Fed Pernambuco, Dept Pharmaceut Sci, Recife, PE, Brazil
hcfmusp.author.externalHERNANDES, Marcelo Z.:Univ Fed Pernambuco, Dept Pharmaceut Sci, Recife, PE, Brazil
hcfmusp.author.externalPITTA, Marina G. R.:Univ Fed Pernambuco, Core Therapeut Innovat, Recife, PE, Brazil
hcfmusp.author.externalPITTA, Ivan R.:Univ Fed Pernambuco, Core Therapeut Innovat, Recife, PE, Brazil
hcfmusp.author.externalRUDNICKI, Martina:Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP, Brazil
hcfmusp.author.externalABDALLA, Dulcineia S. P.:Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP, Brazil
hcfmusp.citation.scopus25
hcfmusp.contributor.author-fmusphcADRIANA MACHADO SALDIBA DE LIMA
hcfmusp.contributor.author-fmusphcMARISA PASSARELLI
hcfmusp.description.beginpage49
hcfmusp.description.endpage60
hcfmusp.description.volume104
hcfmusp.origemWOS
hcfmusp.origem.pubmed26706782
hcfmusp.origem.scopus2-s2.0-84952649439
hcfmusp.origem.wosWOS:000371841800006
hcfmusp.publisher.cityLONDON
hcfmusp.publisher.countryENGLAND
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