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

Autor(es):Mostrar menos -

Silva, Jacqueline C. ^[1] ; Cesar, Fernanda A. ^[1] ; de Oliveira, Edson M. ^[1] ; Turato, Walter M. ^[1] ; Tripodi, Gustavo L. ^[1] ; Castilho, Gabriela ^[2] ; Machado-Lima, Adriana ^[2] ; de las Heras, Beatriz ^[3] ; Bosca, Lisardo ^[4] ; Rabello, Marcelo M. ^[5] ; Hernandes, Marcelo Z. ^[5] ; Pitta, Marina G. R. ^[6] ; Pitta, Ivan R. ^[6] ; Passarelli, Marisa ^[2] ; Rudnicki, Martina ^[1] ; Abdalla, Dulcineia S. P. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Fac Med, Lipids Lab LIM 10, Sao Paulo, SP - Brazil

^[3] Univ Complutense Madrid, Dept Pharmacol, Madrid - Spain

^[4] Inst Invest Biomed Alberto Sols CSIC UAM, Madrid - Spain

^[5] Univ Fed Pernambuco, Dept Pharmaceut Sci, Recife, PE - Brazil

^[6] Univ Fed Pernambuco, Core Therapeut Innovat, Recife, PE - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PHARMACOLOGICAL RESEARCH; v. 104, p. 49-60, FEB 2016.
• Citações Web of Science: 15

Resumo

Peroxisome 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. (C) 2015 Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 12/14360-6 - Investigação dos efeitos de novos derivados tiazolidínicos em modelo animal de síndrome metabólica.
• Beneficiário: Jacqueline Cavalcante Silva
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 09/53072-3 - Novas tiozolidinadionas: propriedades angiogenicas e efeitos em celulas endoteliais
• Beneficiário: Martina Rudnicki
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/51316-5 - Investigação da atividade de biofármacos, agonistas de PPARs e produtos naturais com potencial terapêutico na aterosclerose
• Beneficiário: Dulcineia Saes Parra Abdalla
• Modalidade de apoio: Auxílio à Pesquisa - Temático