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

作者：Silva Jacqueline C; Cesar Fernanda A; de Oliveira Edson M; Turato Walter M; Tripodi Gustavo L; Castilho Gabriela; Machado Lima Adriana; de las Heras Beatriz; Bosca Lisardo; Rabello Marcelo M; Hernandes Marcelo Z; Pitta Marina G R; Pitta Ivan R; Passarelli Marisa; Rudnicki Martina; Abdalla Dulcineia S P^*

来源：Pharmacological Research, 2016, 104: 49-60.

DOI：10.1016/j.phrs.2015.12.010

• Atherosclerosis
• Diabetes
• Obesity
• PPAR gamma
• Thiazolidinediones

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.

• 出版日期2016-2