New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr−/− mice

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 (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 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.This study was supported by São Paulo Research Foundation (FAPESP grant 2012/51316-5 to DSPA) and National Council for Scientific and Technological Development (National Institute of Science and Technology for Pharmaceutical Innovation (INCT_if/CNPq) grant 573663/2008-4 to IRP and CNPq/MICCIN grant BFU2011-2476 to DSPA, LBG and BLH). FAC was supported by CNPq fellowship (201602/2011-03), JCS was supported by FAPESP fellowship (2012/14360-6) and MR was supported by the FAPESP (2009/53072-3) and the CNPq (151568/2013-8) fellowships.Peer Reviewe