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

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Abstract

Graphical abstract

Effects of the PPARγ partial agonist GQ-177 on diet-induced obesity and atherosclerosis in LDLr−/− mice. In obese mice GQ-177 decreased glycemia and insulinemia leading to increased glucose tolerance and adiponectin levels, besides to diminish VLDL and LDL in blood plasma. Moreover, GQ-177 up-regulated mRNA expression of genes associated to the reverse cholesterol transport in liver as well as GLUT4 mRNA in adipose tissue. In experimental atherosclerosis induced in LDLr−/− by the hypercholesterolemic diet, GQ-177 increased the HDL levels and decreased glycemia. In addition, GQ-177 decreased atherosclerosis at aortic arch, up-regulated mRNA of PPARγ, ABCA1 in atheroma. Although CD36 mRNA levels was increased by GQ-177 its protein levels decreased in the atherosclerotic lesions. Thus, this novel PPARγ partial agonist has beneficial effects on diet-induced obesity and atherosclerosis in LDLr−/−.

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.

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