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New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr(-/-) mice
Jacqueline C Silva1, Fernanda A César1, Edson M de Oliveira1
1Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Abstract:
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 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/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.
Insights
GQ-177, a novel thiazolidinedione, acts as a partial Peroxisome proliferator-activated receptor gamma (PPARγ) agonist. It effectively treats diet-induced obesity and atherosclerosis by improving insulin sensitivity and reducing atherosclerotic lesions.
Area of Science:
- Pharmacology
- Metabolic Diseases
- Cardiovascular Research
Background:
- Peroxisome proliferator-activated receptor gamma (PPARγ) plays a crucial role in metabolic regulation and is implicated in obesity and atherosclerosis.
- Thiazolidinediones are known PPARγ agonists, but their therapeutic use is limited by side effects.
- There is a need for novel PPARγ modulators with improved efficacy and safety profiles for metabolic and cardiovascular diseases.
Purpose of the Study:
- To evaluate the therapeutic potential of GQ-177, a new thiazolidinedione, in preclinical models of diet-induced obesity and atherosclerosis.
- To characterize GQ-177 as a partial and selective PPARγ agonist.
- To assess the effects of GQ-177 on insulin sensitivity, lipid metabolism, and atherosclerotic lesion progression.
Main Methods:
- Virtual docking was used to examine the interaction between PPARγ and GQ-177.
- Reporter gene assays determined PPARγ activation by GQ-177.
- Low-density lipoprotein receptor-deficient (LDLr(-/-)) mice were fed high-fat diets and treated with GQ-177, pioglitazone, or rosiglitazone to model obesity and atherosclerosis.
Main Results:
- GQ-177 was identified as a partial and selective PPARγ agonist.
- In diet-induced obesity, GQ-177 improved insulin sensitivity, lipid profiles, and adiponectin levels without altering body weight or fat accumulation.
- In atherosclerosis models, GQ-177 inhibited lesion progression, increased HDL levels, and upregulated PPARγ and ABCA1 mRNA in lesions.
Conclusions:
- GQ-177 demonstrates therapeutic potential as a partial PPARγ agonist.
- GQ-177 effectively ameliorates obesity-associated insulin resistance and dyslipidemia.
- GQ-177 exhibits atheroprotective effects in LDLr(-/-) mice, suggesting its utility in managing metabolic and cardiovascular complications.
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