GQ-11: A new PPAR agonist improves obesity-induced metabolic alterations in LDLr−/− mice

• Published in: International Journal of Obesity 2018-06, Vol.42 (5), p.1062-1072
• Main Authors: Silva, Jacqueline C., de Oliveira, Edson M., Turato, Walter M., Trossini, Gustavo H. G., Maltarollo, Vinícius G., Pitta, Marina G. R., Pitta, Ivan R., de las Heras, Beatriz, Boscá, Lisardo, Rudnicki, Martina, Abdalla, Dulcineia S. P.
• Format: Article
• Language: English
• Subjects: 13/21; 38/77; 59/5; 631/45/287; 692/308/2778; ABCA1 protein; Adipokines - blood; Adiponectin; Adipose tissue; Animals; Arteriosclerosis; Atherosclerosis; ATP-binding protein; Body weight; Body Weight - drug effects; Body weight gain; Cardiovascular diseases; Cholesterol; Diabetes mellitus; Diet; Epidemiology; Fuel consumption; Gene expression; Glucose tolerance; Health Promotion and Disease Prevention; Heart diseases; High density lipoprotein; In vivo methods and tests; Indoles - chemistry; Indoles - pharmacology; Inflammation - metabolism; Insulin; Insulin resistance; Interleukin 10; Internal Medicine; Leptin; Lipids - blood; Lipoproteins (very low density); Liver; Low density lipoprotein; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Molecular chains; Molecular docking; Monocyte chemoattractant protein 1; Morphometry; Nutrient deficiency; Obesity; Obesity - metabolism; Peroxisome Proliferator-Activated Receptors - agonists; Proteins; Public Health; Receptors, LDL - genetics; Receptors, LDL - metabolism; Risk analysis; Risk factors; Rodents; Sensitivity; Thiazolidines - chemistry; Thiazolidines - pharmacology; Tissue analysis; Triglycerides; X ray analysis
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/s41366-018-0011-7

Background Obesity and insulin resistance/diabetes are important risk factors for cardiovascular diseases and demand safe and efficacious therapeutics. Objective To assess the effects of a new thiazolidine compound—GQ-11—on obesity and insulin resistance induced by a diabetogenic diet in LDL receptor-deficient (LDLr −/− ) mice. Methods Molecular docking simulations of GQ-11, PPARα and PPARγ structures were performed. Male C57BL/6J LDLr −/− mice fed a diabetogenic diet for 24 weeks were treated with vehicle, GQ-11 or pioglitazone or (20 mg/kg/day) for 28 days by oral gavage. Glucose tolerance test, insulin, HOMA-IR, adipokines (leptin, adiponectin) and the lipid profile were assessed after treatment. Adipose tissue was analysed by X-ray analysis and morphometry; gene and protein expression were evaluated by real-time PCR and western blot, respectively. Results GQ-11 showed partial agonism to PPARγ and PPARα. In vivo, treatment with GQ-11 ameliorated insulin sensitivity and did not modify subcutaneous adipose tissue and body weight gain. In addition, GQ-11 restored adipokine imbalance induced by a diabetogenic diet and enhanced Glut-4 expression in the adipose tissue. Improved insulin sensitivity was also associated with lower levels of MCP-1 and higher levels of IL-10. Furthermore, GQ-11 reduced triglycerides and VLDL cholesterol and increased HDL-cholesterol by upregulation of Apoa1 and Abca1 gene expression in the liver. Conclusion GQ-11 is a partial/dual PPARα/γ agonist that demonstrates anti-diabetic effects. Additionally, it improves the lipid profile and ameliorates chronic inflammation associated with obesity in atherosclerosis-prone mice.