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

Abstract

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.

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Acknowledgements

This study was supported by the São Paulo Research Foundation (FAPESP grant 2012/51316-5 to DSPA) and the 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, LB and BdlH). JCS was supported by a FAPESP fellowship (2012/14360-6), and MR was supported by FAPESP (2009/53072-3) and CNPq (151568/2013-8) fellowships.

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Correspondence to Dulcineia S. P. Abdalla.

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Silva, J.C., de Oliveira, E.M., Turato, W.M. et al. GQ-11: A new PPAR agonist improves obesity-induced metabolic alterations in LDLr−/− mice. Int J Obes 42, 1062–1072 (2018). https://doi.org/10.1038/s41366-018-0011-7

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