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

International Journal of Obesity volume 42, pages 1062–1072 (2018)Cite this article

Subjects

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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Authors and Affiliations

  1. Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil

    Jacqueline C. Silva, Edson M. de Oliveira, Walter M. Turato, Martina Rudnicki & Dulcineia S. P. Abdalla

  2. Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil

    Gustavo H. G. Trossini & Vinícius G. Maltarollo

  3. Core of Therapeutic Innovation, Federal University of Pernambuco, Recife, PE, Brazil

    Marina G. R. Pitta & Ivan R. Pitta

  4. Department of Pharmacology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain

    Beatriz de las Heras

  5. Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain

    Lisardo Boscá

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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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