Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Scully T. Public health: society at large. Nature. 2014;508:S50–1.

    Article  PubMed  CAS  Google Scholar 

  2. Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell. 2007;131:242–56.

    Article  PubMed  CAS  Google Scholar 

  3. Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab. 2008;34:2–11.

    Article  PubMed  CAS  Google Scholar 

  4. Tateya S, Kim F, Tamori Y. Recent advances in obesity-induced inflammation and insulin resistance. Front Endocrinol. 2013;4:93.

    Article  Google Scholar 

  5. Cartier A. The inflammatory profile associated with abdominal obesity. CMR E J. 2010;3:15–9.

    Google Scholar 

  6. Hayan Xu, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

    Article  CAS  Google Scholar 

  7. Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med. 2004;10:355–61.

    Article  PubMed  CAS  Google Scholar 

  8. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409–35.

    Article  PubMed  CAS  Google Scholar 

  9. Watkins SM, Reifsnyder PR, Pan HJ, German JB, Leiter EH. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. J Lipid Res. 2002;43:1809–17.

    Article  PubMed  CAS  Google Scholar 

  10. Choi JH, Banks AS, Estall JL, Kajimura S, Boström P, Laznik D, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466:451–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Chen R, Yan J, Liu P, Wang Z. Effects of thiazolidinedione therapy on inflammatory markers of type 2 diabetes: a meta-analysis of randomized controlled trials. PLos ONE. 2015;10:e0123703. eCollection

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Harmel ALP, Kendall DM, Buse JB, Boyle PJ, Marchetti A, Lau H. Impact of adjunctive thiazolidinedione therapy on blood lipid levels and glycemic control in patients with type 2 diabetes. Curr Med Res Opin. 2004;20:215–23.

    Article  CAS  Google Scholar 

  13. Hetzel J, Balletshofer B, Rittig K, Walcher D, Kratzer W, Hombach V, et al. Rapid effects of rosiglitazone treatment on endothelial function and inflammatory biomarkers. Arterioscler Thromb Vasc Biol. 2005;25:1804–9.

    Article  PubMed  CAS  Google Scholar 

  14. Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-gamma activators. Circulation. 2000;101:235–8.

    Article  PubMed  CAS  Google Scholar 

  15. Barros CD, Amato AA, de Oliveira TB, Iannini KB, Silva AL, Silva TG, et al. Synthesis and anti-inflammatory activity of new arylidene-thiazolidine-2,4-diones as PPARgamma ligands. Bioorg Med Chem. 2010;18:3805–11.

    Article  PubMed  CAS  Google Scholar 

  16. Jones P, Willett RC, Glen AR, Taylor R. Development and validation of a generic algorithm for flexible docking G. J Mol Biol. 1997;267:727–48.

    Article  PubMed  CAS  Google Scholar 

  17. Dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, et al. Different binding and recognition modes of Gl479, a dual agonist of peroxisome proliferator-activated receptor Alpha/Gamma. J Struct Biol. 2015;191:332.

    Article  PubMed  CAS  Google Scholar 

  18. Traves PG, Hortelano S, Zeini M, Chao TH, Lam T, Neuteboom ST, et al. Selective activation of liver X receptors by acanthoic acid-related diterpenes. Mol Pharmacol. 2007;71:1545–53.

    Article  PubMed  CAS  Google Scholar 

  19. National research council (US) committee for the update of the guide for the care and use of laboratory animals. Guide for the care and use of laboratory animals, 8th ed. National Academies Press: Washington, DC, USA; 2011.

  20. Silva JC, Cesar FA, Oliveira EM, Turato WM, Tripodi GL, Castilho G, et al. New PPARγ partial agonist improves obesity-induces metabolic alterations and atherosclerosis in LDLr−/− mice. Pharmacol Res. 2016;104:49–60.

    Article  PubMed  CAS  Google Scholar 

  21. Amato AA, Rajagopalan S, Lin JZ, Carvalho BM, Figueira ACM, Lu J, et al. GQ-16, a novel peroxisome-proliferator activator receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain. J Biol Chem. 2012;287:28169–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Liao L, Zhang XD, Li J, Zhang ZW, Yang CC, Rao CL, et al. Pioglitazone attenuates lipopolysaccharide-induced depression-like behaviors, modulates NFKB/IL6/STAT3, CREB/BDNF pathways and central serotonergic neurotransmission in mice. Int Immunopharmacol. 2017;49:178–86.

    Article  PubMed  CAS  Google Scholar 

  23. Andrikopoulos S, Blair AR, Deluca N, Fam BC, Proietto J. Evaluating the glucose tolerance test in mice. Am J Physiol Endocrinol Metab. 2008;295:E1323–32.

    Article  PubMed  CAS  Google Scholar 

  24. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.

    Article  PubMed  CAS  Google Scholar 

  25. Calkin AC, Forbes JM, Smith CM, Lassila M, Cooper ME, Jandeleit-Dahm KL, et al. Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects. Arterioscler Thromb Vasc Biol. 2005;25:1903–9.

    Article  PubMed  CAS  Google Scholar 

  26. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.

    PubMed  CAS  Google Scholar 

  27. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.

    Article  PubMed  CAS  Google Scholar 

  28. Nie J, Sage EH. SPARC inhibits adipogenesis by its enhacement of β-catenin signaling. J Biol Chem. 2009;284:1279–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Van Doorn C, Macht VA, Grillo CA, Reagen LP. Leptin resistance and hippocampal behavioral deficits. Physiol Behav. 2017;3:210–21.

    Google Scholar 

  30. Nawrocki AR, Rajala MW, Tomas E, Paivani UB, Saha AK, Trumbauer ME, et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biolol Chem. 2006;281:2654–60.

    Article  CAS  Google Scholar 

  31. Wallberg-Henriksson H, Zierath JR. GLUT4: a key player regulating glucose homeosthasis? Insights from transgenic and knockout mice. Mol Membr Biol. 2001;18:205–11.

    Article  PubMed  CAS  Google Scholar 

  32. Armoni M, Kritz N, Harel C, Bar-Yoseph F, Chen H, Quon MJ, et al. Peroxisome proliferator-activated receptor-gamma represses GLUT4 promoter activity in primary adipocytes, and rosiglitazone alleviates this effect. J Biol Chem. 2003;278:30614–23.

    Article  PubMed  CAS  Google Scholar 

  33. Lastra G, Manrique C, Jia G, Sowers JR. The VASP road to NAFLD: a macrophage detour. Diabetes. 2015;64:2711–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Wang S, Smith JD. ABCA1 and nascent HDL biogenesis. Biofactors. 2014;40:547–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Rigotti A, Trigatti BL, Penmann M, Rayburn H, Herz J, Krieger M. A targeted mutation in the murine gene encoding the High-Density Lipoprotein (HDL) receptor scavenger class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci USA. 1997;94:12610–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Nakamura T, Shibata N, Nishimoto-Shibata T, Feng D, Ikemoto M, Motojima K, et al. Regulation of SR-BI protein levels by phosphorylation of its associated protein, PDK1. Proc Natl Acad Sci USA. 2005;102:13404–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Derosa G, Sahebkar A, Maffioli P. The role of various PPARs and their ligands in clinical practice. J Cell Physiol. 2018;233:153–161.

    Article  PubMed  CAS  Google Scholar 

  39. Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang NHDL. ABC transporters and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 2008;7:365–75.

    Article  PubMed  CAS  Google Scholar 

  40. Karim MF, Al-Mahtab M, Rahman S, Debnath CR. Non-alcoholic fatty liver disease (NAFLD)—A review. Mymensingh Med J. 2015;24:873–80.

    PubMed  CAS  Google Scholar 

  41. Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev. 2000;14:1293–307.

    PubMed  CAS  Google Scholar 

  42. Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, et al. C/EBPα induces adipogenesis through PPARγ: a unified pathway. Genes Dev. 2002;16:22–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4:68–75.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Moon RT, Bowerman B, Boutros M, Perrimon N. The promise and perils of Wnt signaling through beta-catenin. Science. 2002;296:1644–6.

    Article  PubMed  CAS  Google Scholar 

  45. Duan M, Zhou B, Zhou X, Yuan G. TZDs inhibit mouse osteoblastic MC3T3 E1 cell proliferation in part through the Wnt signaling pathway. J Investig Med. 2015;63:758–64.

    Article  PubMed  CAS  Google Scholar 

  46. Zoete V, Grosdidier A, Michielin O. Peroxisome proliferator-activates receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta. 2007;1771:915–25.

    Article  PubMed  CAS  Google Scholar 

  47. Kroker AJ, Brunin JB. Review of the structural and dynamic mechanisms of PPARγ partial agonism. PPAR Res. 2015;2015:816856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Festa A, D’Agostino A Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2002;102:42–7.

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dulcineia S. P. Abdalla.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-018-0011-7

This article is cited by

Search

Quick links