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.

Endocrine Pharmacology

C333H, a novel PPARα/γ dual agonist, has beneficial effects on insulin resistance and lipid metabolism

Abstract

Aim:

To examine the effects of novel peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist C333H on insulin resistance and lipid metabolism.

Methods:

An established dual-luciferase reporter gene assay system was used in vitro to test the activity of C333H with respect to the transcription of human PPARα and PPARγ. A preadipocyte differentiation assay and reverse transcription-polymerase chain reaction were used to detect the functional activities of C333H. In db/db mice, the effects of C333H were investigated with respect to lowering of blood glucose and lipid levels.

Results:

C333H was determined to be a novel PPARα/γ dual agonist because it strongly induced luciferase activity on human PPARα and PPARγ, promoting the differentiation of preadipocytes to adipocytes, and functioning in upregulating the expression of some glucose and lipid metabolic target genes of the PPAR. In addition, C333H efficiently reduced blood lipid and glucose concentrations in db/db diabetic mice.

Conclusion:

C333H has dual action on both PPARα and PPARγ, and might be of interest for the amelioration of lipid metabolic disorders and insulin resistance associated with type 2 diabetes.

References

  1. 1

    Grundy SM, Barnett JP . Metabolic and health complications of obesity. Dis Mon 1990; 36: 641–713.

    CAS  PubMed  Google Scholar 

  2. 2

    Ginsberg H, Plutzky J, Sobel E . Review of metabolic and cardiovascular effects of oral antidiabetic agents: beyond glucose level lowering. J Cardivasc Risk 1999; 6: 337–46.

    CAS  Article  Google Scholar 

  3. 3

    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83: 835–9.

    CAS  Article  Google Scholar 

  4. 4

    Schoonjans K, Martin G, Staels B, Auwerx J . Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol 1997; 8: 159–66.

    CAS  Article  Google Scholar 

  5. 5

    Willson TM, Brown PJ, Sternbach DD, Henke BR . The PPARs: from orphan receptors to drug discovery. J Med Chem 2000 43: 527–50.

    CAS  Article  Google Scholar 

  6. 6

    Bole PJ, King AB, Olansky L, Marchetti A, Lau H, Magar R, et al. Effects of pioglitazone and rosiglitazone on blood lipid level and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records. Clin Ther 2002 24: 378–96.

    Article  Google Scholar 

  7. 7

    Chaput E, Saladin R, Sliverstre M, Edgar AD . Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight. Biochem Biophys Res Commun 2000; 271: 445–50.

    CAS  Article  Google Scholar 

  8. 8

    Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC . Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98: 2088–93.

    CAS  Article  Google Scholar 

  9. 9

    Sadoeski I, Ptashne M . A vector for expressing GAL4 (1–147) fusion in mammalian cells. Nucl Acids Res 1989; 17: 7539.

    Article  Google Scholar 

  10. 10

    Tontonoz P, Graves RA, Budavari AI, Erdjument-Bromage H, Lui M, Hu E, et al. Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPARγ and RXRα. Nucl Acids Res 1994; 22: 5628–34.

    CAS  Article  Google Scholar 

  11. 11

    Camp HS, Li O, Wise SC . Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone. Diabetes 2000; 49: 539–47.

    CAS  Article  Google Scholar 

  12. 12

    Vazquez M, Silvestre JS, Prous JR . Experimental approaches to study PPARγ agonists as antidiabetic drugs. Methods Find Exp Clin Pharmacol 2002; 24: 515–23.

    CAS  Article  Google Scholar 

  13. 13

    Fruchart JC . Peroxisome proliferator-activated receptor-α activation and high-density lipoprotein metabolism. Am J Cardiol 2001; 88: 24N–9N.

    CAS  Article  Google Scholar 

  14. 14

    Lowell BB . PPARγ: an essential regulator of adipogenesis and modulator of fat cell function. Cell 1999; 99: 230–53.

    Article  Google Scholar 

  15. 15

    Okuno A, Tamemoto H, Tobe K . Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese zucker rats. J Clin Invest 1998; 101: 1354–61.

    CAS  Article  Google Scholar 

  16. 16

    Tontonoz P, Hu E, Spiegelman BM . Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 1994; 79: 1147–56.

    CAS  Article  Google Scholar 

  17. 17

    Schoonjans K, Peinado-Onsurbe J, Lefebvre AM . PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO 1996; 15: 5336–48.

    CAS  Article  Google Scholar 

  18. 18

    Wu Z, Xie Y, Morrison RF, Bucher NLR, Farmer SR . PPARγ induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPα during the conversion of 3T3 fibroblasts in adipocytes. J Clin Invest 1998; 101: 22–32.

    CAS  Article  Google Scholar 

  19. 19

    Vidal-Puig AJ, Considine RV, Jimenez-Linan M, Werman A . Peroxisome proliferator-activated receptor gene expression in human tissues. J Clin Invest 1997; 99: 2416–22.

    CAS  Article  Google Scholar 

  20. 20

    Kruszynska YT, Mukherjee R, Jow L, Dana S, Paterniti JR, Olefsky JM . Skeletal muscle peroxisome proliferation-activated receptor-γ expression in obesity and non-insulin-dependent diabetes mellitus. J Clin Invest 1998; 101: 543–8.

    CAS  Article  Google Scholar 

  21. 21

    Escher P, Wahli W . Peroxisome proliferator-activated receptor insight into multiple cellular function. Mutat Res 2000; 448: 121–38.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Li-li Wang or Song Li.

Additional information

Project supported by the National High Technology Research and Development Program of China (863 Program, No 2003AA235010) and the Beijing Technological Program (No H030230070110).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Xu, C., Wang, Ll., Liu, Hy. et al. C333H, a novel PPARα/γ dual agonist, has beneficial effects on insulin resistance and lipid metabolism. Acta Pharmacol Sin 27, 223–228 (2006). https://doi.org/10.1111/j.1745-7254.2006.00263.x

Download citation

Keywords

  • C333H
  • peroxisome proliferator-activated receptor
  • insulin resistance
  • lipid metabolism
  • diabetes

Further reading

Search

Quick links