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.

  • Brief Communication
  • Published:

Development of small-molecule inhibitors targeting adipose triglyceride lipase

Nature Chemical Biology volume 9, pages 785–787 (2013)Cite this article

Subjects

Abstract

Adipose triglyceride lipase (ATGL) is rate limiting in the mobilization of fatty acids from cellular triglyceride stores. This central role in lipolysis marks ATGL as an interesting pharmacological target as deregulated fatty acid metabolism is closely linked to dyslipidemic and metabolic disorders. Here we report on the development and characterization of a small-molecule inhibitor of ATGL. Atglistatin is selective for ATGL and reduces fatty acid mobilization in vitro and in vivo.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Development of ATGL inhibitors and inhibition of lipolysis in vitro.
Figure 2: Inhibition of lipolysis in vivo and tissue distribution of Atglistatin.

Similar content being viewed by others

References

  1. Haemmerle, G. et al. Science 312, 734–737 (2006).

    Article  CAS  Google Scholar 

  2. Lass, A. et al. Cell Metab. 3, 309–319 (2006).

    Article  CAS  Google Scholar 

  3. Zimmermann, R. et al. Science 306, 1383–1386 (2004).

    Article  CAS  Google Scholar 

  4. Fredrikson, G., Tornqvist, H. & Belfrage, P. Biochim. Biophys. Acta 876, 288–293 (1986).

    Article  CAS  Google Scholar 

  5. Zimmermann, R., Lass, A., Haemmerle, G. & Zechner, R. Biochim. Biophys. Acta 1791, 494–500 (2009).

    Article  CAS  Google Scholar 

  6. Boden, G. Curr. Opin. Endocrinol. Diabetes Obes. 18, 139–143 (2011).

    Article  CAS  Google Scholar 

  7. Carobbio, S., Rodriguez-Cuenca, S. & Vidal-Puig, A. Curr. Opin. Clin. Nutr. Metab. Care 14, 520–526 (2011).

    Article  CAS  Google Scholar 

  8. Schaffer, J.E. Curr. Opin. Lipidol. 14, 281–287 (2003).

    Article  CAS  Google Scholar 

  9. Kienesberger, P.C. et al. J. Biol. Chem. 284, 30218–30229 (2009).

    Article  CAS  Google Scholar 

  10. Hoy, A.J. et al. Endocrinology 152, 48–58 (2011).

    Article  CAS  Google Scholar 

  11. Ong, K.T., Mashek, M.T., Bu, S. & Mashek, D.G. FASEB J. 27, 313–321 (2013).

    Article  CAS  Google Scholar 

  12. Li, L.O., Klett, E.L. & Coleman, R.A. Biochim. Biophys. Acta 1801, 246–251 (2010).

    Article  CAS  Google Scholar 

  13. Summers, S.A. Prog. Lipid Res. 45, 42–72 (2006).

    Article  CAS  Google Scholar 

  14. Samuel, V.T., Petersen, K.F. & Shulman, G.I. Lancet 375, 2267–2277 (2010).

    Article  CAS  Google Scholar 

  15. Ebdrup, S., Sorensen, L.G., Olsen, O.H. & Jacobsen, P. J. Med. Chem. 47, 400–410 (2004).

    Article  CAS  Google Scholar 

  16. Ebdrup, S., Refsgaard, H.H., Fledelius, C. & Jacobsen, P. J. Med. Chem. 50, 5449–5456 (2007).

    Article  CAS  Google Scholar 

  17. Schweiger, M. et al. J. Biol. Chem. 281, 40236–40241 (2006).

    Article  CAS  Google Scholar 

  18. Wilson, P.A., Gardner, S.D., Lambie, N.M., Commans, S.A. & Crowther, D.J. J. Lipid Res. 47, 1940–1949 (2006).

    Article  CAS  Google Scholar 

  19. Das, S.K. et al. Science 333, 233–238 (2011).

    Article  CAS  Google Scholar 

  20. Tisdale, M.J. Curr. Opin. Gastroenterol. 26, 146–151 (2010).

    Article  Google Scholar 

  21. Honors, M.A. & Kinzig, K.P. J. Cachexia Sarcopenia Muscle 3, 5–11 (2012).

    Article  Google Scholar 

  22. Haemmerle, G. et al. Nat. Med. 17, 1076–1085 (2011).

    Article  CAS  Google Scholar 

  23. Hirano, K. J. Atheroscler. Thromb. 16, 702–705 (2009).

    Article  Google Scholar 

  24. Taschler, U. et al. J. Biol. Chem. 286, 17467–17477 (2011).

    Article  CAS  Google Scholar 

  25. Kienesberger, P.C. et al. J. Biol. Chem. 283, 5908–5917 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by the Austrian Science Fund (FWF) projects (W901-B05 DK Molecular Enzymology (R. Zimmermann, R.B.), Translational Program TRP4 (R. Zimmermann), Wittgenstein Award 2007 (grant no. Z136, R. Zechner)) and by the Forschungsförderungsgesellschaft und Bundesministerium für Wissenschaft und Forschung (Austrian Genome Project GEN-AU: Genomics of Lipid-Associated Disorders (GOLD, R. Zechner, R. Zimmermann) and Platform for Chemical Biology in Austria (PLACEBO, R.B.)). We are grateful to B. Grumm and B. Wölfl for skillful help in the synthesis of Atglistatin. Furthermore, we thank P. Jacobsen and H. Tornqvist from Novo Nordisk for helpful discussions and for the provision of lead compounds.

Author information

Author notes

  1. Nicole Mayer and Martina Schweiger: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Organic Chemistry, Graz University of Technology, Graz, Austria

    Nicole Mayer, Elisabeth Fuchs, Jakov Ivkovic & Rolf Breinbauer

  2. Institute of Molecular Biosciences, University of Graz, Graz, Austria

    Martina Schweiger, Matthias Romauch, Gernot F Grabner, Thomas O Eichmann, Christoph Heier, Irina Mrak, Achim Lass, Rudolf Zechner & Robert Zimmermann

  3. Institute of Pathology, Medical University of Graz, Graz, Austria

    Gerald Höfler

  4. Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark

    Christian Fledelius

Authors
  1. Nicole Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina Schweiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthias Romauch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gernot F Grabner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas O Eichmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisabeth Fuchs
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jakov Ivkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christoph Heier
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Irina Mrak
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Achim Lass
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gerald Höfler
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christian Fledelius
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Rudolf Zechner
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Robert Zimmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rolf Breinbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R. Zimmermann, R.B., R. Zechner, G.H. and C.F. conceived the study design. N.M., M.S., M.R., T.O.E., J.I., E.F., G.F.G., A.L., C.H. and I.M. performed the experiments. R. Zimmermann and R.B. analyzed the data and wrote the paper. All of the authors read, revised and approved the manuscript.

Corresponding authors

Correspondence to Robert Zimmermann or Rolf Breinbauer.

Ethics declarations

Competing interests

N.M., M.S., M.R., R. Zimmermann and R.B. have filed for a patent on lipase inhibitors.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Table 1, Supplementary Figures 1–9 and Supplementary Note. (PDF 3322 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mayer, N., Schweiger, M., Romauch, M. et al. Development of small-molecule inhibitors targeting adipose triglyceride lipase. Nat Chem Biol 9, 785–787 (2013). https://doi.org/10.1038/nchembio.1359

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.1359

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing