The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15)

  1. Ilja Vietor  Is a corresponding author
  2. Domagoj Cikes
  3. Kati Piironen
  4. Theodora Vasakou
  5. David Heimdörfer
  6. Ronald Gstir
  7. Matthias David Erlacher
  8. Ivan Tancevski
  9. Philipp Eller
  10. Egon Demetz
  11. Michael W Hess
  12. Volker Kuhn
  13. Gerald Degenhart
  14. Jan Rozman
  15. Martin Klingenspor
  16. Martin Hrabe de Angelis
  17. Taras Valovka
  18. Lukas A Huber
  1. Innsbruck Medical University, Austria
  2. Institute of Molecular Biology and Biotechnology, Austria
  3. University of Helsinki, Finland
  4. ADSI - Austrian Drug Screening Institute GmbH, Austria
  5. Helmholtz Zentrum München, Germany
  6. Technical University of Munich, Germany

Abstract

Delta-like homolog 1 (Dlk1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Experimental data presented here identify two independent regulatory mechanisms, transcriptional and translational, by which Ifrd1 (TIS7) and its orthologue Ifrd2 (SKMc15) regulate Dlk1 levels. Mice deficient in both Ifrd1 and Ifrd2 (dKO) had severely reduced adipose tissue and were resistant to high fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation was significantly up regulated in dKO mice. Elevated levels of the Wnt/β-catenin target protein Dlk1 inhibited the expression of adipogenesis regulators Pparg and Cebpa, and fatty acid transporter Cd36. Although both, Ifrd1 and Ifrd2, contributed to this phenotype, they utilized two different mechanisms. Ifrd1 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk1. On the other hand, distinctive experimental evidence showed that Ifrd2 acts as a general translational inhibitor significantly affecting Dlk1 protein levels. Novel mechanisms of Dlk1 regulation in adipocyte differentiation involving Ifrd1 and Ifrd2 are based on experimental data presented here.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file

Article and author information

Author details

  1. Ilja Vietor

    Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
    For correspondence
    ilja.vietor@i-med.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1391-6793
  2. Domagoj Cikes

    Institute of Molecular Biology and Biotechnology, Wien, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0350-5672
  3. Kati Piironen

    Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  4. Theodora Vasakou

    Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  5. David Heimdörfer

    Division of Genomics and RNomics, Biocenter, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  6. Ronald Gstir

    ADSI - Austrian Drug Screening Institute GmbH, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  7. Matthias David Erlacher

    Division of Genomics and RNomics, Biocenter, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  8. Ivan Tancevski

    Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  9. Philipp Eller

    Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  10. Egon Demetz

    Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  11. Michael W Hess

    Division of Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  12. Volker Kuhn

    Department Trauma Surgery, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  13. Gerald Degenhart

    Department of Radiology, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9961-1084
  14. Jan Rozman

    Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8035-8904
  15. Martin Klingenspor

    Chair of Molecular Nutritional Medicine, Technical University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4502-6664
  16. Martin Hrabe de Angelis

    Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7898-2353
  17. Taras Valovka

    Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  18. Lukas A Huber

    Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1116-2120

Funding

Austrian Science Fund (P18531-B12)

  • Ilja Vietor

Austrian Science Fund (P22350-B12)

  • Ilja Vietor

Helmholtz Zentrum München (01KX1012)

  • Martin Hrabe de Angelis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed in accordance with Austrian legislation BGB1 Nr. 501/1988 i.d.F. 162/2005).

Copyright

© 2023, Vietor et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ilja Vietor
  2. Domagoj Cikes
  3. Kati Piironen
  4. Theodora Vasakou
  5. David Heimdörfer
  6. Ronald Gstir
  7. Matthias David Erlacher
  8. Ivan Tancevski
  9. Philipp Eller
  10. Egon Demetz
  11. Michael W Hess
  12. Volker Kuhn
  13. Gerald Degenhart
  14. Jan Rozman
  15. Martin Klingenspor
  16. Martin Hrabe de Angelis
  17. Taras Valovka
  18. Lukas A Huber
(2023)
The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15)
eLife 12:e88350.
https://doi.org/10.7554/eLife.88350

Share this article

https://doi.org/10.7554/eLife.88350

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