The negative adipogenesis regulator Dlk1 is transcriptionally regulated by Ifrd1 (TIS7) and translationally by its orthologue Ifrd2 (SKMc15)
- Innsbruck Medical University, Austria
- Institute of Molecular Biology and Biotechnology, Austria
- University of Helsinki, Finland
- ADSI - Austrian Drug Screening Institute GmbH, Austria
- Helmholtz Zentrum München, Germany
- 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
Martin Klingenspor
Martin Hrabe de Angelis
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.
Reviewing Editor
- David E James, University of Sydney, Australia
Ethics
Animal experimentation: All animal experiments were performed in accordance with Austrian legislation BGB1 Nr. 501/1988 i.d.F. 162/2005).
Version history
- Preprint posted: July 30, 2019 (view preprint)
- Received: April 20, 2023
- Accepted: August 20, 2023
- Accepted Manuscript published: August 21, 2023 (version 1)
- Version of Record published: August 30, 2023 (version 2)
- Version of Record updated: September 5, 2023 (version 3)
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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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
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