The negative adipogenesis regulator DLK1 is transcriptionally regulated by TIS7 (IFRD1) and translationally by its orthologue SKMc15 (IFRD2)
| Autor: | Ilja Vietor, Domagoj Cikes, Kati Piironen, Theodora Vasakou, David Heimdörfer, Ronald Gstir, Matthias David Erlacher, Ivan Tancevski, Philipp Eller, Egon Demetz, Michael Hess, Volker Kuhn, Gerald Degenhart, Jan Rozman, Martin Klingenspor, Martin Hrabe de Angelis, Taras Valovka, Lukas A. Huber |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Wnt signaling pathway Regulator Biology Cell biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine DLK1 IFRD1 chemistry Downregulation and upregulation Adipogenesis 030220 oncology & carcinogenesis Adipocyte Transcriptional regulation 030304 developmental biology |
| DOI: | 10.1101/719922 |
| Popis: | Delta-like homolog 1 (DLK1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Here we identify two independent regulatory mechanisms, transcriptional and translational, by which TIS7 (IFRD1) and its orthologue SKMc15 (IFRD2) regulate DLK1 levels. Mice deficient in both TIS7 and SKMc15 (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 Dlk-1 inhibited the expression of adipogenesis regulators PPARγ and C/EBPα, and fatty acid transporter CD36. Although both, TIS7 and SKMc15, contributed to this phenotype, they utilized two different mechanisms. TIS7 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk-1. On the other hand, here we provide distinctive experimental evidence that SKMc15 acts as a general translational inhibitor significantly affecting DLK-1 protein levels. Our study provides data describing novel mechanisms of DLK1 regulation in adipocyte differentiation involving TIS7 and SKMc15.SYNOPSISThis study uncovered that IFRD1 (TIS7) and its orthologue IFRD2 (SKMc15) are two essential regulators of adipogenesis. These proteins are highly similar on the sequence level, yet they regulate adipocyte differentiation using different but complementary mechanisms. Our main findings are:IFRD1 (TIS7) and IFRD2 (SKMc15) knockout mice are resistant against diet-induced obesityIFRD1 (TIS7) and IFRD2 (SKMc15) are critical for proper nutritional fat uptake and adipogenesisIFRD1 (TIS7) controls adipogenesis via Wnt/β-catenin-dependent transcriptional regulation of adipocyte-specific genesIFRD2 (SKMc15) regulates adipocyte-specific genes acting as a novel general translational inhibitor |
| Databáze: | OpenAIRE |
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