Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria; IMBA, Institute of MolecularBiotechnology of the Austrian Academy of Sciences, Vienna, Austria
Kati Piironen
Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria; Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
Theodora Vasakou
Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
David Heimdörfer
Division of Genomics and RNomics, Biocenter, Innsbruck Medical University, Innsbruck, Austria
Ronald Gstir
Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria; ADSI – Austrian Drug Screening Institute GmbH, Innsbruck, Austria
Matthias David Erlacher
Division of Genomics and RNomics, Biocenter, Innsbruck Medical University, Innsbruck, Austria
Ivan Tancevski
Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
Philipp Eller
Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
Egon Demetz
Department of Internal Medicine II, Innsbruck Medical University, Innsbruck, Austria
Michael W Hess
Division of Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria
Volker Kuhn
Department Trauma Surgery, Innsbruck Medical University, Innsbruck, Austria
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
Chair of Molecular Nutritional Medicine, Technical University of Munich, School of Life Sciences, Weihenstephan, Germany; EKFZ - Else Kröner Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany; ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Chair of Experimental Genetics, Technical University of Munich, School of Life Sciences, Freising, Germany
Taras Valovka
Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria
Institute of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria; ADSI – Austrian Drug Screening Institute GmbH, Innsbruck, Austria
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 upregulated 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.
