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

Abstract

Delta-like homolog 1 (<i>Dlk1</i>), 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 <i>Ifrd1</i> (TIS7) and its orthologue <i>Ifrd2</i> (SKMc15) regulate <i>Dlk1</i> levels. Mice deficient in both <i>Ifrd1</i> and <i>Ifrd2</i> (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 <i>Pparg</i> and <i>Cebpa</i>, and fatty acid transporter <i>Cd36</i>. Although both <i>Ifrd1</i> and <i>Ifrd2</i> contributed to this phenotype, they utilized two different mechanisms. <i>Ifrd1</i> acted by controlling Wnt signaling and thereby transcriptional regulation of <i>Dlk1</i>. On the other hand, distinctive experimental evidence showed that Ifrd2 acts as a general translational inhibitor significantly affecting Dlk1 protein levels. Novel mechanisms of <i>Dlk1</i> regulation in adipocyte differentiation involving <i>Ifrd1</i> and <i>Ifrd2</i> are based on experimental data presented here.