IRS-1 targets TAZ to inhibit adipogenesis of rat bone marrow mesenchymal stem cells through PI3K-Akt and MEK-ERK pathways

• DOI: 10.1016/j.ejphar.2019.01.064
• Publication Date: 2019-02-01T16:04:35Z
• Authors: Na Wang; Yukun Li; Ziyi Li; Jianxia Ma; Xuelun Wu; Runzhou Pan; Yan Wang; Liu Gao; Xiaoxue Bao; Peng Xue
• Keywords: Male; 0303 health sciences; Adipogenesis; Transcription, Genetic; MAP Kinase Signaling System; Intracellular Signaling Peptides and Proteins; Cell Differentiation; Mesenchymal Stem Cells; Rats; Rats, Sprague-Dawley; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Insulin Receptor Substrate Proteins; Animals; Proto-Oncogene Proteins c-akt

Gene modification of mesenchymal stem cells (MSCs) offers a promising approach for clinical stem cell therapy. Transcriptional co-activator with PDZ-binding motif (TAZ) plays a vital role in MSCs' differentiation. We aim to explore the interaction of insulin receptor substrate-1 (IRS-1) with TAZ to regulate MSCs' adipogenesis in this study. Initially, IRS-1 and TAZ followed similar decreasing expression pattern at the early stage of adipogenesis. And, overexpression of IRS-1 decreased the CCAAT/enhancer binding protein β (C/EBPβ) and peroxi-some proliferator-activated receptor gamma (PPARγ) expression with TAZ upregulation. Accordingly, knockdown of IRS-1 induced the upexpression of C/EBPβ and PPARγ with TAZ downregulation. Indeed, IRS-1 targeted TAZ to downregulate the C/EBPβ and PPARγ expression, while knockdown of TAZ attenuated the IRS-1 inhibited adipogenesis. Furthermore, both LY294002 (the PI3K-Akt inhibitor) and U0126 (the MEK-ERK inhibitor) blocked the regulation of IRS-1 on TAZ during adipogenesis. Additionally, IRS-1 and TAZ influenced the cell proliferation in the above process. Taken together, this study suggests for the first time that IRS-1 is a key regulator of the MSCs' adipogenesis and may serve as a potential therapeutic target for differential alterations in bone marrow.