AP-1/C-FOS and AP-1/FRA2 differentially regulate early and late adipogenic differentiation of mesenchymal stem cells.

Abstract

Obesity is defined as an abnormal accumulation of adipose tissue in the body and is a major global health problem due to increased morbidity and mortality. Adipose tissue is made up of adipocytes, which are fat-storing cells, and the differentiation of these fat cells is known as adipogenesis. Several transcription factors (TFs)such as CEBPβ, CEBPα, PPARγ, GATA, and KLFhave been reported to play a key role in adipogenesis. In this study, we report one more TFAP-1, which is found to be involved in adipogenesis. Human mesenchymal stem cells were differentiated into adipocytes, and the expression pattern of different subunits of AP-1 was examined during adipogenesis. It was observed that C-FOS was predominantly expressed at an early stage (Day 2), whereas FRA2 expression peaked at later stages (Days 6 and 8) of adipogenesis. Chromatin immunoprecipitation-sequencing analysis revealed that C-FOS binds mainly to the promoters of WNT1, miR-30a, and ANAPC7and regulates their expression during mitotic clonal expansion. In contrast, FRA2 binds to the promoters of CIDEA, NOTCH1, ARAF, and MYLK, regulating their expression and lipid metabolism. Data obtained clearly indicatethat the differential expression of C-FOS and FRA2 is crucial for different stages of adipogenesis. This also raises the possibility of considering AP-1 as a therapeutic target for treating obesity and related disorders.