All-Trans Retinoic Acid Inhibits Bone Marrow Mesenchymal Stem Cell Commitment to Adipocytes via Upregulating FRA1 Signaling

Abstract

Obesity, caused by an increased number and volume of adipocytes, is a global epidemic that seriously threatens human health. Bone marrow mesenchymal stem cells (BMSCs) can differentiate into adipocytes. All-trans retinoic acid (atRA, the active form of vitamin A) inhibits the adipogenic differentiation of BMSCs through its receptor RARG. The expression level of FRA1 (FOS like 1, AP-1 transcription factor subunit) in atRA-treated BMSCs increased, suggesting that atRA-mediated inhibition of BMSCs adipogenesis involves FRA1. BMSCs were transfected with adenovirus overexpressing Fra1 (ad-fra1) or silenced for Fra1 (si-fra1) and then treated with atRA. BMSCs treated with atRA and treated with ad-fra1 showed decreased mRNA and protein levels of key adipogenic genes (Pparg2, Cebpa) and adipogenesis-associated genes (Cd36, Fabp, Lpl, and Plin); atRA had a stronger inhibitory effect on adipogenesis compared with that in the ad-fra1 group. Adipogenic gene expression in Fra1-silenced BMSCs was significantly upregulated. Compared with that in the atRA group, the si-fra1 + atRA also upregulated adipogenic gene expression. However, compared with si-fra1, si-fra1 + atRA significantly inhibited adipogenic differentiation. Chromatin immunoprecipitation showed that RARG directly regulates Fra1 and FRA1 directly regulates Pparg2 and Cebpa. The results supported the conclusion that atRA inhibits BMSC adipogenesis partially through the RARG-FRA1-PPARG2 or the CEBPA axis or both. Thus, vitamin A might be used to treat obesity and its related diseases.