Forkhead Transcription Factor Foxa1 is a Novel Target Gene of C/EBPβ and Suppresses the Early Phase of Adipogenesis

Forkhead/winged helix transcription factors (Foxs) regulate differentiation, metabolism, and development. Although Foxa1 is expressed in adipocytes, the roles and regulation of Foxa1 in them remain unclear. Here, we found that under the control of C/EBPβ, Foxa1 suppressed lipid accumulation and concomitantly caused a decrease in adipogenic gene expression in adipocytes. Foxa1 was expressed in undifferentiated mouse 3T3-L1 cells and in the early phase of adipogenesis, with its highest expression at 3h after the initiation of adipogenesis, which was followed by a subsequent decrease. SiRNA-mediated suppression of Foxa1 expression activated the expression of adipogenic genes such as PPARγ. Moreover, siRNAs for C/EBPβ, but not those for C/EBPδ, reduced Foxa1 mRNA and protein levels. The results of a promoter-reporter assay and chromatin immunoprecipitation assay demonstrated that C/EBPβ bound to the C/EBP binding element at -529 of the mouse Foxa1 promoter. Furthermore, siRNA-mediated knockdown of C/EBPβ decreased the promoter activity of mouse Foxa1 gene. These results suggest that Foxa1 plays a suppressive role in the early phase of adipogenesis, acting under the control of C/EBPβ, and might be involved in the regulation of the rate of progression of the early phase of adipogenesis.