Early B-cell Factor-1 (EBF1) Is a Key Regulator of Metabolic and Inflammatory Signaling Pathways in Mature Adipocytes

Background: EBF1 is critical for early adipogenesis, yet its targets/function in mature fat cells are unknown. Results: EBF1 binds to and/or regulates many core genes in metabolic and inflammatory signaling pathways, and loss of EBF1 results in impaired insulin and inflammatory signaling. Conclusion: EBF1 regulates signaling pathways in adipocytes. Significance: We have defined a major regulator of metabolism and signal transduction in adipose cells. EBF1 plays a crucial role in early adipogenesis; however, despite high expression in mature adipocytes, its function in these cells is currently unknown. To identify direct and indirect EBF1 targets in fat, we undertook a combination of transcriptional profiling of EBF1-deficient adipocytes and genome-wide EBF1 location analysis. Our results indicate that many components of metabolic and inflammatory pathways are positively and directly regulated by EBF1, including PI3K/AKT, MAPK, and STAT1 signaling. Accordingly, we observed significant reduction of multiple signaling events in EBF1 knockdown cells as well as a reduction in insulin-stimulated glucose uptake and lipogenesis. Inflammatory signaling, gene expression, and secretion of inflammatory cytokines were also significantly affected by loss of EBF1 in adipocytes, although ChIP-sequencing results suggest that these actions are indirect. We also found that EBF1 occupies some 35,000 sites in adipocytes, most of which occur in enhancers. Significantly, comparison with three other published EBF1 ChIP-sequencing data sets in B-cells reveals both gene- and cell type-specific patterns of EBF1 binding. These results advance our understanding of the transcriptional mechanisms regulating signaling pathways in mature fat cells and indicate that EBF1 functions as a key integrator of signal transduction, inflammation, and metabolism.