Regulation of Early Adipose Commitment by Zfp521

Abstract

While there has been significant progress in determining the transcriptional cascade involved in terminal adipocyte differentiation, less is known about early events leading to lineage commitment and cell fate choice. It has been recently discovered that zinc finger protein 423 (Zfp423) is an early actor in adipose determination. Here, we show that a close paralog of Zfp423, Zfp521, acts as a key regulator of adipose commitment and differentiation in vitro and in vivo. Zfp521 exerts its actions by binding to early B cell factor 1 (Ebf1), a transcription factor required for the generation of adipocyte progenitors, and inhibiting the expression of Zfp423. Overexpression of Zfp521 in cells greatly inhibits adipogenic potential, whereas RNAi-mediated knock-down or genetic ablation of Zfp521 enhances differentiation. In addition, Zfp521^−/− embryos exhibit increased mass of interscapular brown adipose tissue and subcutaneous white adipocytes, a cell autonomous effect. Finally, Ebf1 participates in a negative feedback loop to repress Zfp521 as differentiation proceeds. Because Zfp521 is known to promote bone development, our results suggest that it acts as a critical switch in the commitment decision between the adipogenic and osteogenic lineages. Adipocytes or fat cells derive from the same stem cells that give rise to bone, cartilage, and muscle. Understanding the switch between bone and fat is of particular medical importance, with implications for diseases like osteoporosis and obesity. Here, we have identified a transcription factor called Zfp521 which is integral to adipogenesis. Prior work has shown that Zfp521 is important in bone formation. Using a variety of overexpression and knockout models, we show that Zfp521 blocks fat cell formation in cultured cells and in living animals. Furthermore, we show that Zfp521 performs this function by binding to another transcription factor, early B cell factor 1 (Ebf1), and repressing the expression of Zfp423, a transcriptional regulator of preadipocyte determination. Finally, we show that Zfp521 is itself repressed by Ebf1, providing a mechanism that turns the levels of this antiadipogenic protein off once the decision to undergo fat cell development has been made. We postulate that Zfp521 regulates one of the earliest events in the lineage switch between bone and fat.