Identification of a Key Mediator of Fat Cell Development
Scientists used a novel quantitative method to identify molecular regulators needed to form cells with the potential to become fatty tissues in mice and thereby discovered a critical component of the developmental process that generates fatty (adipose) tissues. Significant progress has been made in uncovering the factors and mechanisms that control the process by which mature fat cells (adipocytes) develop from cells with the potential to become adipocytes (preadipocytes) in response to molecular cues. Little is known, however, about how cells become or are maintained as preadipocytes. To identify preadipocyte regulators, the researchers generated new mouse cell lines and evaluated their capacity to form adipocytes. Creation of cell lines with strong propensity to develop into fat cells, as well as lines with little such capacity, allowed the scientists to use a new quantitative molecular tool they developed to identify regulators present at different levels in these different types of cells. They reasoned that factors important for directing cells to be preadipocytes would likely be present at much greater levels in precursors of fat cells compared to precursors of other types of cells or mature fat cells. One factor in particular, called Zfp423, was chosen for further characterization. As one way to test its role in preadipocytes, the scientists engineered high levels of Zfp423 into cells that would not ordinarily have the capacity to become fat cells and looked to see what happened. They found that increased levels of Zfp423 were able to drive these cells to become adipocytes.
The scientists also tested Zfp423’s importance with another approach. Using molecular biology techniques, the scientists decreased levels of Zfp423 in preadipocytes and observed that these cells had reduced ability to become adipocytes and had lower levels of other molecular markers characteristic of adipocytes. They demonstrated that Zfp423 is an important regulator of one of these molecular markers—PPARgamma, itself another regulator of fat cell development. The researchers also found that Zfp423 plays a key role in production of both major forms of fat in mice (brown fat and white fat). Thus, this important study described a new tool for identifying molecular regulators of cell development and revealed the important role of Zfp423 to the preadiopocyte state. Understanding the formation and properties of fat can help inform strategies to prevent or reduce obesity.
Gupta RK, Arany Z, Seale P, et al. Transcriptional control of preadipocyte determination by Zfp423. Nature 464: 619-623, 2010.