Fat Cell Switcheroo*

Humans, mice — indeed all mammals — have two types of fat cells in their bodies; white and brown. White fat cells store energy. In contrast, brown fat cells dissipate energy as heat, thus counteracting obesity. Much to the chagrin of humans living in industrialized societies, most fat cells in our (adult) bodies are white fat cells. While this trait served our kind well throughout our evolutionary history, we now face a vast abundance of inexpensive, easily accessible, high energy content foods. This, combined with our body’s tendency to want to store up energy for times when food is scarce, leads to obesity and its accompanying adverse health effects. Wouldn’t it be great if we could have more brown fat cells and less white fat cells?

Scientists like Harvard Medical School’s Bruce Spiegelman would like to figure out a way to help us do just that! Spiegelman, who studies mammalian embryonic fat cell development, is conducting research to understand the adipogenic (i.e. how adipose, or fat cells arise) lineage. One key question that Dr. Spiegelman and his group seek to address is how white and brown fat cell fates are determined.

To answer this question, Dr. Spiegelman’s group performed a screen for molecular regulators including transcription factors that may be unique to either brown or white fat cells. The researchers identified a transcriptional co-regulator called PRDM16, which is expressed exclusively in brown fat cells. When the investigators studied the effect of increasing PRDM16 expression in white fat cell precursors in culture, they observed that the overall gene expression profile was distinctly that of brown fat cells. Then, they made transgenic mice that selectively overexpressed PRDM16 in white fat cells, and found that pockets of brown fat cells grew in the white fat cell depots. Similar results are obtained when mice are exposed to low temperatures for extended periods of time, or by prolonged exposure to b-adrenergic stimulation. Together, these results suggest that PRDM16 is an excellent candidate for a master molecular switch that can convert white fat cells into brown fat cells. However, since “suggestion” is not proof, the researchers performed additional experiments to investigate this.

To their surprise, the scientists found that when PRDM16 expression is inhibited in primary brown fat cells in culture, they differentiated not into white fat cells, but into myotubes, or skeletal muscle cells! This result suggested that brown and white fat cells did not come from one common progenitor cell type. Instead, they may in fact be two entirely separate lineages. Additional experiments provided strong evidence for this.

So where do these results leave Bruce Spiegelman and his group? The data showing that white fat cells can become brown fat cells by overexpression of PRDM16 still hold promise for therapy. Spiegelman aspires to make this type of therapy a reality, by employing a transplant model. White fat cells, which are easily obtained by liposuction, can be engineered to express PRDM16, and transplanted back into the original fat cell donor. These experiments are currently being performed in mice.

Important questions remain. For example, how many cells would be needed for the procedure to succeed, and how the body would respond to the engineered cells? Could these engineered “brown” fat cells lead to positive results by reducing obesity and restoring energy balance, or could there be negative effects? Bruce Spiegelman as well as many people suffering from obesity are sincerely hoping for the former.

This entry is based on a talk given by Dr. Spiegelman on Thursday, May 15, 2008 at the New York Academy of Sciences. Dr. Spiegelman was a featured speaker at the NYAS Conference on Integrative Physiology.

*Note added in proof, December 2, 2009: I wrote this post before I was aware of “Health at Every Size” and the fat acceptance movement, and recognize that this post contains material that is offensive to this audience. I am leaving it as is to illustrate the highly potent influence of the fat-hating society we have all been brought up in. I apologize for any offense it may cause.

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