Chelsea Merz
Sometimes it's not so bad to get stuck in the airport," notes Gökhan Hotamisligil, recalling a day in early 1998 when he was stranded in Washington's Ronald Reagan Airport with nothing but a briefcase stuffed with fly papers--articles on fruit flies to be precise. Though confined to the terminal, Hotamisligil, associate professor of nutrition at the Harvard School of Public Health, was able to get his research on fat genes off the runway. "That's when I read all the Drosophila literature I had been collecting," he says. "And that's when I decided that this line of research would be a great thing to do." This "great thing" was an unorthodox undertaking--using Drosophila, the common fruit fly, to decode the genetic mechanism that controls the differentiation of adipose stem cells into fat cells in humans.
It wasn't the first time that Hotamisligil had used a transit delay to his advantage. Upon his arrival to the School, the delivery of his lab equipment was held up so he used the down time to read up on genomic databases. "I recognized that the best database at that time was the fly base," he recalls, "and I was also quite pleasantly surprised by how cooperative fly people were. That is how I found my way to the Drosophila fat body."
Hotamisligil, like many another obesity researchers, was interested in the origins of the fat cell, or adipocyte. Earlier experiments had indicated that the adipocyte arises from a precursor cell, which lacks the full-grown adipocyte's appetite for lipids. Once it has differentiated into a fat cell, this "preadipocyte" may wax and wane but can rarely return to pretumescent innocence. Hotamisligil had studied this process previously in genetically engineered strains of mice but was searching for an even more efficient model when he hit upon Drosophila.
It was quite a stretch to assume that the lean and hungry fruit fly has the equivalent of human adipose tissue, so it took some doing to convince the other members of his lab that the Drosophila might be a promising model for fat studies. Qiang Tong, a postdoctoral fellow, was eventually persuaded, and they went to work. Hotamisligil and Tong drew on earlier research that the Drosophila fat body also contains liver and blood cells, an indication that, like human adipose tissue, it contains pluripotent stem cells, which give rise to a variety of tissues. They realized that they could isolate the fat-cell precursors more efficiently from the comparatively simple grouping of Drosophila fat than from human adipose tissue, which is composed of a greater variety of cell types, including vascular endothelium, smooth muscle cells, and macrophages.
Taking a cue from evidence that in Drosophila the serpent (srp) gene controls the formation of fat, the researchers suspected that the srp may have analogs in mammalian species. When testing this hypothesis in mice, they found a family of six genes in srp's stead. In the October 6, 2000 issue of Science, Hotamisligil, Tong, and colleagues report that two of the genes--GATA-2 and GATA-3--act as gatekeepers of the preadipocyte's passage into adulthood. GATA genes accomplish this task by taking as hostage the commanders of the cells' differentiation machinery. Hence, when the GATA genes aren't expressed, the gate is down, and preadipocytes settle into lipid-swilling fat cells.
Hotamisligil is quick to add that the identification of GATA-2 and GATA-3 doesn't spell the end of the story. The genes rely on several enzymes to help them accomplish their task in mice, and in humans the differentiation process is likely to involve additional molecules, which have yet to be identified. Nevertheless, cells from normal mice expressed much higher levels of GATA-2 and GATA-3 protein than did those from their obese littermates, and consequently the genes present inviting targets for the development of drugs for human use.
"After this paper was published, people from a couple of biotechnology companies called me," Hotamisligil reports. "They were very happy that this paper had suggested more targets for drug development." Such drugs may be conceived with obesity in mind, but they won't be limited to the weight- loss clinic; the prospect of gen- etic manipulation is promising for fat and thin alike. For the clinically obese, losing weight means much more than looking better; drugs promoting weight loss would also help reduce the risk of diabetes, heart disease, and a myriad of other health problems related to obesity. The elderly might also benefit from pharmaceuticals that could reverse or slow the age-related shift from lean mass to fat mass--a shift that has been implicated in several degenerative disorders. At the other end of the spectrum, drugs that suppress GATA-2 and GATA-3 might help restore energy balance in people with wasting disorders. For example, they could be a boon in treating burn victims, anorexics, cancer patients, and those who suffer from wasting due to HIV or other chronic infectious diseases.
Hotamisligil cautions that such a day is still on the distant horizon. The next stage is to test their theories in live animals by generating genetic models--for example, a corpulent GATA-deficient strain or a skinny breed whose GATA-2 and GATA-3 genes are at maximum expression. Such models will be essential in testing both classes of drugs. "We need to develop much more sophisticated models than what we usually use to test other genes," says Hotamisligil. Perhaps he should book another airline ticket.
Harvard Public Health Review Winter 2002/text version
This page is maintained by Development Communications in the Office of Resource
Development.
Updated January 2005
To contact us with suggestions, comments, and questions, please e-mail: editor@hsph.harvard.edu
Copyright, 2005, President and Fellows of Harvard College