Ancient Gene May Keep You Leaner

Globular fat cells as seen through a scanning electron microscope. David Gregory and Debbie Marshall, Wellcome Images.

Researchers have discovered a "lean" gene in animals. If the gene works the same for people as it does in worms, fruit flies and mice, the finding could lead to new strategies for combating obesity.

Experimental model systems such as worms and fruit flies can be powerful tools for studying genes involved in human health and disease. But since worm and fly fat isn't stored in specialized fat cells like we have, many researchers thought that the animals couldn't serve as good model systems for human obesity.

The story that may prove this assumption wrong began almost 50 years ago, when Dr. Winifred Doane of Yale University reasoned that animals highly efficient at storing fat would be more likely to survive cycles of famine. Doane successfully isolated an obese fruit fly mutant, which she called adipose (Adp). Such extreme obesity normally reduces a fly's chance for survival, because it can't move very well.

Doane and her colleagues more recently cloned the fly Adp gene and found that it encodes a protein found in animals from flies to humans. The protein turns out to interact with many other proteins. The findings led Dr. Jonathan Graff, of the University of Texas Southwestern Medical Center, and his colleagues to explore Adp's role in fat biology. They set out to study it more closely with support from NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

The research team reported in the September 2007 issue of Cell Metabolism that interfering with Adp in worms causes greater fat accumulation. In fruit flies, raising the level of Adp in fat, even only briefly during adulthood, reduced fat formation in the flies. In mouse fat cells grown in the laboratory, Adp also blocked fat formation.

The researchers next created mice with a disruption in their Adp gene. Very few mice were born with 2 copies of the disruption, showing the importance of the protein. Those born with 1 copy were obese and insulin resistant.

The scientists also created transgenic mice with defective Adp in their fat cells. The mice became obese, with high levels of sugar in their blood. In contrast, transgenic mice created to have more normal Adp in their fat cells were leaner and healthier.

Adp's common function in creatures from worms to mammals implies that it may be a component of an ancient pathway that regulates energy storage and fat accumulation. Understanding more about this pathway may lead to new strategies for treating obesity. Graff says, "Maybe if you could affect this gene, even just a little bit, you might have a beneficial effect on fat."

However, Graff also points out that in the modern world, many people have essentially unlimited access to food but aren't overweight. If this gene plays a similar role in humans, it may be that some people's Adp already works very well.

— by Harrison Wein, Ph.D.