Scientists are one step closer to unraveling the genetic secrets behind why some people become obese and others stay effortlessly slim. Gary Ruvkun and Kaveh Ashrafi of Massachusetts General Hospital and their colleagues have surveyed an entire genomethat of the microscopic worm Caenorhabditis elegans (right) to identify the full panoply of genes involved in regulating fat storage. The work, described today in the journal Nature, may help pinpoint breakdowns in communication between the brain and fat cells in a variety of animals.

To find the fat regulators, the researchers systematically inactivated genes one at a time and measured any subsequent changes in the worms fat. Of the almost 17,000 genes tested, 305 inactivations caused body fat to decrease and 112 caused increased fat storage. About half of the C. elegans fat genes have human counterparts and as such could potentially inform the development of medications to treat obesity and related diseases, such as diabetes."If worm obesity was a health problem, wed have the cure," Ruvkun says. But for humans, there are still steps to be taken. What this work has done, he explains, is narrow the pool of genes that could regulate fat storage in humans down to "200 points on the genome that are the likely culprits."

The findings lend further support to the notion that body fat regulation cannot be explained by a simple energy balance aloneit also depends on a long chain of biochemical command that begins with feeding control in the brain and ends with fat storage and use in the body. A fuller understanding of fat regulation may come from studying the newly discovered worm genes that encode molecules functioning in the nervous system and elsewhere outside of the metabolic pathway. "Weve identified molecules that seem to be olfactory receptors and others involved in sensory functions," Ashrafi says. The team also found that some genes cause fat-storage changes in worms with certain obesity-causing mutations, which bodes well for people whose overly fat figures are the result of a genetic short circuit.

"Presumably, if these genes have the same effect on humans, there is great potential for the development of drugs," Ashrafi remarks. Indeed, pharmaceutical companies should find the large number of genes involved in fat moderation appealing. Says Ruvkun, "I wouldn't be surprised if half or more of these genes have no relevance, [but] my guess is that there are some that are potent."