Gene Defects Tied to Rare Human Obesity

After a long, frustrating hunt, two groups of scientists have finally nabbed genetic defects responsible for obesity in some people. One team has found in two children mutations in the gene for the metabolic hormone leptin, which in mice tells the body it's satiated; defects in this gene had not previously been found in obese people. A second group has found in an obese woman a defect in the gene for a hormone-processing enzyme. Both kinds of mutations, described today at a conference of the American Diabetes Association in Boston, appear to be very rare and are unlikely to lead to treatments for most obese people.

Until now, hundreds of labs searching for a leptin defect or another gene that might cause human obesity had come up empty-handed. Carl Montague, Stephen O'Rahilly, and their colleagues at Cambridge University in the U. K. tested two overweight children--a 2-year-old boy and an 8-year-old girl--for a leptin defect, because the children didn't have any disease known to cause childhood obesity and because they were overeating from birth--just as do mice lacking a leptin gene. The researchers report in this week's issue of Nature that the leptin genes in each child were missing a nucleotide, a mutation that resulted in shortened, malfunctioning leptin molecules.

Most obese people have plenty of good leptin, so a defect in this gene isn't a widespread problem, says O'Rahilly. But treatment with leptin does cure obesity in mice lacking leptin, so it's "possible," O'Rahilly says, that similar treatment could help the few people who do have leptin defects. Even if the prospects for therapy are poor, the findings do help to validate the mouse obesity research, says Rudy Leibel of Rockefeller University in New York City. "This represents proof of the principle that you can identify candidate obesity genes by the study of rodents," he says.

The other obesity gene defect, discovered by Robert Jackson of Addenbrooke Hospital in Cambridge, U.K., with help from O'Rahilly, is a mutation of the enzyme prohormone convertase 1 (PC1). By removing an attached string of amino acids, the enzyme activates hormones such as insulin and two hormones that may play a role in obesity--glucagonlike peptide 1 and melanocortin-stimulating hormone. Jackson's group reports in next month's Nature Genetics that it has found the mutation in one woman; it is unclear how the defect leads to obesity, but Jackson says it almost certainly has something to do with a lack of a hormone normally processed by the enzyme. PC1 is not known to process leptin. "PC1 is simply a steppingstone to understanding other obesity mechanisms," Jackson says.

Posted in Biology