Once, leptin seemed like the ultimate fat-shedding drug: a natural appetite-quelling hormone whose absence causes obesity. Boost someone's blood levels of leptin, obesity researchers suspected, and they'd eat less. A clinical trial nixed that idea when obese people didn't respond to leptin treatment. But a new study shows that that low leptin can lead to chubbiness, suggesting that the hormone might help some people shed pounds.
In 1994 scientists discovered that mice missing both copies of their leptin gene develop excessive body fat, extreme hunger, and sterility. Soon afterwards, endocrinologist Stephen O'Rahilly of Addenbrooke's Hospital in Cambridge, U.K., identified two cousins with defects in both copies of their leptin genes. They produce virtually no leptin and show the hallmarks of mouse leptin deficiency. The childrens' parents weren't grossly obese, even though each carried one defective and one normal copy of the leptin gene.
Now O'Rahilly and his colleagues report that having one defective copy of the leptin gene does influence someone's weight, even though the effect is more subtle than in people with two bad copies of the gene. The team found that people with only one good copy of the gene make roughly half the normal levels of the hormone. Apparently as a result, the 13 people they studied end up heavier and packed with a significantly higher percentage of body fat than family members with two normal copies of the leptin gene, the team reports in the 1 November issue of Nature. O'Rahilly says that in a separate unpublished study people with both leptin genes knocked out respond "extremely well" to leptin therapy, although they haven't tested people with just one bad copy of the gene.
"We now know that having a little less than the normal amount of leptin is enough to cause a problem with body fat and weight," says obesity researcher Jeffrey Flier of Beth Israel Deaconess Medical Center in Boston. And having low leptin levels is a treatable condition. As O'Rahilly says, "There might be an obese subgroup with equivalently low leptin levels, which at least might be worthy of a clinical trial."