Scientists have the first solid evidence that leptin--the hormone famous for making fat mice thin--also affects sexual development in humans. In a remote Turkish village, researchers have located a family with a mutation in the leptin gene similar to the one found in lab mice, and--just like the mice--adults with two copies of the mutation are grossly overweight and don't ever go through puberty. The discovery, published in this month's Nature Genetics, is "a nice validation of the earlier prediction," says Jeffrey Flier of Beth Israel Deaconess Medical Center in Boston.
Leptin, which is made by fat cells, is thought to signal the body that it has enough energy in reserve to launch into the growth spurt and other changes of puberty. Several studies of mice have suggested that leptin helps to regulate sexual maturity, but because the first human mutation was found in young children, scientists couldn't tell if it played the same role in people.
The answer came serendipitously from a screen for mutations linked to obesity in Turkish patients. While measuring a variety of factors that might affect a person's weight, A. Donny Strosberg of the University of Paris and his colleagues found an obese individual with very low leptin levels. That was unusual, because most overweight people have more leptin than normal. When the team analyzed the patient's DNA, they found a mutation in both copies of the leptin gene. The 22-year-old man is not only grossly overweight; he has no beard, scanty pubic hair, small penis and testes, and low levels of testosterone. The patient did not have symptoms of other syndromes that affect sexual development. Another family member with two copies of the mutation, a 34-year-old woman, had never menstruated.
Strosberg and his colleagues found that cells with the mutant gene can make a version of leptin but cannot properly secrete it into the bloodstream. The team also hopes to treat the patients with synthetic leptin. The clincher for leptin's role in sexual development, says Strosberg, "is if when we give them leptin, they do go into puberty."