Appetite Hormone Weakens Bones

The fat-busting hormone leptin curbs the appetite and sends preteens lurching into puberty. Now comes news of a more surprising connection: osteoporosis. Researchers report in the current issue of Cell that mice lacking leptin grow stronger and thicker bones than normal. The finding could eventually lead to new therapies for osteoporosis, which plagues about 28 million Americans, mostly women.

The three best known risk factors for osteoporosis are menopause, intense athleticism, and anorexia. The bone loss seems to be spurred by a hormone imbalance: either a lack of sex steroids, or too many stress or appetite-control hormones. Mice that are bred to be leptin deficient should also be prone to bone loss, based on their similarity to human risk factors--they're sterile, stressed out, and eat as if they are starving. So geneticist Gerard Karsenty of Baylor College of Medicine in Houston, Texas, had a hunch that low leptin levels in the mutant mice would weaken bones as in osteoporosis.

But when Karsenty and his colleagues examined the bones of mice that lacked leptin or its receptor, they found that the mutant animals had up to three times the bone volume and strength of their normal counterparts. "I was flabbergasted," recalls Karsenty. By tracking bone formation with radioisotopes, the researchers traced the bone buildup to overtime work of cells called osteoblasts. Further, leptin infusions into the rodents' brains whittled away the excess bone. But leptin did not appear to be acting directly on the osteoblasts--rather, leptin appears to act on its receptor in the hypothalamus and then relay some secondary signal to the body.

"It is a very strange, unpredicted result and very intriguing," says leptin researcher Joel Elmquist of Beth Israel Deaconess Medical Center in Boston, who is stymied as to the nature of the secondary signal coming from the hypothalamus. Although leptin inhibits bone growth, there may be another compound in the brain that can stimulate the osteoblasts. Karsenty is now searching for such a stimulator, which could be the beginning of a cure for osteoporosis.