The Hunt For Cures: Obesity

So leptin is the answer to obesity--right? Not quite. Only a tiny percentage of obese people have a defect in the leptin gene. Clinical trials with leptin treatments conducted by Amgen, a biotech in Thousand Oaks, Calif., have led to weight reduction in some subjects, but the drug does not remain in the body long enough to do any lasting good. While more testing is under way using a leptin drug with a longer half-life, many scientists are coming to believe that the real secret may be found not in leptin itself but in the complicated steps it follows as it does its appetite-regulating work.

When leptin enters the brain, it follows numerous pathways, some of them manipulating appetite stimulators, some appetite suppressors. In one route, the leptin triggers the release of a large protein known as POMC, which is broken down into individual peptides by an enzyme dubbed PC1. One of these peptides, known as MSH, in turn binds to a receptor known as MC4. This receptor helps put the brakes on appetite. To most people, this is little more than neurochemical gibberish, except that researchers are now discovering that there are genes controlling the production of all these proteins and that damaging any one of them can derail the entire process. "Problems in all of these steps can be associated with specific gene lesions in humans," says O'Rahilly.

The simple answer would seem to be genetic engineering--repair what's wrong with the bum genes, and appetite should fall into line. But genetic engineering is anything but simple. Instead, drug companies are turning to genetic diagnosis. If doctors could screen the genes of obese people to see which ones were on the fritz, they could prescribe drugs that would pick up the slack--elevating PC1 levels, say, or stimulating an understimulated MC4 receptor. Says molecular biologist Joe Grippo of Roche pharmaceuticals: "We are working to mimic the brain's natural appetite-suppressing substances and block out appetite stimulators."

For now, no one knows how successful these strategies will be. The further science travels along the leptin trail, the more genetic stops it will find--and the more therapies these will suggest. What is clear is that obesity is a fantastically complicated condition, with a fantastic number of spots for science to step in and set things right. "What recent research has done," says O'Rahilly, "is take obesity out of the realm of sociology and put it in the realm of biology." For many obese people, that is a welcome start.