The Hunt For Cures: Obesity

If you don't have a weight problem, you have more than your diet or your gym to thank. You also owe a nod to your leptin gene. And while you're at it, tip a hat to your MC4 receptors and your PC1 enzymes and your POMC peptides. Hard to figure out the role this alphabet soup of stuff plays in helping keep you thin? Don't feel bad. It's all new to scientists too.

Nutritionists know that the two great pillars of weight control--diet and exercise--can't be all there is to avoiding obesity. Why else could two otherwise healthy people eat identical foods, keep identically active and still see the numbers on the scale move in opposite directions? For years much of this has been explained with hand-waving references to body types and metabolism--broadly accurate, but cold comfort to the estimated 61% of Americans who are overweight or obese and want to have their weight controlled, not merely explained.

Now, however, explanations are coming. As scientists hack deeper into the underbrush of the human genome, they are at last beginning to understand the genetics of weight regulation--and how the whole system can go awry. With that understanding, they believe, it may be possible to develop drugs that do the job balky genes fail to do--controlling a problem that decades of fad diets and self-help books have never solved. Says molecular biologist Jeffrey Friedman of the Howard Hughes Medical Institute at Rockefeller University in New York City: "Genomics will identify the players in this system, eventually leading to new targets and new treatments."

It was the discovery of leptin in 1994 that got the genetic study of obesity rolling, and it was Friedman's research team that was responsible. Studying the genome of a rare strain of hugely obese mice, the investigators found that all of them shared a defect in a gene that coded for a previously unknown hormone released by body fat. When a normal animal gains too much weight, the hormone signals the brain to turn down the appetite rheostat. When fat stores drop, the hormone is shut off, causing appetite to rebound. In the gene-damaged mice, there was no leptin at all, causing them to eat and eat without satiation. "We called the hormone leptin," Friedman says, "after the Greek word leptos, for thin."

The announcement of leptin's discovery was big news to biologists, particularly after Friedman administered it to the obese mice and saw their weight drop by a dramatic 30% within as little as two weeks. A next, obvious step was to look for humans with the same defective gene. In Britain, endocrinologist Stephen O'Rahilly of the University of Cambridge did find a pair of leptin-deficient children, one of whom at age 9 weighed a staggering 208 lbs. After modest leptin treatments were begun, both children began dropping weight at a steady rate that sometimes exceeded 4 lbs. a month.