JANUARY 22, 2001 VOL. 157 NO. 3

The Hunt for Cures

Obesity
Healthy genes could mean smaller jeans
By JEFFREY KLUGER

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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 those who are overweight or obese and want to have their weight controlled, not merely explained.

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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 94 kg. After modest leptin treatments were begun, both children began dropping weight at a steady rate that sometimes exceeded 1.8 kg a month.

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, U.S., 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.

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