WEIGHT-LOSS NIRVANA?

By J. Madeleine Nash/Chicago

How many people struggling mightily to keep their weight in check wouldn't trade places with the mice in Dr. Jeffrey Friedman's laboratory? Two weeks earlier, these roly-poly fur balls weighed three times as much as a mouse should, and they still couldn't stop snacking. After daily injections of a new hormone, however, the tubby rodents suddenly started consuming less food and burning more fat. They shed those excess ounces and trimmed 30% off their bloated size. Even better, their cholesterol readings fell, as did the high glucose levels that made them mildly diabetic. Virtually overnight, it seemed, the mice perked up, preening and prancing about their cages.

In a country where 1 in 3 adults is seriously overweight, the news carried by the journal Science last week--that Friedman and his colleagues at the Howard Hughes Medical Institute and New York City's Rockefeller University had discovered a magical potion that melts fat in a matter of weeks--resonated with unusual force. Momentarily, at least, it buoyed the spirits of millions of such lifelong dieters as Barbara Cady, a former teacher from Fairmont, West Virginia, and boosted the stock of Amgen, the biotechnical firm based in California that holds the license on the underlying technology. For if Cady, who has struggled to bring her weight down from 264 lbs. to 195, is any example, the market for such a compound could be huge. "Almost anyone," she wryly observes, "would be sorely tempted to try something that seems to promise nirvana."

It is too early to predict, however, whether this rare elixir (called leptin, after the Greek leptos, meaning slender) will be a stunning pharmaceutical success or just another "miracle" cure that never pans out. Even if all goes well, it could be five to 10 years before leptin is approved for human use. Researchers must first demonstrate that leptin benefits people as well as rodents and that it causes no serious side effects.

The search for leptin began in the 1960s, when Douglas Coleman, a researcher at the Jackson Laboratory in Bar Harbor, Maine, began studying a strain of obese laboratory mice. In a series of ingenious experiments, Coleman surgically joined the blood vessels of an obese mouse to those of a normal-size mouse, creating a sort of artificial Siamese twin. What happened then was astonishing: the fat animal immediately began to lose weight. This suggested that the blood of nonobese mice carried a potent biochemical messenger, one that played a vital role in regulating appetite and metabolism. But the mysterious agent was present in such minuscule quantities that no one was able to isolate it.

Friedman picked up the challenge, applying new tools developed by the field of molecular genetics. The secret factor, he reasoned, must be produced by a gene that was defective in the obese mice. So he began to hunt for such a gene, the ob, or obese, gene. Sure enough, late last year, after eight years of effort, Friedman and his colleagues pinpointed the ob gene in both average-weight and obese mice. They then inserted the normal gene into bacterial cells, providing at long last detectable quantities of the protein they called leptin.

By injecting leptin into obese mice, three separate teams of researchers, including Friedman's, have confirmed that this protein is indeed the blood factor that makes fat mice thin. But they are still trying to puzzle out just how it works. Friedman, for one, believes leptin is almost certainly a hormone that travels through the bloodstream to act on the brain. In fact, it appears leptin may act in a feedback loop like the temperature sensor in a thermostat--or in this case a "fatstat"--to tell the body whether to turn metabolism and appetite up or down. Thus when leptin is low, hunger pangs increase, body temperature drops, and metabolism slows. When leptin is high, everything reverses. In such fashion, the brain strives to keep body weight stable and fluctuations small.

Because leptin is produced in fat tissue, the fatter an animal is, the more leptin its cells should make. Normal mice then respond to weight gain by turning out more leptin. As a result, their appetites slacken and their energy consumption speeds up. But the obese mice cannot produce leptin, so their brains never receive this vital message. "These animals," marvels Friedman, "get fat because they think they're starving, and then when we give them the protein, they get thin because they think they're fat!"

What, if anything, does this have to do with people? Perhaps a good deal. For humans have an ob gene that is virtually identical to the mouse gene, and it is possible that at least some folks have trouble keeping off pounds because of a mutation in this gene. Barbara Cady, for one, welcomes the notion that she and others become fat not because they lack willpower or moral character but because they have a biochemical abnormality. "I'm not lazy or unintelligent," she says. "I do as many of the right things as slimmer people. But something's going on in my body that makes controlling my weight more difficult than it is for everyone else."

Defects in the ob gene are not likely to be a major reason for obesity in people, most experts concur. But that does not mean leptin might not be therapeutically useful for many other overweight people. In last week's Science, for example, a team of researchers from the pharmaceutical company Hoffmann-LaRoche described how they plumped up lean mice by giving them unrestricted access to high-fat food. Then they administered leptin. The mice responded by cutting their food intake and shedding the extra ounces, suggesting leptin may have value in reversing more typical cases of weight gain.

What about side effects? Injections of leptin do not, as one might fear, turn lean mice into starving wretches. After losing weight, researchers from Amgen reported, normal mice stabilize both their food intake and their metabolism. Obese mice likewise reach an optimal leanness, then stop losing weight. The pattern of weight loss is also encouraging. For unlike extreme calorie restriction, which can weaken muscle, leptin appears to dissolve fat while leaving lean tissue intact. On the basis of such data, Amgen (which paid Rockefeller University $20 million for patent rights to make products based on the ob gene) has announced that it hopes to begin conducting human trials as early as next year.

Many experts find these plans too optimistic. Just because researchers have not noted worrisome side effects yet, critics say, does not mean that none will emerge. Leptin, they point out, is a serious drug, not the easy-to-swallow "thin pill" dieters have dreamed of for so long. To do its work, leptin would probably have to be either injected daily, like insulin, or implanted under the skin for the rest of one's life. In the laboratory experiments reported last week, the obese mice started regaining weight as soon as the injections stopped. Even with a boost from something like leptin, cautions Dr. Ahmed Kissebah, an obesity expert at the Medical College of Wisconsin, the formerly fat cannot afford to become less vigilant. "People will still have to lose weight the hard way," he predicts. "It'll be like diabetes: you still have to exercise and watch your food intake."

Regardless of what eventually happens in the marketplace, the discovery of leptin is occasion for celebration. It has provided scientists with a new avenue for exploring a still poorly understood metabolic pathway, one that probably consists of many other equally powerful compounds, each of which could lead to new drugs.

And that is the best news Barbara Cady could hope for. "I don't expect that this is going to be a panacea and that we'll all live happily ever after on hot-fudge sundaes," she says. "I don't think anyone who is overweight expects that. All we want is some help with a frustrating condition." After years of guilty eating and self-recrimination, it looks as though help for Cady, and for more than 50 million other seriously overweight Americans, may finally be on the way.

--With reporting by Lawrence Mondi/New York

With reporting by Lawrence Mondi/New York