Beating the Urge to Eat

Science offers new hope for a future without fat.

Leptin

By the time they arrived at the hospital at the University of Cambridge in England, the two children were dangerously obese. Rolls of fat encased their bodies, making walking difficult. The eight-year-old girl weighed 190 pounds. Almost 60 percent of her body was made up of fat. Her cousin, a boy of two, already weighed more than 63 pounds. They were ravenously hungry all the time. Nothing the parents or doctors could do kept them from eating -- or from getting fatter.

Then, a kind of miracle. Doctors injected the children with a genetically engineered version of a hormone that controls appetite and metabolism. "Within days their hunger subsided," says Sadaf Farooqi, one of the physicians who treated the kids. "Without any prompting, after two weeks they were eating 90 percent fewer calories." The fat began to melt off. By the end of a year, they were down to a normal weight for children their ages.

Such is the dream of every dieter: a treatment that makes you slim by magically suppressing hunger. In reality, the children treated at Cambridge are among a group of perhaps a dozen around the world with a genetic defect that makes them eat ceaselessly and never feel satisfied. But their extraordinary case points up how far science has come in understanding why some people are thin and others fat, no matter how much they diet. The latest insights into genetics, proteins, hormones -- and a virus -- could soon lead to personalized weight loss and even a shot or a pill to "cure" fatness.

Survival of the Fattest
"Given the world we live in, the real question isn't why people get fat, but why some people manage to stay thin," says Eric Ravussin, a scientist at the Pennington Biomedical Research Center in Baton Rouge, Louisiana.

"People who could take in lots of calories when food was available and store them efficiently in the form of body fat were the people most likely to survive through famines and pass on their genes," says Ravussin. "For millions of years, evolution favored people of this 'thrifty' genetic type." Only now, in an environment of restaurants, grocery stores or quickie food marts on nearly every corner, has it turned into a liability.

Not all of us possess thrifty genes. "Populations that lived as hunter-gatherers were probably more vulnerable to periodic feasts and famines, so evolutionary pressure was more intense to select thrifty genotypes," says Ravussin. Populations that began farming early on stored food for the winter -- an alternative to storing it as body fat. "As they evolved, they may have begun to lose the thrifty genotype."

So while some people really can eat all they want and stay thin, they are evolutionary oddities, not the norm, says Ravussin. Most of us have a genetic profile that leads us to get fat when there's plenty of food.

Popular diet plans have fostered a myth that obesity is due to a lack of willpower. But Jeffrey Friedman of Rockefeller University, a leading researcher in exploring the reasons we get fat, insists that's not true. Says Friedman: "Genes play as big a role in determining how fat we are as they do in determining our height."

The Hunger Switch
Somewhere along the evolutionary ladder, fat cells began communicating with the brain (and the message wasn't "More Twinkies"). The first understanding of this chatter came in 1994, when Friedman discovered a hormone called leptin. "Leptin is part of a complex system that closely regulates body fat and hunger," says Friedman. "When we put on fat, fat cells release leptin, which signals the brain to suppress appetite." What's more, leptin sends a message to crank up metabolism. "When we burn fat, leptin levels fall, and the hunger center of the brain says, 'Eat something.' "

The Cambridge children had a genetic defect that kept their bodies from making leptin. With the discovery of leptin and proof of its dramatic effect on leptin-deficient patients, jubilant scientists thought they had finally found a magic bullet for dieters. But extreme leptin deficiency turns out to be exceedingly rare. Paradoxically, 85 to 90 percent of obese people actually turn out to have higher than normal levels. "The problem isn't that they don't make enough," Friedman explains, "but that they are comparatively insensitive to leptin's effects."

St. Louis University professor William A. Banks recently offered a provocative reason for leptin resistance: The hunger-suppressing hormone may have trouble reaching the brain. In findings reported in March, Banks showed that triglycerides -- fat particles in the blood -- can gum up the blood-brain barrier, making it hard for leptin to get across. "As people gain weight, levels of triglycerides rise, which may prevent leptin from reaching the brain," explains Banks, who conducts his research at the VA Medical Center in St. Louis. "People are hungry and eat more, adding even more fat."

Whether triglycerides or another factor blocks leptin, once people become overweight, resistance to the hormone makes it harder to lose pounds. People who are resistant need more leptin to suppress appetite. But as fat cells shrink, levels of the hormone fall. That drop-off triggers hunger pangs and slows down metabolism. The brain responds as if to a famine, conserving energy and ordering you to eat, eat, eat. With each pound of fat lost, shedding weight and keeping it off becomes more difficult.

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