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Why We Eat (and Eat and Eat)


iven the opportunity, it seems that people just about everywhere will eat and eat, and then eat some more. Most know there is a price to pay — all those extra calories have to go somewhere — and yet they cannot resist that second piece of pumpkin pie.

Worldwide, a billion people are now overweight or obese, including 22 million children under the age of 5. Obesity and ills linked to it, including heart disease and high blood pressure, have joined the World Health Organization's list of the Top 10 global health risks. Rates of obesity are going up in developing countries as well as industrialized ones, with the greatest increases taking place in the last 10 years.

In the United States, 64.5 percent of adults and 15 percent of children ages 6 to 19 are overweight. Dieting is rampant, but most who lose weight gain it back. Some experts blame ever-increasing portion sizes and the proliferation of tasty, high-calorie fast foods that make it all too easy to eat a day's worth of calories in one supersize meal.

Most people know lean and less are better, but fat carries flavor, and so they pack in the rich foods anyway. Extremely obese people have begun trying to sue McDonald's for failing to warn them that too many French fries and cheeseburgers can make them fat.

This year, 60,000 Americans who are morbidly obese, meaning 100 pounds or more overweight, will have major surgery to seal off most of their stomachs and shorten their intestines to lose weight.

Lawsuits? Drastic operations? Why don't these people just stop eating so much?

"People can't stop eating any more than they're able to stop having sex or grabbing money or anything else," said Dr. Stephen R. Bloom, an obesity researcher at Hammersmith Hospital at the Imperial College school of medicine in London. "When you crash a plane in the Andes and there's no food, you eat your neighbor. Here we have the action of a very important, basic human drive."

Though most researchers advocate exercise programs and education about nutrition to try to prevent obesity, especially in children, they say people who already have a weight problem need more help. Rather than just telling heavy people to resist eating too much, Dr. Bloom and other researchers hope to find ways to ease the hunger pangs.

"I think we should do what we do for high blood pressure and high cholesterol," Dr. Bloom said. "We give them a tablet. It's not their fault. They're designed to get fat."

He and other scientists hope to decipher the signals that travel between the digestive system, the body's fat stores and the brain centers that control eating and metabolism, in a region called the hypothalamus. Then, researchers say, it may be possible to develop drugs that modify those signals to give people something dieters crave: the feeling of fullness.

Three prescription weight-loss drugs are already on the market, but researchers say they hope to develop more effective drugs with fewer side effects.

Hunger, of course, is not the only reason people eat. Stress, boredom and pleasure all come into play. Most scientists who study obesity believe that people were designed to get fat because we are descended from hunter-gatherers whose evolution over millions of years was shaped by periods of scarcity and the threat of starvation. Those who could eat a lot and build up reserves of fat had an advantage when lean times came. So they survived and transmitted the ability to their descendants. But today, with rich food ever abundant, it is a liability.

Dr. Gordon Jensen, director of the Center for Human Nutrition at Vanderbilt University, said: "It is likely that we have a biologic drive to eat that served us well historically in terms of survival. Genetically, that made sense when you didn't know if your next meal would be tomorrow or five days from now, but when your next meal is whenever you walk by the refrigerator, that's a problem."

When a hormone called leptin was identified by researchers at Rockefeller University in 1994, many scientists thought it would be the solution to obesity. Mice lacking leptin ate voraciously and grew enormously fat; leptin injections made them stop eating and slim down. The discovery led researchers to think that fat people might also lack leptin, and that it could make them lose weight. But it was not so. Scientists found that most fat people had lots of leptin, and giving them more had little effect.

Researchers came to realize that having too little leptin was more important than having too much. Leptin is made by fat cells, and it is apparently the body's way of letting the brain know when fat stores are being depleted. If leptin levels fall, the brain sends out signals to slow down metabolism and increase eating, to put weight back on. It is one of the reasons dieting can be so difficult.

A small study published recently in The Journal of Clinical Endocrinology and Metabolism suggests that even though giving people leptin does not help them lose weight, it may help them keep weight off after dieting. The study was directed by Dr. Rudolph Leibel, the director of the division of molecular genetics at Columbia's College of Physicians and Surgeons. His team studied six people, three obese and three normal, who dieted until they lost 10 percent of their body weight. When they lost weight, their bodies tried to regain it by slowing their metabolism.

"Then we gave them injections of leptin at very low doses, just enough to put back into the blood the amount that would have been produced by the fat they'd lost," Dr. Leibel said. "We were trying to trick the brain."

The trick worked; the added leptin was apparently interpreted as a signal that the missing fat was back. The subjects' metabolism perked up.

To maintain the effect, Dr. Leibel said, "You'd probably have to continue leptin indefinitely or for pretty long periods of time, similar to the way you have to treat high blood pressure or diabetes. Nobody thinks you can treat those disorders with a transient intervention. You're interrupting a major regulatory process in the body."

Leptin is still experimental, and not on the market, according to a spokeswoman for its maker, Amgen.

In May, researchers reported on another hormone that might affect weight, through its powerful ability to stimulate appetite. The substance, called ghrelin, acts on the brain, but is made in the stomach and small intestine, and it is the only natural appetite stimulant known to be made outside the brain.

People given shots of ghrelin get very hungry and eat 30 percent more than they normally would. Ghrelin spikes in the blood before meals and falls afterward, possibly helping to explain why people feel hungry at mealtimes.

Ghrelin levels rise in dieters who lose weight and then try to keep it off, as if their bodies are trying to regain the lost fat. But the levels drop sharply in people who have the type of weight loss operation known as gastric bypass, and may help explain why their appetites sharply decline.

Dr. David E. Cummings, an endocrinologist at the University of Washington and the Department of Veterans Affairs in Seattle, was the first author of an article about ghrelin levels in dieters and gastric bypass patients that was published in May in The New England Journal of Medicine.

Drug companies are very interested in ghrelin. Dr. Cummings said, "I've been consulting with a lot of the companies under sworn secrecy pacts."

Small companies that look for niche markets want to make drugs that will mimic ghrelin and increase appetite, as possible treatments for the wasting that can accompany diseases like AIDS and cancer, he said. Several big companies, which typically do not develop drugs unless there is a potential market of $1 billion a year, are working on ghrelin blockers to treat obesity.

"Each one doesn't want the other to know they're doing it," Dr. Cummings said of the big companies.

So far, he said, it has been easier to find ghrelin mimics than ghrelin blockers. That is unusual, he said: most of the time, when working with natural molecules, the opposite is the case.

"I like to think it's good evolutionary design, making it harder to turn off appetite," Dr. Cummings said.

He said that some of the blockers may need to be injected but that drug companies were often reluctant to develop such products because people do not like shots. But most are so desperate to lose weight that, Dr. Cummings said, "I maintain a shot or a few shots a day would be something they'd be willing to do."

In August, Dr. Bloom's research team discovered that another gut hormone, called PYY, is made in response to food and then circulates to the brain, where it switches off the urge to eat. People given the hormone and then offered a buffet two hours later ate 33 percent fewer calories than when they did not have the hormone, and the effects lasted about 12 hours.

Since then, Dr. Bloom's group has tested PYY in obese patients to see if it could help them eat less and lose weight, but Dr. Bloom said he could not reveal the results because they had not been published.

As to whether PYY will be marketed, Dr. Bloom said: "We're in the middle of complex, tricky negotiations. The patent position is unclear."

But, he added, "I'm a physician. I treat people dying of obesity. I'd sure like to get an effective agent out there. I think this is an effective agent."

Other molecules are also being studied. They include chemicals secreted within the brain, in a part of the hypothalamus called the arcuate nucleus. Some form important links in the chain of events touched off to make a person either start eating or stop when hormones like leptin, ghrelin, insulin and PYY reach the brain.

One candidate that Dr. Cummings described as the "darling" of obesity researchers would be a drug that could stimulate a brain structure called the melanocortin-4 receptor, to decrease appetite and cause weight loss. But side effects always loom, and one drug tested in animals made them lose weight but also caused erections.

"That may sound great, but when the erections are unsolicited and prolonged, that's a bad side effect," Dr. Cummings said.

Still other possibilities include drugs that will sensitize people to leptin or act as a stronger version of leptin.

Dr. Cummings said that it was unlikely that any one approach would work for all obesity, and that different classes of drugs would be needed. Eventually, he said, combinations of medicines may be available to help people manage obesity in much the way that they manage other chronic conditions like hypertension and diabetes.

Copyright 2003 The New York Times Company

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