Scientists Seek 1 Pill to Make You Smaller

Feeling famished? Or so full you couldn't eat another bite? It may be all in your head.

Research has shown when it comes to appetite, certain hormones, enzymes and genes all play a role in signaling the brain when it's time to eat. Understanding how these mechanisms interact is a key pursuit in the United States, where two-thirds of the population is overweight and nearly 59 million are obese.

Keeping the pounds off is also an expensive problem. Researchers at the Center for Disease Control and Prevention in Atlanta recently estimated weight-related health problems cause $93 billion in U.S. treatment costs every year.

"We've been telling people for more than 150 years that in order to prevent obesity, they need to eat less and take more exercise," said Stephen Bloom, a British obesity researcher at London's Imperial College. "And yet the population has gotten fatter and fatter and thousands of people die unnecessarily every week because they overeat. So obviously it doesn't work."

What could work, argue Bloom and others, is fooling the brain into thinking it's full.

The Hungry Hormone

This has certainly been tried before. A popular diet-drug cocktail of fenfluramine and phentermine, known as fen-phen, entered the market and then exited when it was determined it could have dangerous side effects on the heart.

Ephedra, an herbal diet supplement, will soon carry warning labels following the February heatstroke death of Baltimore Orioles pitcher Steve Bechler, who had been taking the supplement. Other pills remain available and carry no warnings, but appear to be less effective as weight-loss aids.

Recently, however, scientists have directed their attention to a small group of hormones and enzymes that, they believe, could play a role in developing a diet wonder drug.

Among the hottest targets are the hormones known as ghrelin and PYY. Japanese scientists discovered ghrelin in 1999 and American researchers proved its role in appetite a year later.

According to work by David Cummings, an endocrinologist at Seattle's Veterans Administration Medical Center at the University of Washington, ghrelin is produced in the stomach and, when delivered to the brain, tells the body to eat — immediately.

What's more, Cummings research showed that obese people who are dieting and losing weight have increased levels of the hungry hormone in their blood. The more pounds they lose, the more their bodies demand they eat more to make up the difference.

By finding a way to artificially reduce the level of ghrelin in the blood, scientists hope to turn off the body's demand to eat.

The ‘Stop Eating’ Signal

Ghrelin appears to have a counterpart — another hormone that sends the opposite signal — telling the brain to hold off the forkfuls.

PYY, which stands for peripheral hormone peptide YY (PYY 3-36), is secreted in the gut and released on a bundle of brain neurons in the hypothalamus that control appetite.

Tests on mice suggest that infusing even small amounts of the hormone into the bloodstream leads to dramatic weight loss. And Bloom and colleagues have shown that tinkering with levels of PYY in people works to suppress appetite.

When his team at Imperial College infused a test group with the hormone they ate a third less food from a free, fancy buffet than people who had received a placebo infusion of saline. Both groups had refrained from eating for a day before the test to ensure they had hearty appetites.

"We need to do further human studies to prove there are no side effects when you take it every day and we need to show it would work in the very overweight," Bloom said. "But right now it's looking like a strong solution."

Failed Promise

It remains to be seen whether ghrelin or PYY are sensible targets or just more dead ends in the search for the perfect diet drug. Other discoveries have looked equally promising in the past.

In 1994, for example, a Rockefeller University scientist identified a mouse gene that makes a protein called leptin. Mice bred without the leptin-producing gene grew to be grossly obese while those with higher levels of leptin stayed slim.

The fervent hope was by packaging leptin in a pill, dieters might finally get the help they need to resist overeating. But follow-up studies showed that, thanks to genetics or lifestyle patterns, many overweight people and nearly all obese people tested already have unusually high levels of leptin in their blood and seem to lose their sensitivity to it. So leptin boosts proved to be no help.

But slumps like these can lead to new discoveries.

Ludiano Rossetti, for example, was investigating why some people lose sensitivity to leptin when he found that hormones and proteins aren't the only things sending "stop eating" signals to the brain. It turns out nutrients, themselves, send signals as well.

Rossetti, a medical researcher at Albert Einstein College of Medicine in New York City, found that when fats are digested, the enzymes used to break down the fat tell the brain that the body's getting full. Rossetti is eager to find out if increasing levels of this enzyme in the brain could be a more direct method of helping people cut back on eating.

"I think what we've been learning in the past decade is the body is full of responses that are designed regulate how much we eat," he said. "It's a tightly controlled system."

Exercise, Exercise, Exercise

Because we have such "precisely controlled systems," many health experts have concluded it's best to simply try and work with what we've got. That of course, involves following the well-known refrain: eat right and exercise.

Lisa Sutherland, a nutritionist at the University of North Carolina at Chapel Hill, believes that exercise may be the most important part of that prescription.

"When I was growing up I had physical education in schools five days a week and only three channels on TV," she said. "That has changed and I think that may be a big part of the problem."

Sutherland analyzed federal data on the diet and weight and physical activity of teens from 1980 to 2000 and found that kids in the most recent year were eating only 1 percent more calories while their level of physical activity dropped by 13 percent.

William Banks, a professor of geriatrics at Saint Louis University School of Medicine and the Veterans Affairs Medical Center, points out that some may have to work harder than others at staying slim, thanks to genetics. (See sidebar below.)

Still, unlike Bloom, Banks is hopeful that eventually the eat less and exercise mantra will stick.

He points out that in the 19th century, obesity was more common among those with wealth, since wealthier people could afford more comfortable lifestyles. Today the reverse is true — those in higher socioeconomic groups are less overweight than those who have less.

"This shift suggests people can educate themselves and introduce important lifestyle changes," he said. "It's hard because we're so entrenched in a calorie-ridden society. But it's possible."