hen Dr. Jeffrey Flier decided to specialize in diabetes, he knew that most of his patients would be fat. Obesity is a leading cause of the disease. And weight loss is the best way for most fat diabetic patients to get their disease under control.
But after years of seeing patient after patient, fat and frantic to lose weight, Dr. Flier retreated to the lab. Although he still treats people with diabetes, he no longer treats obesity. He has rebuffed all suggestions by his hospital, Beth Israel Medical Center in Boston, that he run a weight loss clinic.
And he is telling anyone who asks that the truth about weight loss is that the medical and behavioral treatments that doctors can offer are usually ineffective. People often lose weight, but they almost always gain it back.
"It's not the kind of therapy you can get very excited about," Dr. Flier said.
Dr. Flier says he is waiting for something to offer that truly works. But now, for the first time, he and others say there is real reason to hope. Obesity research seems to have entered a new phase.
The excitement is in the lab and not yet in the clinic, much less in the drugstore. Nonetheless, experts agree, the field that many had dismissed as a scientific backwater has been shaken to its roots.
Instead of endlessly rejiggering diets and exercise regimens, a new wave of scientists is getting at the molecular causes of appetite and satiety, unraveling elaborate chemical pathways that control how much animals, including people, eat. Some of the newly discovered molecules are thought to keep body weight stable by controlling appetite, so that someone who eats a huge meal one evening will not have a voracious appetite the next morning. Other molecules react to signals from the body that it is not fat enough, making people feel an urge to gorge on calorie-laden foods. Many scientists now believe that everyone's eating is controlled by these and other molecules that send signals between the brain and the body but that obese people are likely to have a different balance of them or are less reponsive to them.
Drug companies have rushed to invest in the new research; today nearly every major company is competing to develop antiobesity drugs. And researchers who had embarked on their work out of scientific curiosity are starting to hope they might strike it rich with a magic pill that will melt away pounds.
Until research succeeds, though, many fat people are left with few options.
"It's a very difficult situation," said Dr. Rudolph Leibel, an obesity researcher at Columbia Presbyterian Medical Center in New York. "You have to be very careful about instituting treatment for something when you know from first principles that the treatment is not likely to be efficacious."
"On the other hand," Dr. Leibel added, "the patients are so desperate."
A Losing Battle
Some weight loss programs promote special food combinations. Others advise calorie counting. But the bottom line is almost always the same: losing weight and keeping it off is a matter of diet, exercise and discipline.
If only it were so, obesity experts say.
The fact, however, is that more than 90 percent of dieters gain back every pound they lose and no diet or behavioral modification has improved those odds. Now, leading obesity researchers say they have been forced by an overwhelming body of evidence to reach a surprising conclusion: the simple decisions of what, when and how much to eat may not be completely under people's conscious control. Each person, they say, inherits a range of weights that his or her body can comfortably maintain. A person's weight range typically varies by about 10 percent from a midpoint. A 150-pound woman, for example, might be able to weigh from 135 to 165. But every time her weight dips below 135 pounds or creeps beyond 165 pounds, her body will institute controls, like an insatiable urge to eat or a feeling of disgust at the sight of food, to bring its fat levels back in line.
People can keep their weight at the lower end of their genetically determined range, often by watching what they eat and exercising. Or they can allow their weight to soar to the top of their range. But there is little anyone can do to change their range itself, these researchers say.
"There is very strong biological evidence that the brain receives signals from the body and the brain talks back," Dr. Leibel said. And this, not conscious decisions about how many calories to take in over days or weeks, is what regulates body weight to keep it in a narrow range, he added.
While acknowledging that this notion of weight ranges runs counter to beliefs about willpower and even free will, Dr. Leibel and others said it does not surprise them because the brain signals other sorts of behavior, like drinking and excreting the right amounts of water to maintain a precise balance in the body, and even making sure that people eat to maintain their blood sugar, when necessary.
"If you had an abnormally low blood sugar level, would you be surprised if you got hungry and agitated?" Dr. Leibel said. Yet, he added, few would question that such behavior is driven by the brain, independently of willpower or free will.
Support for Range Theory
Dr. Leibel and others say that the existence of preset weight ranges is consistent with results from voluminous research on dieting. For example, an expert panel convened by The National Institutes of Health, reviewing the most rigorous studies it could find, said that dieters lose an average of 8 percent of their weight, 16 pounds for a 200-pound woman, for example, after dieting for three months to a year and that the goal after six months of dieting should be to simply maintain whatever weight was lost.
In fact, obesity researchers say, looking back, they have had hints since the 1930's that there is a system in the hypothalamus in the brain that seems to control eating.
In those early days, the evidence was clumsy and imprecise. Researchers found that when this part of the brain was destroyed, animals, and people, ate ceaselessly and grew massively obese.
That happened to a 14-year-old boy seen by Dr. Steven B. Heymsfield, the deputy director of the obesity research center at St Luke's Roosevelt Hospital in New York. The boy was hit by a car while he was sledding and suffered a brain injury that destroyed the eating center of his hypothalamus. "He became 400 pounds literally in weeks," Dr. Heymsfield said.
In recent, carefully controlled experiments, Dr. Leibel and his colleagues Dr. Hirsch and Dr. Michael Rosenbaum discovered just how precisely the body regulates its weight. Their study involved almost 100 volunteers who had maintained a stable weight without effort for at least six months, an indication that their weights were within their biologically determined range. They agreed to live a sedentary life in a metabolic ward at the hospital while researchers controlled what they ate, making the people first gain weight until they weighed 10 percent more than their original weights and then lose weight until they weighed 10 percent less than they did when they began.
Whether the subjects started fat, thin, or between, the study showed that they each burned 1,360 calories per square meter of body surface per day. But when the volunteers ate so much that they gained an extra 10 percent of body weight, their metabolisms sped up by 15 percent. It was as though their bodies were trying to drive their weight back down. When they then ate so little that their weights fell 10 percent below where they started, their metabolisms slowed by 15 percent. And, Dr. Leibel said, his studies indicate that people's metabolisms never seem to permanently adjust to their new weights.
But it is not just metabolism that changes if people's weights get outside their natural range, Dr. Leibel said. People who are below their comfortable weights are miserable — ravenous, obsessed with food. Those above it complain that they feel sluggish and full nearly all the time and lose interest in food.
The weight range studies lead to an inevitable conclusion, obesity experts say: if researchers want to enable fat people to lose weight permanently, they have to enable them to change their natural weight range. And that means identifying the biochemical signals between the brain and the body that control weight.
Not the Answer, but a Clue
Not too long ago, Dr. Jeffrey Friedman of Rockefeller University in New York thought he had found the elusive signal between body and brain, and most obesity researchers agreed.
In 1994, after eight years of work, he finally isolated one defective gene that made a strain of mice grow immensely obese. The gene's role was to direct fat cells to make a small protein that acts like a hormone, signaling the brain. It seemed to be the missing link between body and mind, allowing the exquisite control over eating that could put animals, and people, into rigidly regulated weight ranges.
It was, Dr. Friedman recalled, almost a religious experience to find that molecule. "Here is this simple hormone that solves the problem of how to track millions of calories over a lifetime," he said. "I actually found it quite humbling that this was around all the time."
Dr. Friedman named the molecule leptin, derived from the Greek root leptos, meaning thin. "The idea is that in the absence of leptin you're fat, so leptin keeps you thin," he explained. Over the next few months, he and his colleagues accumulated evidence that, in mice at least, when leptin was missing, the brain responded by sending constant signals to the body to eat, eat, eat, and the animals grew immense. With leptin injections, the animals stopped eating and lost weight. He also discovered that humans, too, made leptin.
Rockefeller University applied for a patent on the discovery, and a biotechnology company, Amgen of Thousand Oaks, Calif., licensed the commercial rights for $20 million. Dr. Friedman got part of the money. Suddenly obesity research was transformed. Obesity, it seemed, might be caused by a leptin deficiency, and treating it might be as simple as supplying fat people with the hormone.
"People were shocked," Dr. Heymsfield said. "It set off a worldwide excitement."
But, scientists said, leptin proved disappointing in Amgen's preliminary studies. They found that most fat people made plenty of leptin and when they took the drug it appeared to have little effect on appetite or weight loss. Amgen's spokesman, David Kaye, said that the company's scientists think the problem might be that their drug did not last long enough in the body. Mr. Kaye said Amgen was testing a longer lasting formulation. But some researchers say leptin may act differently from what was originally thought.
These scientists say that the important signal in the brain may be a decline in leptin levels. If someone loses weight by dieting, he will have less fat and should make less leptin. The brain, sensing that something is wrong, will signal the body to eat and put on more fat, bringing leptin levels up again. If there is no leptin at all because the leptin gene does not function, or if the brain does not recognize leptin, the brain thinks the body has starved itself to emaciation and signals it to eat ceaselessly.
Consistent with this view, Dr. Flier finds that leptin levels drop when people are losing weight. If so, there is still hope for leptin as a drug to keep people thin once they have lost weight, possibly resetting the lower bound of a person's natural weight range and solving the fundamental problem of weight loss programs, recidivism.
Meanwhile, scientists are using leptin as a key to unlocking the entire brain pathway that controls appetite, finding dozens of molecules in the brain that may be new candidates for obesity drugs.
Reason for Optimism?
Of course, researchers caution, laboratory excitement often does not translate into success in the clinic. But, said Dr. Elfetheria Maratos- Flier, an obesity researcher at the Joslin Diabetes Center in Boston, there is good reason to be optimistic about the findings. All the new research points to the conclusion that obesity is a hormonal problem resulting from too little or too much of molecules like leptin or molecules that are linked to it in elaborate paths and that signal the body to eat or abstain.
"In general, endocrine problems can be treated," Dr. Maratos-Flier said. "If you have too much of something you can get rid of it, and if you have too little you can add it back."
Among the host of newly discovered molecules is a small protein, AGRP, for agouti related protein, that seems to regulate how many calories mice consume and whose production is controlled by leptin. Dr. Gregory S. Barsh of Stanford University, an associate professor of pediatrics and genetics, and, independently, Dr. Kevin Stark, a researcher at Amgen, found the protein two years ago . Dr. Barsh explains that it attaches itself to brain cells in the eating control centers in the hypothalamus. Researchers have already tested a drug that mimics AGRP — one injection makes animals gorge for a week. Another drug blocks AGRP, making animals stop eating. Humans also have AGRP, and Dr. Stephen O'Rahilly, a professor of metabolic medicine at Addenbrooke's Hospital in Cambridge, England, has found that about 5 percent of massively obese people have mutations that cause them to behave as though they are overresponding to AGRP, many more than have mutations preventing them from making leptin.
"We think it helps control the long- term energy balance," Dr. Barsh said. "In one 24-hour period, you or I may eat half of what we eat in another 24-hour period. But over the long term our body fat remains stable. So there needs to be a mechanism to account for that stability. Or supposing you went on a drastic diet for three or four days. There will be a drive to eat; you feel hungry. Where does that drive come from?" The regulator, Dr. Barsh suggests, could be the protein he found. By manipulating its action, he hopes, it may some day be possible to stanch those irresistible drives to eat.
Another protein, known as melanin concentrating hormone, or M.C.H., makes mice and rats eat and grow fat. Dr. Maratos-Flier, who discovered the protein's role, also found that it is in the hypothalamus and that it, too, is made when leptin flows to the brain. "People have the exact same hormone," Dr. Maratos-Flier said.
It is no accident that there is now a proliferation of discoveries of brain chemicals that control eating, Dr. Heymsfield said. "Most look at the discovery of leptin as the seminal event," he said. "It's like a jigsaw puzzle, and suddenly there was a puzzle to put together."
Ultimately, scientists predict, obesity will be medically treatable.
"There's been a prejudice, a bias, that obesity is a behavioral abnormality," Dr. Barsh said. "Somehow in the past, obesity was thought of as a poor relation to a real disease like heart disease or cancer."
"That misperception is being corrected," Dr. Barsh said.
