Scientists say they may have found out why people get hungry at mealtime, why dieters who lose weight often gain it back and why a certain type of stomach surgery helps severely obese people lose a great deal of weight.
The reason may be a hormone called ghrelin, which makes people hungry, slows metabolism and decreases the body's ability to burn fat.
Ghrelin levels in the blood spike before meals and drop afterward. People given ghrelin injections feel voraciously hungry, and, turned loose at a buffet, eat 30 percent more than they normally would, studies have shown.
Dieters who lose weight and then try to keep it off make more ghrelin than they did before dieting, as if their bodies are fighting to regain the lost fat, researchers are reporting today in The New England Journal of Medicine. By contrast, the study showed that extremely obese people who have an operation called gastric bypass to lose weight wind up with relatively little ghrelin, which may help explain why their appetites decrease markedly after the surgery.
But scientists caution that the research is in its infancy. They say that ghrelin is not likely to be the cause of most obesity, and that further experiments are needed to find out whether it will lead to new therapies. The study included only 28 people.
Ghrelin (pronounced GREL-in) is one of a complex array of natural substances that carry messages between the brain and the digestive system and help the body regulate eating. Secreted by specialized cells in the stomach and the upper part of the small intestine, ghrelin acts on the brain, but it is the first natural appetite stimulant found to be made outside the brain.
Because it occurs outside the brain, it may be an easier target than molecules made in the brain for scientists looking for ways to manipulate weight gain and loss.
If drugs could be developed to decrease ghrelin levels or block its action, they might help people lose weight, researchers say. Finding drugs that could mimic ghrelin's action might stimulate appetite and weight gain in people who are wasting away from cancer, heart failure, aging or eating disorders.
''It would be interesting to know what would happen if we could block the rise of ghrelin,'' said Dr. David E. Cummings, the first author of the new study and an endocrinologist at the University of Washington and the Department of Veterans Affairs in Seattle. ''Would it facilitate weight loss, or make it easier to lose weight through dieting or exercise?'' But, he said, it might be easier to use ghrelin to help people who need to gain weight.
Dr. Cummings said ghrelin might be an important part of the body's system for defending itself against starvation.
''A powerful mechanism to increase appetite and decrease metabolism when weight loss occurs is likely to have evolved because our species was subjected to periods of famine, and the threat to survival came from starvation, not overnutrition,'' he said. But in the developed world, Dr. Cummings said, ''where we have continuous access to highly caloric, highly palatable food and no need to work to get it, those genes do us a disservice.''
Dr. Jules Hirsch, an obesity expert at Rockefeller University in Manhattan, said whether ghrelin ''will be useful in any way in the treatment of obesity remains to be seen.'' He added, ''There are so many redundant loops that something else may take over to restore the fat that people want to lose.''
Another promising discovery, leptin, a natural appetite suppressant made by the body's fat cells and thought to have great promise as a treatment for obesity, has turned out to be a disappointment thus far because most overweight people are resistant to its effects.
Ghrelin was first described by Japanese researchers in the journal Nature in December 1999. They chose the name ghrelin because ''ghre'' is the Proto-Indo-European root of the word grow, and ghrelin also stimulates the pituitary gland to release growth hormone.
Ghrelin soon became a hot topic of research, and scores of scientific papers about it have already been published. But the studies reported today are the first to measure its levels in dieters and people who have had weight loss surgery.
Dr. Cummings and his colleagues measured ghrelin levels in three groups of people: 10 who had normal weight, 13 who were obese but had lost weight by dieting and 5 who were still obese but who had lost large amounts of weight after gastric bypass surgery.
Their ghrelin levels were measured before they began dieting and then six months later. The levels were markedly higher after the weight loss.
That finding may help explain why diets fail for the majority of overweight people; the most they can realistically hope to lose is 5 percent to 10 percent of their body weight, and keeping off even that amount usually requires a lifelong struggle.
Increasingly, people who are ''morbidly obese'' -- 100 pounds or more overweight -- are having surgery to lose weight. The American Society for Bariatric Surgery estimates that 62,500 weight-loss operations will be performed in the United States this year. There were more than 47,000 in 2001, and 20,000 in 1995. Like any major operation, the surgery has risks, including a death rate that is estimated at 0.5 to 1 percent.
The most commonly performed operation is the gastric bypass, in which much of the stomach is sealed off, leaving just a small pouch that will hold only a few tablespoons of food. The small intestine is also re-routed, so that only part of it is available to absorb nutrients. People can eat only tiny meals, and their absorption is also limited. Within two years of the surgery, many have lost 100 pounds.
But many surgeons say that the operations work much better than they would predict, judging from just the physical changes made to the stomach and intestine. Many patients lose their appetites to a greater degree than doctors would expect.
Dr. Walter J. Pories Jr., a professor of surgery and biochemistry at East Carolina University in Greenville, N.C., and president-elect of the society for bariatric surgery, said he and other doctors had long suspected that the gastric bypass operation might be decreasing the levels of some hormone made in the gut that was affecting appetite and weight.
Ghrelin might be the mystery hormone. When Dr. Cummings and his colleagues measured it in people who had had the surgery from 9 months to 31 months earlier, they found ghrelin levels to be a third or less of the lowest levels found in normal weight or overweight people who had not had the surgery.
Dr. Cummings said the surgery may shut down the ghrelin-making cells by preventing them from being exposed to food, an important signal. The lack of ghrelin, he said, might help explain the patients' loss of appetite.
Dr. Pories said: ''The ghrelin drops like a rock. It's lovely.''
The true test of this idea will be studies in obese rats that are given gastric bypasses, lose weight and are then given ghrelin. If the rats regain an unusual amount of weight, that will help prove that the surgery works in part by acting on ghrelin.
The study was paid for by federal grants, the Andrew W. Mellon Foundation and the Burroughs Wellcome Fund of GlaxoSmithKline.
Chart/Graph: ''A Day's Hunger Changed by Surgery'' Blood levels of the hormone ghrelin, which prompts hunger, rise before meals. It is reduced and stable in people with gastric bypass surgery. OVERWEIGHT PEOPLE -- Ghrelin spikes before meals, indicating hunger. PEOPLE WHO HAVE LOST WEIGHT -- make even more ghrelin; they may feel greater hunger. PEOPLE WITH GASTRIC BYPASS -- have much less ghrelin. Graph tracking the blood levels of the hormone ghrelin in people who are overweight, people who have lost weight and people with gastric bypass. (Sources: Dr. David E. Cummings, University of Washington; National Institutes of Health)(pg. A28)