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You could ask Oprah how hard it is to keep weight off even with diet and exercise, but most dieters already know: 75 percent to 95 percent of people who lose weight regain most of the pounds within two or three years.

But unsuccessful dieters are not just lazy and undisciplined. Obesity is a biological, not a psychological, illness, say Dr. Rudolph Leibel, codirector of the Naomi Berrie Diabetes Center and head of the Division of Molecular Genetics, and Dr. Michael Rosenbaum, associate professor of clinical pediatrics and medicine.

The weight each person tends to return to again and again is determined by genes interacting with the environment. Our bodies fight any reduction in how much energy we store as fat. In their new research, Drs. Leibel and Rosenbaum have found more evidence for how the body's battle to maintain the bulge is instigated by a molecule, called leptin, and that administration of leptin may someday help dieters maintain a reduced weight.

In 1994, Dr. Yiying Zhang, assistant professor of molecular and cell biology (in pediatrics), cloned the leptin gene. Research revealed leptin was a hormone produced by fat cells, and some researchers at the time thought the molecule worked primarily to keep body fat low. As fat cells increase and produce more leptin, the theory went, the excess leptin tells the brain to reduce food intake until fat levels and leptin go back down.

The theory that leptin would help people lose weight was put to the test when overweight people were injected with large doses of the hormone in a study supervised by Dr. Steven B. Heymsfield, professor of medicine at P&S at St. Luke's-Roosevelt Hospital Center. Drs. Leibel and Rosenbaum weren't surprised when the weight loss produced by these injections was generally small. After all, obese individuals have very high leptin levels in their blood yet remain obese.

To the Columbia researchers, leptin's role as a weight loss hormone didn't make evolutionary sense for the human species, which has spent most of its 5 million years struggling to find enough food to eat. They hypothesized that leptin works to keep us fat, not thin. In their scenario, weight loss reduces the amount of leptin in the circulation, and the reduction in leptin tells the brain to fight the loss of fat.

Prior research by Drs. Leibel and Rosenbaum in humans had shown that the brain fights fat loss partly by making our bodies, especially our muscles, more efficient at using calories. Loss of 10 percent of body weight will require someone to cut the number of calories eaten daily by 22 percent. A woman who drops from 150 to 135 pounds, for example, needs to eat about 250 calories per day less, or exercise 250 calories per day more, to maintain her new weight compared with a woman whose stable weight is 135. Dr. Rosenbaum says, “Whatever lifestyle changes you make to lose weight must be continued indefinitely beyond the period of weight loss if you want to keep the weight off.”

In the current study, Drs. Rosenbaum and Leibel gave leptin to people who had lost weight to see if the hormone could help overcome their bodies' tendency to gain the weight back. They sequestered four people, one of whom was overweight, in the hospital and reduced their weight by 10 percent with a strict diet and prescribed amounts of activity. As predicted, after weight loss, each person needed 20 percent to 25 percent fewer calories to maintain their lower body weight, their muscle efficiency increased, and they had lower leptin levels due to fat loss.

The researchers then injected each person with leptin twice a day, just enough to return leptin to each person's pre-weight loss level. They found that restoring pre-weight loss levels of leptin reversed many of the metabolic changes that make it necessary for people to cut calories or increase activity levels to maintain their reduced weight. In fact, the four subjects on the leptin and the maintenance diet/activity level actually lost weight. The research is published in the May Journal of Clinical Endocrinology and Metabolism.

“This research provides strong evidence that body weight is regulated and that leptin sensing is pivotal to the regulation system,” Dr. Rosenbaum says. “Each person apparently has his or her own leptin threshold and when levels fall below that threshold, your body responds by eating more and burning fewer calories until your usual leptin level is restored.”

“The biggest problem in obesity is not weight loss, but weight maintenance,” Dr. Leibel says. “It's plausible that giving low doses of leptin to people trying to maintain a lower weight will trick the brain into thinking that the body has its usual level of fat. But more research needs to be done to test leptin as a potential weight maintenance aid in people who have lost weight.”

If you are overweight and healthy and would like to volunteer for the research described in this article, please contact Ellen Murphy at 212-851-5300.


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