Leptin May Hold Key To Better Weight Loss

New York, NY—Aug. 2, 2001— Dieters know the phenomenon all too well: They cut calories, exercise, and lose some weight but at some point they can’t seem to get rid of any more of the excess poundage. Now researchers from Columbia University College of Physicians & Surgeons, St. Luke’s-Roosevelt Hospital Center, and the Weill Medical College of Cornell University, in a study of rats, may have some new clues why the plateau effect occurs and what could be done to overcome it. The findings have led to clinical tests in people. The investigators theorized that rats--and humans--may not be able to lose weight after a certain amount of dieting, even with drugs or surgery, such as gastric bypass, because the loss of fat decreases the amount of the hormone leptin in the body. Leptin, a hormone mostly manufactured by fat cells, is present in obese animals (and humans) but as the animal loses fat, levels of the hormone go down. With reduced levels of the leptin, the researchers say, the brain mistakenly thinks the animal needs food and sends signals to the body to slow metabolism down and increase appetite, two conditions that make it harder to fight the battle of the bulge. Prior research has shown that rats with diet-induced obesity and obese humans both have high levels of leptin. Giving more to them is minimally effective. The researchers in this study, therefore, gave obese rats a mixture of the weight-loss drug sibutramine, known commercially as Meridia, and leptin, to see if the two substances together might help the overweight animals lose weight. The addition of leptin, they believed, would trick the brain into thinking that no weight was being lost. “By preventing the decrease in leptin levels that normally occurs with weight loss, we theorized that sibutramine would be able to have a greater weight-loss effect,” says Carol Boozer, D.Sc., assistant professor of nutritional medicine in the Institute of Human Nutrition at Columbia, and lead author of the study. Dr. Boozer is also director of the Energy Metabolism Laboratory in the New York Obesity Research Center at St. Luke’s-Roosevelt Hospital Center. “This study shows that an active system resists weight loss, but that the resistance can be overcome,” says Dr. Louis J. Aronne, clinical associate professor of medicine at Weill Cornell Medical College and senior author on the study. “Hopefully, it will point us towards more successful treatments of obesity.” The investigators compared a group of obese rats getting the weight loss drug and leptin to three other weight-matched groups: one that received only saline; one that received sibutramine alone; and one that received only replacement levels of leptin. They found that the rat group taking sibutramine alone lost more weight than rats that received either leptin or saline. The amount of weight lost on the drug, though, started to plateau after five days. But the rat group given a mixture of sibutramine and leptin shed significantly more weight than the group given sibutramine alone. Rats getting sibutramine and leptin also ate less food and had significantly less body fat. Trials with the drug and leptin are under way to test whether the two together facilitate weight loss in obese people, too. The William R. Berkley, Michael Steinhardt and Isaac Blech Research Fund, and the National Institute of Diabetes and Digestive and Kidney Diseases supported this research. Knoll Pharmaceuticals of Cedar Knolls, N.J., which manufactures Meridia, provided the researchers the drug at no cost for this study. The research results are published in the August issue of the peer-reviewed medical journal Metabolism.

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· Other researchers in this study were Dr. Rudolph L. Leibel, professor of pediatrics and medicine, P&S, head of the Division of Molecular Genetics at P&S, deputy director of the New York Obesity Research Center and co-director of the Naomi Berrie Diabetes Center; Robert J. Love, who was a graduate student at the Institute of Human Nutrition during the study; and Ming C. Cha, who was a postdoctoral fellow at the Institute and the Obesity Research Center during the study.

· P&S is home to two of the researchers who participated in the experiments that first identified the leptin gene: Dr. Leibel and Yiying Zhang, Ph.D., assistant professor of molecular and cell biology in the Department of Pediatrics, division of molecular genetics. Dr. Zhang now studies the control of leptin gene expression in fat cells.

· Obesity is a serious health threat in the United States. Since 1991, obesity among adults has increased by nearly 60 percent nationally, according to the Centers for Disease Control and Prevention.

· Obesity is defined as having a body mass index of 30 or higher (this is equivalent to weight of 174 lbs. in a 5’5” woman, or 202 lbs. in a 5’10” male). Such people are often about 30 pounds or more overweight. Excess weight and physical inactivity account for more than 300,000 premature deaths each year, second only to tobacco-related deaths.

· Being overweight makes it more likely that someone will develop health problems, such as heart disease, stroke, diabetes, certain types of cancer, gout, and gallbladder disease.