April 11, 2003

Guest lecturer explains hormonal causes of obesity

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Dr. Rudolph Leibel

Guest lecturer explains hormonal causes of obesity

Leptin may the key to understanding why most diets fail, a leading obesity expert told a Vanderbilt audience on Tuesday.

Leptin is a hormone released by fat tissue that helps the brain regulate appetite and body weight. Among other things, it is designed to ensure reproductive fitness and survival in often-hostile environments by preserving an adequate amount of body fat, said Dr. Rudolph Leibel, who co-discovered the hormone nearly a decade ago at Rockefeller University in New York.

Fat cells shrink during dieting, and so does the amount of leptin they secrete into the blood. When leptin falls below a genetically and developmentally determined “threshold,” the hypothalamus in the brain is triggered to release other hormonal and neurological signals that increase food intake and reduce energy expenditure.

The result is the well-known "rebound" effect – re-gaining the weight lost through dieting, over and over again. “This is one of the biological mechanisms that tends to defeat efforts to treat this disease,” said Leibel, now professor of Pediatrics and Medicine at Columbia University.

There is hope for dieters, however. Extra leptin given to people who have lost weight appears to “trick” the hypothalamus into accepting their new, lower body mass. The amount of energy burned by their muscles increases, and they are less hungry, he said.

Leibel said it is too early to think about implementing "leptin replacement therapy" because the long-term effects of leptin administration are not known. It also will probably take more than one type of therapy to reverse obesity, which results from a complex interplay between genes and environment.

But the discovery of leptin and its receptor in the mid-1990s has led to new understanding of the molecular pathways that regulate body fat, and how those pathways might be tweaked to help dieters fool Mother Nature.

Leibel, who also is head of the Division of Molecular Genetics and co-director of the Naomi Berrie Diabetes Center at Columbia, gave three lectures at Vanderbilt University Medical Center this week as part of a Pfizer Visiting Professorship in Diabetes. He was a guest of the Division of Pediatric Endocrinology.

Obesity and its twin epidemic, type 2 diabetes, are the consequences of genetic susceptibility in the presence of too much food and not enough exercise.

More needs to be done to encourage lifestyle changes, including reducing caloric intake and sedentary activities, Leibel said. At the same time, it is important to understand why some people seem to be more susceptible to becoming obese, and why it is so hard to lose weight once it has been acquired.

“Knowing by which genetic mechanisms the system is predisposed to lay on additional calories in this way could probably help us to design more effective environmental interventions,” Leibel said in an interview.

Genetics also is helping physicians and the public realize that “obesity is not the result of slothfulness or misbehavior,” he said, “that in fact body weight is a regulated system like blood pressure.”

The evolutionary necessity for efficient reproduction depends on having an adequate amount of body fat. “More fat is better than less fat in this regard, so the system has actually been evolved to protect body fat – not prevent its accumulation,” Leibel said.

This is why dieting, liposuction and other efforts to remove fat without changing the signals going to the brain usually fail. “If we’re going to successfully treat obesity … we need to figure out how to set this threshold downward and keep it there,” Leibel concluded.