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A weighty matter: Obesity, leptin and beyond

Early genetic insights are based on mouse studies, but applying findings to the human body has proved challenging.

By Victoria Stagg Elliott, amednews staff. Aug. 6, 2001.

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Mapping Disease
As the results of the Human Genome Project began to shake out into clinical applications, this 2001-02 series detailed progress in the prevention and treatment of a variety of diseases and conditions -- both on the near horizon and possibilities far into the future.

In 1994, when researchers at Rockefeller University in New York discovered the weight-regulating hormone leptin and the gene responsible for producing it, the world cheered. Mice genetically engineered not to produce the hormone became morbidly obese.

But when they received leptin supplementation, they lost weight. A solution for the millions of overweight people worldwide seemed to be around the corner.

Not so fast.

The discovery of the leptin gene is still regarded as one of the last century's greatest breakthroughs in obesity research. But, as many researchers are quick to point out, humans are not as simple as mice. Your average obese human is not leptin-deficient, and only about a dozen individuals around the world have been found to be morbidly obese because they do not produce the hormone.

"It was sad in a way that it couldn't be a single gene. A lot of people were hoping it would be an easy answer," said Rudolph Leibel, MD, a member of the research team that cloned the gene at Rockefeller University. "But if you think about obesity and everything we knew about obesity up until the time that the gene was cloned, you would have predicted that there was not going to be a single gene that could explain all this."

What the discovery did, however, was rapidly expand the amount of research into the genetics of obesity, even though the condition has a significant environmental component, and obesity has often been blamed on individual behavior.

"It's not like Huntington's. If you have the defective gene for Huntington's, you will get it no matter what you do," said Dr. Leibel, who is now head of the division of molecular genetics at Columbia University, New York. "There are powerful predispositions to being obese. It's a genetic disease. The environment just makes it possible to show the genetic derangement that you've got." [...]