The Mouse on the Left Needs Leptin

By Shawna VogelJan 1, 1996 6:00 AM


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Make a drug that can get rid of fat, and Americans will waddle slowly but resolutely to your door. We are a nation groaning under the weight of our own flab (fully a third of us are obese), and we spend over $30 billion a year trying to lose it. So it seemed too good to be true when three groups of researchers independently reported last July that they’d found a protein that--at least in mice--made fat melt away.

The mice were missing the protein, called OB, because they have a defect in the gene that codes for it. Late in 1994, researchers in Jeffrey Friedman’s molecular genetics lab at Rockefeller University in New York had cloned the ob gene and learned a few tantalizing details about its protein product. Secreted by fat cells and carried in the bloodstream, the protein appears to be a signal that tells an animal just how much fat it has. The data suggest that if an organism became fatter than it was meant to be, it would make more protein, which would then act to return the weight to the set point, explains Friedman. And people, Friedman’s group found, have a similar gene.

In July, Friedman’s team as well as groups of researchers from Amgen in Thousand Oaks, California, and from Hoffman-La Roche in Nutley, New Jersey, announced that they’d isolated the mouse protein, which is believed to be a hormone, and showed that it does indeed make OB mice lose weight. When researchers injected it into the mice once a day, it decreased the animals’ appetite and increased their metabolic rate. This is the first hormone that has clearly been proved to regulate body weight, says Jos´e Caro, an obesity researcher at Jefferson Medical College in Philadelphia.

But can leptin, as Friedman’s group has dubbed the protein, be developed into a fat-melting drug for people? Nobody knows. While it’s certainly effective in animals if you give them enough, it’s an open question as to how effective it might be in humans, says Friedman. Indeed, there’s good reason to be skeptical: unlike the OB mice, most obese people don’t have any problem producing leptin.

Caro has measured leptin levels in 140 obese people, and so far he hasn’t found anyone with below-normal amounts of the protein. Most obese people have an overabundance--five times the level found in lean people, on average. The majority of humans with obesity are insensitive to their own leptin, says Caro. Their bodies simply aren’t getting the blaring message to slim down.

One theory is that the problem lies in leptin’s target, thought by many researchers to be a receptor in the brain. Obesity researchers are hot on the trail of this receptor. If they can figure out what’s causing it to lose its sensitivity to leptin, they may be able to design a drug to counteract the problem.

But though such a drug might be useful as a diet aid, most researchers doubt it could cure obesity. Leptin is likely to be just one of many competing biological signals that tell us whether to eat, what to eat, and how efficiently to burn that food. And unlike mice, people also respond to social and psychological influences. We don’t always eat because we have a signal that we’re hungry, says obesity researcher James Hill at the University of Colorado. We see a wonderful cake in the window and it looks good and we’re not hungry, but we eat it.

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