Drug tried in mice gives dieters hope

The chemical, not yet tested in humans, fools the brain into thinking the mice have eaten without slowing metabolism.

©Associated Press

© St. Petersburg Times, published June 30, 2000

WASHINGTON -- Scientists were testing a possible cancer treatment when they noticed something that might prove rather valuable: The experimental drug made mice lose a dramatic amount of weight without apparent side effects.

Just 20 minutes after taking the chemical, the rodents' appetites were wiped out. The effect lasted about a day.

The discovery indicates scientists may be able to regulate a major pathway in the brain responsible for appetite and fat-building. The chemical apparently fooled the brain into thinking the mice had eaten, so their metabolisms never slowed and they burned fat, researchers report in today's edition of the journal Science.

"This is a real trick. The mice drop their weight like a stone, losing 25 percent of their body mass in a couple of days," said Dr. Frank Kuhajda, who led the research team at Baltimore's Johns Hopkins University that produced the chemical, called C75.

No one knows whether C75 would work in humans, experts caution. More animal research is needed before dieters could even test it.

But the Hopkins discovery is "extraordinarily intriguing and provocative," said Denis McGarry, an expert on fat metabolism at the University of Texas Southwestern Medical Center in Dallas. If confirmed, he said, "it would obviously have a profound impact on the field of obesity research."

Doctors have long hoped for better weight-loss treatments. Over half of all Americans are overweight, and about one-quarter are obese, government estimates show.

At issue is "fatty acid synthase" or FAS, an enzyme system pivotal for turning carbohydrates into the building blocks of fat.

Surprisingly, in the early 1990s scientists discovered cancer cells use FAS to produce their own fat for fuel, Kuhajda said. So the Hopkins researchers created an FAS blocker to see if it could fight cancer. In mouse testing, C75 made cancer cells die without harming nearby normal cells, he said.

But the mice also all had a stunning side effect: They stopped eating and dramatically lost weight until the drug wore off.

Weight loss in a cancer patient is a serious problem, so puzzled scientists hunted for an explanation.

It turns out that production of a brain chemical called neuropeptide Y, a well-known appetite regulator, plummeted in the C75-treated mice. Normally when animals fast, neuropeptide Y sharply jumps and appetite consequently increases. But the C75 prevented that, fooling animals into thinking they were fed, Kuhajda said.

How? To build fat, FAS uses another molecule called malonyl-CoA. Blocking FAS didn't stop the body's normal production of that molecule. Instead, malonyl-CoA just piled up without that next step in the fat-building assembly line. High levels of the molecule somehow signaled the brain not to produce neuropeptide Y, Kuhajda said.

C75 didn't permanently harm the appetite system. When scientists injected C75-treated mice with neuropeptide Y, they immediately stuffed themselves. When C75 wore off, they ate normally and regained weight.

But C75 had another important benefit, the researchers reported. One reason dieting is so hard is that fasting slows metabolism. Metabolism didn't seem to slow in the C75-treated mice, however. They lost 45 percent more weight than untreated mice deprived of food.

The Hopkins researchers are pursuing C75 as a possible cancer treatment, figuring appetite suppression isn't an insurmountable side effect. But the newest findings "give us some hope" of a new way to fight obesity, too, Kuhajda concluded.

- Information from the Washington Post was used in this report.

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