MONDAY, June 10, 2002 (HealthDayNews) -- When you diet, your body tries to conserve energy. But in a puzzling paradox, an experimental drug that reduces appetite in mice also spurs their cells to throw fatty molecules into the biochemical boiler.
Now, Maryland scientists said they've resolved that apparent contradiction by showing that the compound, called C75, overrides the fat preserving system, sharply enhancing its weight shedding powers in the process.
Because the research was conducted in mice, it has no immediate relevance for obese people. And the scientists said C75 may never become a human therapy. However, the work does shed light on the way the drug -- and presumably others like it -- work in the body and could improve the odds for a viable weight-loss pill in the future.
A report on the findings appears in the latest issue of the Proceedings of the National Academy of Sciences.
A multi-talented chemical, C75 does two things well (at least in the lab): it blocks cancerous cell growth and it muzzles appetite. In both cases, its target is an enzyme called fatty acid synthase (FAS), which helps the body store energy in the form of fat molecules.
In earlier research, scientists at Johns Hopkins University showed that blocking FAS causes mice to eat less and slim down significantly. At the same time, though, and puzzlingly, the animals also burned up their fat stores, promoting even greater weight loss.
That didn't make much sense, said Dr. Francis Kuhajda, a Hopkins pathologist and leader of the research effort. The rodents should have been protecting their fat stores as they began to thin, not consuming them. "Not only did they stop eating, they also burned more fat than" untreated animals, Kuhajda said. "It's good that it did that, but how did it work?"
The answer, the researchers have found, is that C75 seems to override a molecular switch at the level of mitochondria, cellular power plants that convert chemicals into mechanical energy.
That switch, a substance called malonyl-CoA, is an energy regulator whose rise and fall tells certain cells to boost or cut their production of long, fatty-acid chains that are the body's strategic reserves. Malonyl-CoA also serves another function in fat and liver cells by preventing the oxidation of these long molecules as they're coming off the assembly line.
Mitochondria have a molecular "door" that allows fats to enter when fuel is needed. Malonyl-CoA is normally a lock on that door, preventing the power generators from burning fat. But C75 acts as a chemical wedge that props the portal ajar and allows mitochondria to break down as much fat as they can. "Even if malonyl-CoA is around, C75 will inhibit its action and allow fatty acid" burning, Kuhajda said.
The experimental approach is still years from becoming a treatment for obesity, and Kuhajda expressed doubts that C75 will be the final version of such a drug. "But it gives us a blueprint for how to do this trick and now we can design other compounds that might be more suitable," he added.
Dr. Jules Hirsch, a nutrition expert at Rockefeller University in New York City, said that judging from the past success -- or lack thereof -- of other weight loss drugs, a therapy like C75 "is not likely to be the answer" to obesity. Still, said Hirsch, author of a commentary accompanying the journal article, the latest findings should help researchers better understand the mechanisms underlying obesity.
One thing that seems clear, Hirsch added, is that weight gain appears to be like death from a thousand cuts: Even one or two extra bites of food at a meal can add up over time to a massive calorie surplus that pads the waistline. "It's an absolute mathematical necessity," he said.
That suggests people can shed pounds by keeping a keen eye on the fork. Yet it bodes poorly for weight-loss drugs that promise short-term suppression of appetite but no long-term strategy. "Something that in the very short run will affect food intake is not what you're looking for," Hirsch said. "You have to have the whole mechanism reset."
What To Do
To learn more about the dangers of being obese, visit this Centers for Disease Control and Prevention Web page. To calculate your body mass index and learn more about fat, visit Shape Up America!
