By Merritt McKinney

NEW YORK, Feb 18 (Reuters Health) - When obese mice are given an experimental compound called C75, their appetite diminishes and they rapidly lose weight. But normal-weight mice quickly adjust and get their appetite back just a day after starting C75, researchers report.

They say there must be "something" about being obese that makes these animals sensitive to the drug.

Dr. M. Daniel Lane, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues have been working with C75 for several years. The molecule causes weight loss by blocking an enzyme called fatty acid synthase that is involved in storing energy. This sets off a chain reaction in the brain that causes mice to eat less and lose weight.

In previous experiments, Lane and his colleagues found that a single injection caused both lean and obese mice to stop eating. Since they knew that lean mice, lacking the fat stores of obese mice, would not survive long without eating, the researchers gave the lean mice lower doses of C75 in the 5-day experiment.

As expected, the lean mice ate about 50% less food on the first day of the study. But the animals quickly recovered their appetite, with their food intake returning to normal or close to it during the remaining days of the study.

"If we gave it daily, the animals become tolerant to it," Lane told Reuters Health in an interview. "They begin eating again."

In contrast, obese mice continued to eat less and lose weight throughout the study. Lane said mice that were genetically engineered to be obese--weighing two to three times more than normal mice--did not become resistant to the effects of C75. Another group of obese mice, which weighed 30% to 40% more than lean mice after being on a high-fat diet, did begin to show some resistance to C75, but only after they lost a substantial amount of weight, Lane said.

"There is something about the obese state that renders animals sensitive to the drug," Lane said.

The findings are published in the February 19th issue of the Proceedings of the National Academy of Sciences.

As anyone who has ever tried to lose weight knows, the key to shedding pounds is to burn more calories than you eat. Besides suppressing the urge to eat, C75 also seems to have an effect on the burning of calories, according to the researchers.

A group of obese mice that did not receive C75 but were only allowed to eat the same amount of calories as the obese mice on C75 also lost weight during the study. However, their weight losses were 24% to 50% smaller than the mice on C75.

This result "indicates that something else is going on, possibly an increased energy expenditure," Lane said. The effect of C75 seems to be "double-barreled," making mice eat fewer calories and burn more of them, the researcher explained.

Lane and his colleagues are now conducting a long-term study of the effects of C75 on obese and lean mice. It is too soon to know the results, but they predict that the obese animals will become resistant to C75 once they reach a normal weight.

The hope is that the research eventually will lead to anti-obesity therapy for people, but that will not happen anytime soon, according to Lane. It is too early to know whether C75 or a similar compound would be safe and effective in people, he said.

SOURCE: Proceedings of the National Academy of Sciences 2002;99:1921-1925.

http://www.reutershealth.com/archiv...218elin018.html