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Appetite Drug Wears Off Fast in Fit Mice

But its effects last longer in obese rodents

SATURDAY, Feb. 23, 2002 (HealthDayNews) -- Fit mice given a drug that suppresses appetite in obese rodents stop eating briefly, but quickly shrug off the effects of the treatment and within about a day are back at the trough with gusto.

"Somehow the lean animals adapt and they adapt very quickly," says M. Daniel Lane, a Johns Hopkins University biochemist and a co-author of the study, which appears in the latest issue of the Proceedings of the National Academy of Sciences.

The compound, C75, blocks an enzyme called fatty acid synthase (FAS). In doing so, the drug tells the body that it's experiencing a fuel glut and that no eating will be necessary for a while. Suppressing appetite reduces food intake, forcing the body to deplete its reservoirs of fat and promoting weight loss.

Lane says C75 seems to work by raising the concentration in the brain's appetite center -- a region called the hypothalamus -- of malonyl-CoA. This protein is an important 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. "Malonyl-CoA shuts off fatty acid degradation," Lane says.

Earlier studies have shown that obese mice slim down dramatically when given C75. The latest work sought to learn what happens when lean animals get the drug.

The researchers studied both genetically engineered rodents, missing the gene that produces the appetite-inducing hormone leptin, and mice who earned their extra ounces by eating high-fat diets.

After a single injection of the drug, lean and obese mice almost completely ceased eating, cutting their food intake by roughly 90 percent. But within about a day, the thin rodents were hungry again, and once the treatment stopped they began overeating.

The genetically obese animals, on the other hand, didn't begin to resist the shots until day four of the five-day trial, after they'd already lost 15 percent of their body weight. For the mice fattened-up by diet, the effect of the drug fell somewhere in the middle, with resistance developing faster than in the mutant rodents but not as fully as in the lean animals.

Lane's group found that mice with the same, reduced-calorie intake as the treated animals also lost weight, but only about a quarter to half as much as the mice given the drug. "The C75 animals lose more weight, and the significance of that is that it suggests that energy expenditure is actually increased" in the treated animals, he says.

How that happens isn't clear, Lane adds. But some evidence points to a role for specialized proteins that help cells store chemical energy in a biochemical battery called adenosine triphosphate (ATP). Scientists have found that some rodents develop "leaks" in this system: A substantial share of the fuel that they'd normally convert into ATP goes to generate heat. When exposed to cold, these animals produce enough internal warmth that they don't need to shiver.

Although these "non-shivering" mice probably hold little relevance for humans, Lane says quirks of uncoupling proteins may help explain how C75 ratchets up energy expenditure -- if it indeed interacts with them. He and his colleagues are now looking into the question.

Richard Palmiter, a University of Washington biochemist familiar with the new research, agrees that the effects of C75 on weight loss almost certainly involve something beyond less eating. "That something, broadly defined, has to be an effect on metabolism." But he's not prepared to say what, exactly, the mechanism might be.

What To Do

It will be years, if ever, before C75 is fit for human consumption. Meanwhile, other diets-in-a-pill are making their way slowly through the research process, and with underwhelming results.

Until one arrives, the best bet for losing weight is to eat less and exercise regularly. Doing so is also good for your heart, bones, and the rest of your body.

To learn more about how to follow a healthful diet, try the American Dietetic Association or the National Heart, Lung, and Blood Institute.

SOURCES: Interviews with M. Daniel Lane, Ph.D., professor of biological chemistry, Johns Hopkins University, Baltimore; Richard Palmiter, Ph.D., professor of biochemistry, University of Washington, Seattle, and investigator, Howard Hughes Medical Institute; Feb. 19, 2002, Proceedings of the National Academy of Sciences
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