Expanding their studies of an experimental compound that causes dramatic weight loss and appetite suppression in mice, Johns Hopkins researchers now report that lean mice rapidly adjust to daily doses of the drug and get their appetites back, while their obese counterparts do not.
Reporting in the Feb. 19 issue of the Proceedings of the National Academy of Sciences, the scientists show that the compound, called C75, kills the appetites of lean mice only the first day it's given. Mice engineered to be obese failed to start eating normally during the entire five days of the study, says Daniel Lane.
"The results suggest that being at a normal weight gives mice the ability to become quickly insensitive to the compound; that normal lean mice couldn't starve even when given C75 daily," says Lane, professor of biological chemistry in the School of Medicine's Institute for Basic Biomedical Sciences. "We need to continue the experiment longer to see if obese mice develop insensitivity to the compound as they approach a normal weight, but so far it's very encouraging. We are closing in on a powerful biological signal in weight control."
C75, Lane says, blocks the action of the key machine for storing energy, an enzyme called fatty acid synthase, that is found in fat-producing tissues and in the brain, where it seems to be part of an appetite-sensing system. Building on his team's recent report that C75 alters levels of brain messengers that regulate appetite, the scientists set out to see how the compound worked over a period of five days.
"At the high doses we used for earlier, one-day studies, the lean mice didn't eat at all," Lane says. "We knew they wouldn't be able to survive not eating over the course of four or five days, so we used a lower dose that limited their eating to about half of normal."
Surprisingly, the scientists' concern was unnecessary, as the lean mice resumed normal eating habits after the first day on C75, even though they continued to get daily injections. Mice genetically engineered to be obese (they lack a functioning gene for a hormone called leptin) stopped eating completely at the lower dose and didn't recover their normal food intake.
"We also see a trend toward the obese mice eating slightly more as they reach a more normal weight, although we need to do a longer study to know for sure," says Lane, whose research has focused on finding the signals that create fat cells.
The scientists also considered the weight loss of mice whose food intake was limited to that consumed by the C75-treated mice. Even though the two groups of mice ate the same number of calories, the C75-treated mice lost more weight, report the researchers, who caution that although C75 appears to have desirable qualities for treating obese people, there's still much to learn about how it works and if it is safe.
"Weight loss comes from burning more calories than are consumed, so increasing that difference leads to greater weight loss," Lane says. "Since the mice are eating the same number of calories, we presume the mice given C75 are burning more calories."
Future studies are planned to measure the calorie-burning rates of regular mice and mice on C75, but the findings already link three biological pathways: C75 directly blocks the fat-storing pathway, causes changes in the signals that control appetite and seems to influence the energy-burning pathway. The scientists are still testing whether a molecule called malonyl CoA is the go-between.
Other authors on the report are Monica Kumar of Hopkins; Teruhiko Shimokawa, a visiting scientist at Hopkins who has returned to Yamanouchi Pharmaceutical Co. in Tokyo; and Tim Nagy of the University of Alabama Medical Center at Birmingham.