June 29, 2000
Team finds a key pathway to appetite regulation
Videos of mice with C75, ignoring food, and mice pigging out are available at this Web site: http://pathology2.jhu.edu/kuhajda/FASinhib.htm
Johns Hopkins scientists have produced a compound capable of rapidly turning off appetite in mice and causing weight loss similar in many ways to that achieved by fasting. When injected, the substance, which is apparently non-toxic to the mice, wipes out the animals' interest in food within 20 minutes. The effect of the chemical called C75 wears off a few days after injections stop, the researchers say, and the mice resume normal feeding.
The report on the work appears today in the journal Science.
"We are not claiming to have found the fabled weight-loss drug," says pathologist/biochemist Frank Kuhajda, M.D., spokesperson and research team member. "What we have found, using C75, is a major pathway in the brain that the body uses naturally in regulating appetite at least in mice." A similar system is likely in humans, the researchers say, but whether C75 works the same way awaits further research.
What's unusual, they explain, is that the pathway exists in the brain at all. Scientists normally look for the cascade of reactions, used to synthesize molecules called fatty acids, in the body's fat or liver tissue. Yet not only is the pathway found in certain brain cells, but these cells are concentrated in areas known to control appetite.
"It's unlikely that C75 ties directly into the wasting that occurs with cancer or infectious diseases," says biochemist Thomas M. Loftus, Ph.D., a team member. The scientists have also discounted direct links to leptins appetite-affecting substances produced by fat tissue whose discovery a few years ago sparked headlines and as-yet unrealized hopes for the perfect diet drug.
In support of their characterization of C75, the investigators note it caused a dramatic weight drop in leptin-free mice predisposed to obesity. Yet the compound also reversed the insulin-resistant form of diabetes those mice experience. It may, they suggest, have a future application in diabetes control.
Scientists have long known that a hormone called neuropeptide Y (NPY), located in the appetite centers in the brain's hypothalamus, is a major appetite regulator. If animals fast, NPY increases and appetite jumps sharply. In C75-treated mice, though, NPY production drops sharply. "This gives us a good idea that C75 stops feeding by blocking NPY production in the brain," Kuhajda says.
In the study, the researchers injected mice with a single dose of C75, then observed them for changes in behavior, weight or body chemistry. "The mice had a dramatic weight loss of up to 30 percent, depending on the dose of C75 they received," says biochemist M. Daniel Lane, Ph.D. "That loss came mostly because the mice stopped feeding," Kuhajda explains. A moderate dose, for example, reduced feeding behavior more than 90 percent in the first day. Feeding returned to normal in the next few days as the drug's effect faded.
C75-injected mice resembled fasting mice in the way they lost body tissue in fasting, some muscle is lost as well as fat. But the C75-treated mice lost far more weight than their untreated, fasting brothers in the study. "Even more significant," says Kuhajda, "were metabolic differences. If you try to lose weight by starving, your metabolism slows down after a few days: It's a survival mechanism that sabotages many diets. We see this in fasting mice. Yet metabolic rate in the C75-treated mice doesn't slow at all."
C75 is a small member of a family of organic molecules called butyrolactones. It's a novel molecule purposely created by the Hopkins scientists to inhibit fatty acid synthase (FAS), an enzyme the body uses to create fatty acids. Fatty acids are, among other things, building blocks for body fat.
"The pathway for creating fatty acids becomes active during times that an animal takes in excess food," Kuhajda says. This study may show how this excess is signaled in the brain. "The usual response to excess food is a decreased appetite," he says, "C75 appears to trigger this response artificially, by regulating the pathway, decreasing NPY and, thus, lowering appetite."
The C75 work comes out of the team's 14-year exploration of the abnormal fat metabolism that exists in many cancer cells. "Breast, prostate and cancer cells, for example, make a lot of fat. They have, correspondingly, a lot of constructive enzymes such as FAS," says Kuhajda. C75 was one of the chemicals the researchers created to inhibit FAS and clarify what was happening. "But it had this side effect," he adds, "that the lab animals always lost a lot of weight."
"We badly need effective drugs for weight loss," he comments. "Obesity is a huge problem. We're hoping to explore the possibilities of this new pathway."
The team of Johns Hopkins scientists includes Thomas M. Loftus, Ph.D., and M. Daniel Lane (Department of Biological Chemistry), Donna Jaworsky and Gabriele V. Ronnett, M.D., Ph.D. (Department of Neuroscience), Gojeb Frehywot and Craig A. Townsend, Ph.D. (Department of Chemistry, Johns Hopkins University), and team spokesperson Frank Kuhajda, M.D. (Department of Pathology). The study was funded by grants from the National Institutes of Health, Department of Defense, the W.M. Keck Foundation and the Steward and the Raynam Research Trusts.
Under a licensing agreement between The Johns Hopkins University and Fasgen Inc., Drs. Kuhajda, Townsend, Ronnett, Loftus, and Lane are entitled to a share of royalties received by the University on sales of products based on the technology described in this news release. Dr. Kuhajda and Dr. Townsend own Fasgen stock and Dr. Ronnett has an interest in Fasgen stock; the stock is subject to certain restrictions under University policy. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.
Related Web sites:
http://pathology.jhu.edu/MCGI/SEND1^WEBUTLTY(1096,981) This is Dr. Kuhajda's site.
http://neuroscience.miningco.com/science/neuroscience/msubDisOb.htm This site gives additional information on leptins.