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
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Contact: Marjorie Centofanti
mcentofanti@jhmi.edu
410-955-8725
Johns Hopkins Medical Institutions
29-Jun-2000