January 8, 2002
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Experimental Appetite Suppressant Affects Numerous Brain Messengers In Mice

Johns Hopkins scientists report success in figuring out how an experimental compound prevents mice from recognizing that it's time to eat, profoundly suppressing appetite and causing weight loss.

The compound, called C75, alters the natural balance of brain messengers that normally send signals of hunger during fasting and of satiety when full. In both lean and obese mice, C75 affects those signals, according to a report on the work in the Dec. 26 online version of the Proceedings of the National Academy of Sciences.

Obesity in humans is a major public health problem and is linked to a heightened risk of developing diabetes, stroke and heart disease. While mice are not men, there are common pathways in fundamental activities.

"If we can understand the pathway that triggers eating, we may be able to find safe ways to intervene," says Daniel Lane, Ph.D., professor of biological chemistry in the School of Medicine's Institute for Basic Biomedical Sciences. "We're close to figuring out how these neurotransmitters are connected, at least in mice, and what really affects their expression."

Building on the knowledge that C75 blocks the enzyme fatty acid synthase, which helps the body store energy, Lane and others last year reported that mice given C75 stopped eating and lost about 5 percent of their body weight in just a day.

In the new study of lean (normal) mice and mice genetically engineered to be obese, the scientists looked for changes in the appetite signals in animals that fasted for one day and those injected with C75. While neither group ate, mice injected with C75 had more of the "satisfied" signals and less of the "hungry" signals than other mice.

Normally, fasting dramatically increases the amounts of two neurotransmitters, AgRP and NPY. Coming from neurons in a particular area of the hypothalamus, a small structure inside the brain, these messengers tell the animal to eat. When fasting animals are given food, they'll eat immediately, says Lane.

In both lean and obese mice treated with C75, however, levels of these two messengers did not increase, instead staying close to the levels of mice allowed to eat at will. The C75 mice ignored food, even though they had access to it, says Lane.

Two other messengers in the hypothalamus, CART and POMC, usually inhibit appetite. Lean mice that fasted had lower levels of these two messengers, while the C75-treated lean mice had CART and POMC levels similar to mice that were eating. Levels of these messengers didn't change in obese mice.

"Essentially, animals given C75 don't recognize that they are not eating," says Lane. "The levels of neurotransmitters that stimulate appetite and those that inhibit appetite are in line with what they would be if the mouse were eating normally."

The scientists are still trying to understand exactly how C75 has these effects. C75 blocks fatty acid synthase, but isn't directly involved in the production of any of these neurotransmitters, says Lane. Their working hypothesis is that a molecule called malonyl CoA is the real trigger for these changes in neurotransmitter levels. Malonyl CoA is normally transformed into a fatty acid by fatty acid synthase. When C75 blocks fatty acid synthase, levels of malonyl CoA rise.

Lane says the hypothalamus may recognize increased levels of malonyl CoA as a signal that the animal is eating enough, and thus the molecule may be directly involved in regulating appetite-related messengers. Malonyl CoA is already known as a regulator in some energy-burning processes.

"Our experiments show that NPY and AgRP are blocked at the signal of gene expression by C75 treatment," says Teruhiko Shimokawa, Ph.D., a visiting scientist, working with Lane, from Yamanouchi Pharmaceutical Co. in Tokyo. "In this story, the malonyl CoA hypothesis is very attractive and very promising."

Shimokawa, who developed a technique to measure RNA of the neurotransmitters, notes that obesity is a growing problem in Japan as lifestyles have become more Westernized since World War II. "Obesity is a very serious situation," he says.

The scientists will continue studying C75 and whether malonyl CoA is the real trigger. In particular, they're interested in whether animals adapt to C75 and begin eating again, and also whether there's an increase in energy burning that contributes to C75's profound effects on weight loss in lean and obese mice.

Authors on the report are Shimokawa, Lane and Monica Kumar, Ph.D., a postdoctoral fellow in biological chemistry at Johns Hopkins.

Under a licensing agreement between FASgen, Inc. and the Johns Hopkins University, Dr. Lane is entitled to a share of royalty received by the University on sales of products that embody the technology described in this article. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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