Experimental Appetite Suppressant Affects Numerous Brain Messengers In Mice

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.

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