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The NAPE Effect on Appetite

Chemical messenger tells your brain when you've had enough to eat, spurring hopes for an obesity therapy.

Some 300 million adults around the world are severely overweight and at risk for life-threatening illness such as type-2 diabetes and cardiovascular disease. Now, researchers have identified a molecule that tells the brain when the stomach is full, providing hope for the creation of better appetite suppressants or obesity drugs.

In studies with mice and rats, researchers have found that a chemical messenger called NAPE exists in the small intestine after animals eat a particularly greasy meal. After eating, NAPE — actually N-acylphosphatidylethanolamine — enters the bloodstream and goes to the brain, where it overrules hunger signals. Rats treated with extra NAPE for five days consumed less food and lost weight.

The study is reported in a recent issue of the journal Cell by lead investigator Gerald Shulman of the Yale School of Medicine. Renowned for its work on insulin resistance and diabetes, Shulman's research group turned to obesity after developing a sensitive system to identify and measure lipids in tissue samples.

"We do not have good medical therapies for obesity," Shulman said in a release. "It's very important to find other targets that might affect food intake."

The team used the new lipid analysis system to chronicle what happens to fat that enters the bloodstream after ingesting a high-fat meal. Reasoning that the fat itself might serve as a messenger to tell the brain the body has been fed, the researchers compared the lipids present in blood plasma from rats that had fasted or eaten, and they focused on NAPE. Low levels of NAPE appeared only in the blood of rats that had fasted for 12 hours; the NAPE level increased by 40 to 50 percent in animals that had dined on high-fat food. And because NAPE didn't increase in rodents that consumed only proteins or carbohydrates, it stands to reason that NAPE levels reflect the amount of fat eaten during a meal.

The rodents' appetites also diminished significantly when the researchers injected synthetic NAPE into the abdominal cavity or blood: The more NAPE they received, the less food the rodents ate.

"It's really quite effective," Shulman said. "At the highest doses, it keeps the animals from eating for up to 12 hours." A tiny amount of NAPE injected into the brain had the same effect as a larger dose delivered to the blood, suggesting the compound communicates directly with the brain.

Shulman and his team are now monitoring NAPE levels in humans, to see if they can chart a similar post-meal increase to the one observed in rodents. Tests on non-human primates are also scheduled. If these studies parallel the results they have observed in mice and rats, Shulman said, a clinical trial with NAPE or NAPE-like compounds may happen soon.