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Gut-brain communication failure may spur overeating

Restoring a depleted molecule in obese mice repaired their abnormal response to food

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Repairing a faulty communication line between the gut and the brain can quell the urge to overeat, an experiment that cured chubby mice of their junk food addiction indicates. A similar strategy might be used to treat compulsive eating in people.

Some scientists have proposed that, in both mice and humans, overeating can resemble drug addiction; the more food a person consumes, the less responsive the brain becomes to the pleasure of eating. By restoring normal communication between the gut and brain, researchers were able to resensitize overfed rodents to the pleasures of both fatty and healthy foods.

"The therapeutic implications are huge,” says neuroscientist Paul Kenny of the Scripps Research Institute in Jupiter, Fla., who was not involved in the study.

In the brain, a chemical called dopamine surges in response to pleasurable experiences like eating, sex and taking drugs. But brain-scanning studies suggest that obese individuals have muted dopamine reponses to food. These changes could lead overeaters to seek more and more food to satisfy their cravings, suggests study leader Ivan de Araujo of Yale University.

De Araujo and his colleagues looked for ways to restore the dopamine response of overfed mice by studying the signals sent by their guts. In previous work, the researchers found that mice get a dopamine rush when fat is introduced directly into the small intestine via catheters. This shows that the gut communicates with the brain’s reward center even when the mouse can’t taste food.

But de Araujo’s team reports in the Aug. 16 Science that mice fed a high-fat diet for 15 weeks don’t experience the normal dopamine surge after an infusion of gut calories. In fact, fat delivered directly to the gut caused dopamine levels in these mice to fall.

The team hypothesized that the disruption in dopamine levels involved a molecule called oleoylethanolamine, which is thought to suppress appetite. In normal mice, eating boosts levels of the molecule in the small intestine. That increase is thought to help animals stop feeding when they are full. But rodents eating a high-fat diet have abnormally low levels of oleoylethanolamine.

The researchers gave the overfed mice injections of oleoylethanolamine and found that, instead of dopamine levels dropping when fat infusions hit the intestines, the mice experienced a dopamine surge. The animals also ate less and lost weight.

Unexpectedly, the fat-fed mice treated with oleoylethanolamine were also more likely to eat low-calorie food than untreated obese mice, which “have a complete contempt” for such food, de Araujo says. Oleoylethanolamine treatment seems to repair damaged communication lines between the gut and brain, he suggests.

De Araujo points out that they do not yet know whether the same approach would work in humans, but his team is now planning a collaboration to test whether similar treatments would help people stick to a low-fat diet.

Nora Volkow, director of the National Institute on Drug Abuse in Rockville, Md., says she is very interested to see whether oleoylethanolamine, or a drug that mimics its effects, could treat obesity in people.

Kenny suggests that targeting gut-brain signaling with oleoylethanolamine is less likely to have damaging side effects than drugs that affect how dopamine is produced or sensed in the central nervous system. “Dopamine is a really, really hard system to modify,” he says. For example, most drugs to treat schizophrenia target dopamine receptors in the central nervous system, but these drugs often cause unwanted side effects like altered mood and involuntary movements.

The beauty of oleoylethanolamine is that it could be provided in a food supplement or a drug that doesn’t enter the central nervous system, Kenny says. “Maybe it will address obesity and maybe it won't, but I think it's a wonderful place to start.”

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