Natural brain substance blocks weight gain in mice, UT Southwestern researcher...( DALLAS Jan. 28 2009 Mice with incr...)

DALLAS Jan. 28, 2009 Mice with increased levels of a natural brain chemical don't gain weight when fed a high-fat diet, researchers at UT Southwestern Medical Center have found.

The chemical, orexin, works by increasing the body's sensitivity to the "weight-loss hormone," leptin, the researchers report.

Finding a way to boost the orexin system may prove useful as a therapy against obesity, said Dr. Masashi Yanagisawa, professor of molecular genetics at UT Southwestern and senior author of the study, which appears in the January issue of Cell Metabolism.

"Obese people are not deficient in leptin," Dr. Yanagisawa said. "They have tons of leptin floating around. The problem is that their brain isn't very sensitive to it." Orexin, which Dr. Yanagisawa discovered about a decade ago, is involved in controlling appetite and sleep. He found that reduced levels of orexin lead to the sleep disorder narcolepsy in both rodents and humans.

Orexin can boost the appetite in the short term, but, paradoxically, a lack of orexin leads to obesity in the long run. "It's been confusing," said Dr. Yanagisawa, an investigator with the Howard Hughes Medical Institute at UT Southwestern.

Part of the confusion comes about because orexin acts on two different molecules in the brain, OX1R and OX2R. In the current study, the researchers aimed to distinguish which action was involved in weight control.

The researchers increased the levels of orexin in mice, either through genetic engineering or by administering the hormone into the brain.

When these mice were fed a healthy diet, the increased levels of orexin made little difference in their weights compared to normal mice; however, when the mice were fed a high-fat diet, the high-orexin mice remained lean while the normal animals became obese. This difference was due to an increase in the rate of metabolism high-orexin mice burned fuel up to 20 percent faster t
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