The high-orexin mice had lower blood levels of leptin, implying that the leptin was more effective in controlling weight in these mice. In addition, when the researchers administered leptin to the high-orexin mice, the animals responded with a much greater loss of appetite and weight compared to normal mice given leptin.
The researchers also administered a substance that activates only OX2R to separate out orexin's possible double action. The mice given this substance showed the same beneficial response to high-fat diets and leptin, confirming that OX2R controls the interaction.
These results clarify the action of orexin and point to OX2R as a potential route to help treat obesity, but any practical use is still far off, Dr. Yanagisawa said.
A primary hurdle to orexin-based drug development is a defense system in the body called the blood-brain barrier, which prevents many substances in the blood from penetrating into the brain. Because of this, orexin cannot reach the brain when it is given orally or as an intravenous or subcutaneous injection.
"Fortunately, however, high-orexin mice show no sleep/wake disturbance or other serious side effects," Dr. Yanagisawa said.
"This study suggests that if we can develop a compound that mimics the action of orexin on its receptor, we might be able to treat narcolepsy and other sleep disorders, as well as obesity," Dr. Yanagisawa said. "We have already screened out some such 'orexin mimics.' The next step is to do serious medicinal chemistry to make variations of these compounds to get them more potent and specific. If we could advance to early clinical trials in five years, I'd say we'd be lucky.
"I hope that in the long run a suitable orexin mimic might help people be more mentally productive during the day, as well as be able to lose weight more easily."
|Contact: Aline McKenzie|
UT Southwestern Medical Center