Hormone Links Sleep, Hunger And Metabolism
While investigating how the hormone orexin might control sleep and hunger, researchers at UT Southwestern Medical Center have discovered, to their surprise, that it activates a protein, HIF-1, long known to stimulate cancerous tumor growth.
"HIF-1 is very big in the cancer community," Dr. Kodadek said. "So we were intrigued to find this important and very basic mechanism that is unrelated to cancer."
Orexin was already known for its role in sleep and hunger. Researchers, including Dr. Masashi Yanagisawa, professor of molecular genetics at UT Southwestern, had found that lack of orexin causes the sleep disorder narcolepsy.
"It's really the most straightforward system relevant to the biology of sleep you can look at," Dr. Kodadek said. "You lack orexin" You've got narcolepsy. End of story."
Surprisingly, the activity of a component of HIF called HIF1-alpha was among the most highly activated of any gene in the study. And when orexin stimulated HIF1-alpha, it in turn increased the expression of a variety of genes dedicated to burning sugar to provide energy for the body. Studies in brain slices of mice with and without orexin receptors support their results.
The findings help explain orexin's link to the metabolic system, the researchers said. The body is known to step up its production of orexin when blood sugar gets low. The researchers hypothesized that when a body has low blood sugar and gets hungry, the increase in orexin activates HIF-1 production, revving up metabolism so the body gets the most energy out of the sugar on hand.
This action of HIF-1 when stimulated by orexin is different than how it acts in tumors, Dr. Kodadek said. In tumors, HIF-1 changes cells' metabolism so they can burn sugar for energy without oxygen. This method is inefficient, but allows cells to stay alive.
Orexin, on the other hand, forces HIF-1 to switch cells to burn sugar using oxygen, which burns sugar faster but more efficiently. This strategy makes sense, they said, in terms of evolution.
"You need to be active and energetic, especially when you're hungry, so you can search for a meal," said Dr. Devanjan Sikder, instructor of internal medicine and lead author of the study.
"This orexin pathway we found is basically an overdrive function. Even though blood sugar levels are low, you're not only awake, but you're also energetic because of the action of HIF-1," said Dr. Kodadek. "In retrospect, our findings make a lot of sense, but they were surprising at the time."
This is confusing, a little. So high blood sugar means low orexin. This means low alertness and wakefulness, and you burn sugar w/o oxygen, in the fashion that tumors also prefer. Low blood sugar means high orexin, which means more awakeness and energy, and you burn sugar in a more efficient manner, with oxygen. Some people in Germany are experimenting with low carb diets to starve tumors of their energy source. Perhaps this is why it works?