Minutes after you eat a meal, as nutrients rush into your bloodstream, your body makes massive shifts in how it breaks down and stores fats and sugars. Within half an hour, your liver has made a complete switch, going from burning fat for energy to storing as much glucose, or sugar, as possible. But the speed at which this happens has flummoxed scientists--it's too short a time span for the liver's cells to activate genes and produce the RNA blueprints needed to assemble new proteins to guide metabolism.
Now, researchers have uncovered how the liver can have such a speedy response to food; liver cells store up pre-RNA molecules involved in glucose and fat metabolism.
"The switch from fasting to feeding is a very quick switch and our physiology has to adapt to it in the right time frame," says lead author of the paper, published in Cell Metabolism. "Now we know how our body quickly handles that extra rush of sugar."
It was known that a RNA-binding protein called NONO was implicated in regulating daily ("circadian") rhythms in the body. But researchers wondered whether NONO had a specific role in the liver. They analyzed levels of NONO in response to feeding and fasting in mice. After the animals ate, speckled clumps of NONO suddenly appeared in their liver cells, newly attached to RNA molecules. Authors show that NONO binds and regulates the rhythmicity of genes involved in nutrient metabolism post-transcriptionally. Within half an hour, the levels of corresponding proteins--those encoded by the NONO-bound RNA--increased.
"After mice eat, it looks as if NONO brings all these RNAs together and processes them so they can be used to make proteins," says the lead author.
When mice lacked NONO, it took more than three hours for levels of the same proteins, involved in processing glucose, to increase. During that time lag, blood glucose levels shot up to unhealthy levels. These NONO deficient mice shift from glucose storage to fat oxidation, and therefore remain lean throughout adulthood. Since blood glucose levels are also heightened in diabetes, the researchers think that the mice without NONO may act as a model to study some forms of the disease.
"Understanding how glucose storage and fat burning are regulated at the molecular level will be important for the development of new therapies against obesity and diabetes," says the first author.
Questions still remain about how exactly NONO is triggered to attach to the pre-RNA molecules after a meal. And the researchers are hoping to assemble a more complete list of all the pre-RNAs that NONO binds to--in both the liver and other parts of the body. NONO has been found at high levels in the brain and muscle cells, so the researchers are planning studies to see whether is reacts similarly in those organs to food.
How liver responds so quickly to food
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