Hormone tumbles in drunken mice: study

Fibroblastic growth factor 21, commonly abbreviated FGF21, is a hormone known to be induced by various metabolic stresses, including young And alcohol consumption both in humans and in mice. It has also been shown reduce alcohol consumption And stimulate water consumption in animal models, functions that may have evolved to regulate alcohol consumption and prevent its potentially harmful consequences – after all, a small mammal that eats too much fermenting fruit could find itself in trouble very quickly.

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Now, scientists have discovered another property of this hormone: without it, drunken mice take longer to recover their motor skills, while a much larger pharmacological dose speeds up recovery. The effect, reported yesterday (March 7) in Cell metabolismis mediated by the activation of noradrenergic neurons in a region of the brainstem that regulates wakefulness and alertness.

The findings could lead to clinical interventions for alcohol poisonings, the authors say, although experts warn that a “sobering” drug could be misused.

The team behind the work, led by researchers at UT Southwestern Medical Center David Mangelsdorf And Steven Kliewer, exposed controls, and mice engineered to run out of FGF21 at a single dose of ethanol — an amount equivalent to the volume that would get a human drunk enough to pass out, says Mangelsdorf, who is also affiliated with the Howard Hughes Medical Institute. Next, the researchers tested the animals’ “ability to wake up,” explains Mangelsdorf; that is, they put them on their backs and gauged how often they could straighten up. Mice unable to produce the hormone took almost two hours longer to recover this righting reflex than unmodified controls (5.8 versus 3.9 hours, on average).

The team then tested whether a pharmacological dose of FGF21 about a thousand times greater than that which occurs naturally in mice could reduce the time needed for recovery in unmodified mice. Indeed, the mice were able to recover about 1.5 hours earlier than the mice that did not receive the hormone. Notably, however, neither the absence nor the supplementation of FGF21 altered the rate at which alcohol was cleared from the animals’ blood, suggesting that the hormone does not affect the breakdown of ethanol.

The effect of the hormone was absent in transgenic mice engineered to lack FGF21 receptors in noradrenergic neurons located in the locus coeruleus, a region of the brainstem involved in mediating wakefulness, alertness and attention. The results of the study indicate that these neurons are essential for FGF21 to exert its sobering effect.

Panel where the FGF21 hormone co-receptor is shown in magenta (center) and the locus coeruleus is shown in green (left).  The two merged images (right) show the subpopulation of noradrenergic neurons – in white – where the hormone acts.

FGF21 hormone co-receptor (magenta) and brainstem region locus coeruleus (green), where FGF21 acts to counter the sedative effects of alcohol. When the two images are merged, the coreceptor is found to be expressed in a subpopulation of noradrenergic (blank) neurons from the locus coeruleus.

Mihwa Choi

While it’s unclear if the effects of these FGF21s translate to humans, the University of Iowa neuroendocrinologist Kyle Flippo says it “forecasts” what they will do, based on current knowledge in the field. “I think, physiologically, it plays an important role, but I don’t know if you would want to give humans pharmacological FGF21 to prevent the sedative effects of alcohol intoxication,” says Flippo, who was not involved in the study. ‘study. He adds that he is “skeptical of the clinical application this could have in humans” because it is important for humans to be “able to feel when they are . . . getting drunk”, for example, to prevent dangerous behavior.

Mangelsdorf, who along with Kliewer is the founder of Atias Pharma, LLC and co-author of a patent related to this work, says he thinks “the most useful treatment may be for patients who come to the emergency room with acute alcohol poisoning, as being able to increase their alertness” would be helpful in preventing them from choking, aspirating their own vomit – which can lead to death – and evaluating them for treatment for other injuries. Pharmacological FGF21 is currently being tested in various clinical tests to assess some of its other functions.

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