Summary: Increasing concentrations of fibroblast growth factor 21 (FGF21) by injection significantly accelerates recovery from intoxication in mice.
Source: Cell press
A hormone called fibroblast growth factor 21 (FGF21) protects mice against ethanol-induced loss of balance and righting reflex, according to a study published March 7 in the journal Cell metabolism.
“We discovered that the liver is not only involved in alcohol metabolism, but also sends a hormonal signal to the brain to protect it against the harmful effects of intoxication, including loss of consciousness and of coordination,” says the co-lead author of the study. Steven Kliewer of the University of Texas Southwestern Medical Center.
“We have further shown that by increasing FGF21 concentrations even further per injection, we can significantly speed up recovery after intoxication. FGF21 does this by activating a very specific part of the brain that controls alertness,” Kliewer explains.
Consumption of ethanol produced by the natural fermentation of simple sugars in ripening fruits and nectars can cause intoxication, impairing mobility and judgment. Animals that consume fructose and other simple sugars have evolved liver enzymes to break down ethanol.
FGF21 is a hormone that is induced in the liver by various metabolic stresses including starvation, protein deficiency, simple sugars, and ethanol. In humans, ethanol is by far the most potent FGF21 inducer described to date. Previous studies have shown that FGF21 suppresses preference for ethanol, prompts drinking water to prevent dehydration, and protects against alcohol-induced liver damage.
In the new study, Kliewer and study co-lead author David Mangelsdorf of the University of Texas Southwestern Medical Center show that FGF21 plays a broader role in defending against the harmful consequences of exposure to ethanol than previously thought.
In mice, FGF21 stimulated arousal from intoxication without modifying ethanol degradation. Mice lacking FGF21 took longer than their congeners to recover their righting reflex and balance after exposure to ethanol. Conversely, pharmacological administration of FGF21 reduced the time required for mice to recover from ethanol-induced unconsciousness and lack of muscle coordination.
Surprisingly, FGF21 did not counteract the sedation caused by ketamine, diazepam, or pentobarbital, indicating specificity for ethanol. FGF21 mediated its anti-intoxicating effects by directly activating noradrenergic neurons in the locus coeruleus region in the brain, which regulates wakefulness and alertness.
Taken together, the results suggest that the liver-brain pathway of FGF21 evolved to protect against ethanol-induced intoxication. According to the authors, this pathway can modulate a variety of cognitive and emotional functions to improve survival under stressful conditions.
However, it remains to be determined whether the activation of the noradrenergic system contributes to the other effects of FGF21, in particular those on metabolism and the preference for ethanol and sugar. Although FGF21 and noradrenergic nervous system activity are induced by ethanol in humans, further studies will also be needed to determine whether the anti-intoxicant activity of FGF21 translates in humans.
“Our studies reveal that the brain is the primary site of action for the effects of FGF21,” Mangelsdorf says. “We are now exploring in greater depth the neural pathways through which FGF21 exerts its sobering effect.”
Funding: This work was supported by the National Institutes of Health, the Robert A. Welch Foundation, and the Howard Hughes Medical Institute. Information on potential conflicts of interest can be found in the paper text.
About this neuroscience research news
Author: Bench Christopher
Source: Cell press
Contact: Kristopher Benke – Cell Press
Picture: Image is credited to Cell Metabolism/Choi et al (CC BY-SA)
Original research: Free access.
“FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system” by Steven Kliewer et al. Cell metabolism
FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system
- FGF21 hormone counteracts alcohol-induced loss of consciousness and coordination
- Pharmacological FGF21 accelerates recovery after alcohol intoxication
- FGF21 exerts its sobering effect by activating the noradrenergic nervous system
Animals that consume fermenting fruit and nectar are at risk of exposure to ethanol and the adverse effects of drunkenness. In this report, we show that the hormone FGF21, which is strongly induced by ethanol in mouse and human liver, stimulates arousal from intoxication without altering ethanol catabolism.
Mice lacking FGF21 take longer than their wild-type counterparts to recover their righting reflex and balance after exposure to ethanol. Conversely, pharmacological administration of FGF21 reduced the time required for mice to recover from ethanol-induced unconsciousness and ataxia.
FGF21 did not reverse sedation caused by ketamine, diazepam, or pentobarbital, indicating specificity for ethanol. FGF21 mediates its anti-intoxicating effects by directly activating noradrenergic neurons in the locus coeruleus region, which regulates wakefulness and alertness.
These results suggest that this liver-brain FGF21 pathway has evolved to protect against ethanol-induced intoxication and may be pharmaceutically targeted for the treatment of acute alcohol intoxication.