Intoxicated Mice Sober Up after FGF21 Shot

Fibroblast growth factor 21 (FGF21) protects mice against ethanol-induced loss of balance and righting reflex, according to a study recently published in Cell Metabolism.

Researchers led by Steven Kliewer, PhD, and David Mangelsdorf, PhD, both of the University of Texas Southwestern Medical Center in Dallas, point out that simple sugars in ripening fruits and nectars are a rich source of calories for many animals, but the ethanol produced by this natural fermentation can cause intoxication. “Accordingly, animals that consume fructose and other simple sugars have evolved liver enzymes to catabolize ethanol,” the authors write. “Comparative genetic analyses of alcohol dehydrogenases across species reveal that many strict herbivores and carnivores that are not exposed to ethanol appear to have lost the ability to catabolize it, underscoring the importance of ethanol as an evolutionary driver.”

FGF21 is induced in the liver by a variety of metabolic stresses, including starvation, protein deficiency, simple sugars, and ethanol. In humans, ethanol is by far the most potent inducer of FGF21 described to date. Previous studies showed that FGF21 suppresses ethanol preference, induces water drinking to prevent dehydration, and protects against alcohol-induced liver injury.

In the new study, researchers show that FGF21 plays a broader role in defending against the harmful consequences of ethanol exposure than previously thought. In mice, FGF21 stimulated arousal from intoxication without changing the breakdown of ethanol. Mice lacking FGF21 took longer than their littermates to recover their righting reflex and balance following ethanol exposure. Conversely, pharmacologic FGF21 administration reduced the time needed for mice to recover from ethanol-induced unconsciousness and lack of muscle coordination.

FGF21 did not counteract sedation caused by ketamine, diazepam, or pentobarbital, indicating specificity for ethanol. FGF21 mediated its anti-intoxicant effects by directly activating noradrenergic neurons in the locus coeruleus region in the brain, which regulates arousal and alertness.

“These results reveal a mechanism for selectively targeting noradrenergic neurons that could prove useful for treating both the loss of consciousness and impaired mobility that occur during acute alcohol poisoning.”

Taken together, the results suggest that the FGF21 liver-brain pathway evolved to protect against ethanol-induced intoxication. According to the authors, this pathway may modulate a variety of cognitive and emotional functions to enhance survival under stressful conditions.

It remains to be determined whether activation of the noradrenergic system contributes to FGF21’s other effects, including those on metabolism and ethanol and sweet preference. Although both FGF21 and noradrenergic nervous system activity are induced by ethanol in humans, additional studies will also be required to determine whether FGF21’s anti-intoxicant activity translates to humans.

“In summary, FGF21 serves as an endogenous hormonal signal from liver to noradrenergic neurons in the brain to defend against ethanol-induced intoxication. Post hoc pharmacologic administration of FGF21 also markedly accelerates arousal from ethanol’s detrimental effects on righting reflex and rotarod performance,” the authors conclude. “These results reveal a mechanism for selectively targeting noradrenergic neurons that could prove useful for treating both the loss of consciousness and impaired mobility that occur during acute alcohol poisoning.”

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