Hormone Shot Sobers Up Drunk Mice

Researchers at the University of Texas Southwestern (UT Southwestern) Medical Center found they could protect mice against loss of balance and disorientation induced by ethanol through administering a hormone. The research is published in Cell.

Can a hormone protect against ethanol-inducted intoxication?

After one too many alcoholic beverages, your words may start to slur, thoughts begin to blur and while you might think the moves you’re busting out on the dance floor are flawless, in reality, you’re probably flailing your arms in an uncoordinated fashion.

Ethanol – the active ingredient in alcohol – is to thank (or not) for this side effect of drinking. A new study has found that, in mice, a hormone called fibroblast growth factor 21 (FGF21) can protect against ethanol-induced loss of balance and righting reflex. The research is led by Professor David Mangelsdorf, Alfred G. Gilman Distinguished Chair in Pharmacology at UT Southwestern.

FGF21 is a liver-derived hormone that is produced in response to metabolic stresses, including protein deficiency, starvation and ethanol consumption. In humans, prelinical and clinical studies show that alcohol consumption increases the levels of endogenous FGF21. These preliminary data have led to FGF21’s consideration as a target for treating alcohol use disorder (AUD), however, further work is necessary to unpick the molecular mechanisms involved in its effects.

A sobering effect

In the Cell study, Mangelsdorf and colleagues suggest that FGF21’s role in protecting against harmful levels of ethanol exposure is more complex than previously thought.

In mouse studies, FGF21 was found to stimulate alertness from a state of intoxication as anticipated. When the researchers engineered knockout mice lacking FGF21, they required 1.5 hours longer to regain their righting reflex compared to control mice expressing FGF21. Interestingly, this effect occurred without impacting ethanol breakdown in the body. “There were no differences in plasma ethanol clearance between the knockout lines and control mice. These results indicate that liver-derived FGF21 accelerates recovery from ethanol induced loss of righting reflex by acting on its receptor in the nervous system,” the authors write.

Next, the team pharmacologically administered FGF21 to elevate the circulating levels of the hormone beyond a “normal” level. They found that the time required for mice to recover from ethanol-induced unconsciousness and loss of balance was accelerated “dramatically”.

FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system. Credit: Cell Metabolism/Choi et al.

The researchers discovered that FGF21 exerts its protective effects against ethanol via activation of noradrenergic neurons located in the locus coeruleus, a group of neurons found in the brainstem implicated in physiological functions such as alertness, arousal, attention and memory.

Mangesldorf and team tested FGF21’s abilities against the sedation induced by drugs like diazepam, ketamine and pentobarbital. The hormone could not counteract the effects, which indicates a specificity against ethanol. Collectively, their results imply that the FGF21 liver–brain pathway could have evolved to protect the body against ethanol intoxication.

“We’ve discovered that the liver is not only involved in metabolizing alcohol but that it also sends a hormonal signal to the brain to protect against the harmful effects of intoxication, including both loss of consciousness and coordination,” says Professor Steven Kliewer, Diana K. and Richard C. Strauss Distinguished Chair in Developmental Biology at UT Southwestern and co-senior author of the study. 

Further research is required to confirm whether the protective effects discovered in mice translate to humans. “Our studies reveal that the brain is the major site of action for FGF21’s effects,” Mangelsdorf says. “We are now exploring in greater depth the neuronal pathways by which FGF21 exerts its sobering effect.”

Reference: Choi M, Schneeberger M and Fan W et al. FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system. Cell. 2023. doi:10.1016/j.cmet.2023.02.005.

This article is a rework of a press release issued by the University of Texas Southwestern Medical Center. Material has been edited for length and content.