Research led by University of Texas Southwestern Medical Center researchers has shown how a hormone called fibroblast growth factor 21 (FGF21) that is produced by the liver in response to ethanol consumption protects mice against ethanol-induced loss of balance and righting reflex. The research showed that FGF21 effectively signals to the brain to speed recovery from intoxication, with mice lacking the hormone taking longer than their wild-type littermates to recover their righting reflex and balance following ethanol exposure. The study results point to the potential to target the FGF21 liver-brain pathway using drugs to treat acute alcohol poisoning.
“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,” said Steven Kliewer, PhD, who is co-senior author of the team’s published paper in Cell Metabolism. “We’ve further shown that by increasing FGF21 concentrations even higher by injection, we can dramatically accelerate recovery from intoxication. FGF21 does this by activating a very specific part of the brain that controls alertness.”
Kliewer and colleagues reported on their study in a paper titled “FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system,” in which they concluded, “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.”
Fructose and other simple sugars in ripening fruits and nectars are a rich source of calories for many animals, but the consumption of ethanol produced by the natural fermentation of these sugars can cause intoxication, which can impair both mobility and judgement, the authors noted. “Accordingly, animals that consume fructose and other simple sugars have evolved liver enzymes to catabolize ethanol.”
FGF21 is a hormone that is induced in the liver by a variety of metabolic stresses, including starvation, protein deficiency, simple sugars, and ethanol, the team continued. “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. “Thus, FGF21 plays a broad role in defending against the harmful consequences of ethanol exposure.”
Human genome wide association studies have, in addition, linked single nucleotide polymorphisms (SNPs) in and around the FGF21 gene to alcohol consumption, while studies in mice have shown that FGF21 crosses blood brain barrier “through an unknown mechanism,” and acts to suppress ethanol preference and induce water consumption.
Through their newly reported study, Kliewer and UT Southwestern Medical Centre colleague and co-senior study author David Mangelsdorf, PhD, showed that FGF21 plays a broader role in defending against the harmful consequences of ethanol exposure than previously thought. Their studies in mice showed that FGF21 stimulated arousal from intoxication without altering ethanol breakdown. Mice lacking FGF21 took longer than their littermates to recover their righting reflex and balance following ethanol exposure, whereas, conversely, pharmacologic FGF21 administration reduced the time needed for mice to recover from ethanol-induced unconsciousness and lack of muscle coordination. Surprisingly, FGF21 did not counteract sedation caused by ketamine, diazepam, or pentobarbital, indicating its specificity for ethanol.
Further studies showed that FGF21 mediated its anti-intoxicant effects by directly activating noradrenergic neurons in the locus coeruleus (LC) region in the brain, which regulates arousal and alertness. “Norepinephrine (NE) is an abundant neuromodulator in the CNS,” they noted. “Most central NE is synthesized in the locus coeruleus (LC), a small nucleus in the pons of the brainstem … we show that FGF21 directly activates noradrenergic neurons in the LC region. We further show that this FGF21-NE pathway accelerates recovery of righting reflex and balance following ethanol intoxication.”
The collective results suggest that the FGF21 liver-brain pathway evolved to protect against ethanol-induced intoxication. “Taken together, this work reveals that FGF21 is an endogenous, ethanol-selective amethystic agent that complements the liver’s alcohol metabolizing enzymes in defending against ethanol toxicity and its potentially dangerous sequelae,” the authors concluded.
In addition to ethanol and fructose, FGF21 is also induced by starvation and low-protein diets. “We speculate that the FGF21-NE pathway may also heighten arousal and alertness in order to increase foraging during periods of nutritional deficiency,” the researchers noted. The noradrenergic system in addition impacts on neuronal processes other than arousal, including attention, memory, perception and motivation. “Thus, the FGF21-NE pathway may modulate a variety of cognitive and affective functions to enhance survival under stressful conditions,” they continued.
Acknowledging some limitations of their study, the team pointed out that it still 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. “Our studies reveal that the brain is the major site of action for FGF21’s effects,” Mangelsdorf said. “We are now exploring in greater depth the neuronal pathways by which FGF21 exerts its sobering effect.”
