Xiaobu interprets the "sobering agent" for mice - new ideas for research on the "liver-brain" pathway

The incidence of hepatitis B, hepatitis C, alcoholic hepatitis and other hepatitis liver diseases in my country is increasing year by year, and people's health is facing serious threats. Excessive drinking can be accompanied by acute alcoholic hepatitis. The simple sugars in ripe fruits and nectar are a rich source of calories for many animals, but animals that consume fermented fruits and nectar are at risk of being exposed to harmful factors such as ethanol and intoxication, which can cause loss of mobility and judgment.

Fibroblast growth factor 21 (FGF21) is a hormone induced by various metabolic stresses in the liver, including starvation, protein deficiency, simple sugars, and ethanol. In humans, ethanol is the most potent inducer of FGF21 studied to date. Studies have shown that FGF21 can inhibit people's preference for ethanol and prevent alcohol-induced liver damage. Therefore, FGF21 plays a broad role in protecting against the deleterious consequences of ethanol exposure.

The research team of Steven Kliewer, joint senior research author at the University of Texas Southwestern Medical Center, published a research paper titled "FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system" online in the journal Cell Metabolism on March 7. The study reports that fibroblast growth factor 21 (FGF21) can protect mice from drunkenness-induced loss of balance and help restore the righting reflex.

FGF21

Helping "drunk" mice regain consciousness and coordination

The researchers explored the role of FGF21 in drunken awakening by giving ethanol orally to wild mice and systemic Fgf21 knockout mice (Fgf21-/-), examining the mice's righting emission, and found that Fgf21-/- mice were smaller than WT It takes longer for the mice to recover their righting reflex, indicating that FGF21 can help the mice recover their consciousness and coordination after being drunk without affecting the catabolism of ethanol. Studies in hepatocyte-specific Fgf21 knockout mice (Fgf21Alb) and neuron-specific Klb knockout mice (KlbCamk2a) have found that liver-derived FGF21 can accelerate the recovery of the righting reflex by acting on its receptors in the nervous system. Intraperitoneal injection of the drug FGF21 stimulated drunken arousal in both wild-type and Fgf21-/- mice, but had no effect in KlbCamk2a mice. In addition, FGF21 did not stimulate the recovery of mice from sedatives such as ketamine, diazepam, and pentobarbital, indicating that FGF21 is selective for ethanol.

Studies have shown that ethanol can activate neurons in the locus coeruleus (LC), which is the central brain area where most NE is synthesized. In addition, dopamine β-hydroxylase (Dbh enzyme) knockout mice are unable to synthesize NE, which prolongs the recovery time after ethanol-induced loss of righting reflex without any changes in ethanol catabolism, consistent with that observed in Fgf21-/- mice. The reactions are similar. Is physiological FGF21 related to ethanol-induced activation of noradrenergic neurons in LC? The researchers further performed immunostaining for c-Fos and NE transporter (NET) on LC sections, and the results showed that ethanol can induce enhanced c-Fos expression in NET+ LC neurons of WT mice. It is worth noting that this situation was observed in Fgf21 -/- Completely absent in mice. Results demonstrate that FGF21 is required for ethanol activation of noradrenergic neurons in the LC.

FGF21

Acts directly on noradrenergic neurons to stimulate arousal from drunkenness

In order to explore whether noradrenergic neurons are necessary for FGF21 to stimulate drunken arousal, the researchers used gene knockout and drug inhibition methods. Establishing a mouse model in which DBH is not expressed in the LC but is expressed in the adrenal medulla (DbhCamk2a) selectively eliminates NE production in neurons, and these knockout mice are fully resistant to the pharmacological effects of FGF21 on the righting reflex. Pretreating WT mice with DSP-4 also eliminated the effect of FGF21 on the righting reflex. The antitoxic effects of FGF21 were blocked by the selective a1- and b-adrenergic receptor antagonists prazosin and propranolol, respectively. These genetic and pharmacological data suggest that FGF21 stimulates wakefulness by activating noradrenergic neurons in the nervous system.

Next, Klb knockout mouse models were established to selectively disrupt the activity of FGF21 in noradrenergic neurons, consistent with the above Dbh knockout and pharmacological inhibitor studies, in KlbDbh and KlbAAV-Cre mice. The effect of FGF21 on the righting reflex was lost, as was its ability to stimulate c-Fos expression in the LC.

in conclusion

FGF21 accelerates the recovery of the righting reflex in mice after drunkenness by acting directly on noradrenergic neurons, and the deletion of KLB in the LC region changes the sobering effect of FGF21. Since the FGF21 receptor complex is also abundantly expressed in other brain regions, such as the nucleus tractus solitarius, more research is needed to dissect its potential mechanism of action. The FGF21 liver-brain pathway can protect against ethanol-induced intoxication and may be a targeted drug for the treatment of acute alcoholism. However, whether the activity of FGF21 against alcoholism is also applicable in humans requires more research to determine.

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