Fibroblast growth factor 21 (FGF21) halved the alcohol consumption of alcohol-preferring vervet monkeys. The researchers see great potential in using this hormone to treat people with alcohol dependence.
Researchers have mapped a previously unknown function of FGF21, a hormone secreted by the liver.
A new study published in Cell Metabolism and carried out by researchers from Denmark, the United States and other countries shows that administering FGF21 to alcohol-preferring vervet monkeys (Chlorocebus sabaeus) suppresses their alcohol consumption.
The discovery may pave the way for completely new ways of treating people with alcohol dependence.
“We will test this in human trials in the coming years. FGF21 is very effective in vervet monkeys, but how it affects people’s alcohol consumption is unknown. We would also like to determine the underlying mechanism that suppresses monkeys’ alcohol consumption. This will improve understanding of how alcohol dependence develops,” explains a researcher involved in the discovery, Matthew Gillum, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
May be the liver’s equivalent of a gut hormone
FGF21 is secreted by the liver and reduces the amount of fat in both the liver and in the blood. However, researchers know very little about what FGF21 actually does.
However, large databases show that FGF21 seems to affect alcohol dependence.
Data from biobanks such as the UK Biobank have shown, for example, that mutations in the gene encoding for FGF21 increase the risk of developing alcohol dependence.
Previous experiments by the same researchers behind the new study also showed that consuming alcohol greatly increases the concentration of FGF21 in the blood.
“This led us to hypothesise that FGF21 has the same effect on alcohol consumption as the gut hormone GLP-1 has on food consumption. When we eat, the gut secretes GLP-1, which signals to the brain that we should stop eating. This is a feedback mechanism that should stop us from overeating. We envision that FGF21 works similarly when consuming alcohol, preventing us from consuming enough alcohol to become intoxicated,” says Matthew Gillum.
Made monkeys drink to intoxication
To test the hypothesis, the researchers conducted an experiment with a specific type of monkey that is very fond of alcohol. Vervet monkeys live in Saint Kitts in the Caribbean.
Young adult male vervet monkeys like to consume the equivalent of a young human drinking about three bottles of wine in 4 hours.
The researchers gave these monkeys access to alcohol ad libitum for 4 hours to determine how much they would drink if they had previously received FGF21 or a placebo.
The result was dramatic. The monkeys receiving FGF21 drank 50% less alcohol.
“The interesting thing is also that FGF21 seems to suppress the urge to drink and does not act like disulfiram by being toxic,” explains Matthew Gillum.
Potential for treating people
The discovery has many interesting perspectives, the obvious one being that FGF21 should be studied among people.
Usually, the time elapsing from discovery in a laboratory until a drug comes on the market is long. However, clinical trials of FGF21 may take less time than normal.
Akero Therapeutics is already investigating FGF21 in a Phase 2b trial as a treatment for people with fatty liver disease. Other drug companies are also investigating FGF21 for treating people with liver disease.
If FGF21 turns out to be safe, it could be quickly tested clinically to treat people with a strong urge to drink alcohol.
“FGF21 may not do anything about the physical abstinence experienced by many people with a severe alcohol disorder, but it may remove the urge to drink among people who have been through a detoxification programme,” says Matthew Gillum.
Glucose also affects FGF21
Another interesting perspective is that better mapping of how FGF21 affects the body and brain may bring researchers closer to understanding why some people drink moderately and others excessively.
The reason may well be because we each secrete different amounts of FGF21 when we drink.
Long-term high alcohol consumption may also make us resistant to the effects of FGF21, just as long-term excessive consumption of sugar can make the body resistant to insulin.
The third interesting perspective in the new research also relates to glucose.
The urge to drink alcohol and the urge to eat sugar are closely linked. FGF21 seems to play a role in both forms of dependence, and the researchers started by examining how FGF21 is related to having a sweet tooth.
“We want to understand the underlying neurobiological mechanism. What makes FGF21 stop us from drinking or putting our hand in the candy jar? Is it because the alcohol or the candy simply does not taste as good after we have consumed it for some time? And what happens in the brain?” asks Matthew Gillum.
The research indicates that FGF21 seems to send signals to the amygdala, a region of the brain that is primarily associated with emotional processes. This may help explain why many people drink alcohol or eat more unhealthily when they are undergoing emotional distress.
