FGF21, a liver hormone, may regulate alcohol consumption by acting directly on a receptor in the brain, a new study by researchers from King’s College London, Imperial College London and UT Southwestern Medical Center has found.
The biggest genome-wide meta-analysis and replication study ever mapped and compared the DNA of more than 105,000 light and heavy social drinkers.
This study reveals, for the first time, a liver-brain axis that has an key role in regulating the consumption of alcohol, opening up the potential for a new therapeutic pathway that could one day be targeted to reduce the desire for alcohol in problem drinkers.
Major Public Health Problem
Dr. Steven Kliewer, a Professor of Molecular Biology and Pharmacology and a corresponding author of the study, said:
“Excessive alcohol consumption is a major public health problem worldwide, causing more than 3 million deaths per year. Much of the research on alcohol consumption has focused on addiction. However, the overall burden of alcohol-associated disease reflects the total amount of alcohol consumed, not just addiction.”
A shift from heavy to moderate social drinking could have major public health benefits, such as reduced cardiovascular disease risk. Increased alcohol consumption is linked to two heart disease risk factors in particular: high blood pressure and obesity, according to the American Heart Association.
The researchers found variations of a gene called β-Klotho that were related to the amount of alcohol people were consuming, indicating that this gene may regulate drinking behavior. The less frequent variant, seen in approximately 40 percent of people in the study, was associated with a decreased desire to drink alcohol.
To investigate if β-Klotho affects alcohol drinking in mice, and whether it does so through actions in the brain, they also measured alcohol intake and alcohol preference of mice in which β-Klotho had been removed. They found that mice lacking β-Klotho in the brain showed significantly increased alcohol preference and consumption compared to mice with β-Klotho, indicating that intact β-Klotho might help to control alcohol intake.
Liver Hormone FGF21
Normally, FGF21 inhibits alcohol preference in mice. However, when these mice were lacking β-Klotho, FGF21 had no effect on drinking behavior, suggesting that FGF21’s effects on alcohol consumption depend on β-Klotho expression in the brain.
The researchers also found that mice lacking β-Klotho did not show any difference in measures of anxiety, which might influence drinking behavior, compared to mice with β-Klotho.
Professor Gunter Schumann from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, commented:
“Our study reveals a previously unrecognised liver-brain pathway which regulates alcohol consumption in humans, and which could one day be targeted therapeutically to suppress consumption in problem drinkers.
The results point towards an intriguing feedback loop, where FGF21 is produced in the liver in response to sugar and alcohol intake, which then acts directly on the brain to limit consumption.
We cannot rule out the possibility that β-Klotho acts by affecting neighbouring genes, so further genetic studies are warranted. It will also be important to explore these findings in more severe forms of alcohol drinking, as we only examined non-addictive consumption.”
The study compared the genetics of light and heavy social drinkers of European ancestry participating in nearly four dozen other large population studies worldwide. In addition to providing samples for genetic analysis, the participants answered questionnaires on their weekly drinking habits.
Heavy drinking was defined as more than 21 drinks per week for men and more than 14 drinks per week for women. Light drinking was considered to be 14 drinks or less per week for men and seven drinks or less per week for women. A “drink” was the equivalent of a small glass or wine, or a half pint of beer.
The β-Klotho gene codes for the protein β-Klotho, which forms a receptor complex in the central nervous system (the brain and spinal cord) with classic receptors for FGF21, a hormone produced in the liver.
Gunter Schumann, et al.
KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference
PNAS; doi: 10.1073/pnas.1611243113