LARS IGUM RASMUSSEN and his mates were going large. Donning their lederhosen, the three middle-aged men headed into Oktoberfest in Munich, Germany, the world鈥檚 biggest folk and beer festival. There, each proceeded to quaff an average of 7.5 litres of beer a day, for three days. It was a spectacular bender.
Getting hammered wasn鈥檛 the main aim of the exercise, however: Rasmussen is health correspondent for Danish magazine Politiken and was writing a story exploring the physiological effects of binge drinking. To understand what was happening to him and his friends, he had enlisted the help of metabolic physiologist Filip Knop at the University of Copenhagen. While Rasmussen was interested in finding out what havoc excessive boozing wreaks on the bodies of middle-aged men, Knop had another motive for getting involved. He and his colleague Matt Gillum had been itching to test a new idea about people鈥檚 appetite for alcohol 鈥� but couldn鈥檛, in good conscience, solicit anyone to partake in a binge of this magnitude. 鈥淚t would give the ethics officer a heart attack,鈥� says Gillum. Volunteers, however, were a different matter.
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What Knop and Gillum discovered is helping to build a picture of how our bodies control our boozing habits, from the amount we drink to when we stop. The research is homing in on a hormone that partly explains the huge variation in our social drinking habits: why some people are teetotal or can鈥檛 drink much, while others are lushes. It also points to the startling idea that our livers have more say in directing our behaviour than anyone imagined.
Of course, people choose to drink alcohol for all sorts of reasons. Delicious and complex flavours is one. Writing about his Oktoberfest experiences, Rasmussen described another: the 鈥渞eality-dissolving joy of intoxication鈥�, of being 6 litres of beer into a rowdy evening with 5000 fellow revellers. 鈥淭here are so many ways and motivations to drink alcohol,鈥� says psychiatrist Gunter Schumann at King鈥檚 College London. 鈥淚t could be stress relief, it could be sensation seeking, wanting to be social and whatnot.鈥� What we do know, however, is that drinking behaviour is strongly influenced by genetics. It is the result of each making a small contribution, says Alexandra Sanchez-Roige, a psychiatrist studying the genetics of substance-use disorders at the University of California, San Diego.
Results from the latest genomic tools suggest little overlap between the genetics underlying social drinking 鈥� like Rasmussen鈥檚 happy carousing 鈥� and problem drinking, such as alcohol addiction. Yet, given the wrong circumstances, normal consumption can spiral into harmful drinking. 鈥淎lcohol use disorders are very complex and are formed by a series of transitions,鈥� says Sanchez-Roige. This is one reason for a growing interest in the genes and mechanisms that underpin regular alcohol consumption, and it is where fits in. They wanted to find out what would happen to a hormone produced in the liver, fibroblast growth factor 21 (FGF21), when Rasmussen and his friends went on their bender.
This hormone first drew attention in the mid-2000s for its ability to cause weight loss in obese mice. Since then, FGF21 has been found to have , including : whether we crave carbohydrates or hanker after proteins, for example. It might even help explain why some people have a sweet tooth. In 2013, two studies scanning the human genome spotted associated with a tendency for people to eat a diet .
These genetic findings inspired Steven Kliewer and David Mangelsdorf at the University of Texas Southwestern Medical Center to discover a link with alcohol consumption. When they raised the levels of FGF21 in mice and monkeys, they found that this dramatically decreased the animals鈥� preference for sweetened water. Intrigued, they decided to look at a simple sugar-derivative, ethanol 鈥� the alcohol in our drinks. They found that FGF21 reduced the mice鈥檚 appetite for that too. Meanwhile, Gillum and Matthew Potthoff at the University of Iowa were also hot on the trail of FGF21, and discovered that it , part of the brain involved in creating our sensation of reward. 鈥淪o rather than affecting the taste directly, our thinking now is that FGF21 is affecting the pleasure sensation that you get from sugar,鈥� says Kliewer.
Liver: do you read me?
Further evidence of FGF21鈥檚 modus operandi came when Kliewer and his team disabled a protein called beta-klotho, which helps cells in a mouse brain receive FGF21鈥檚 signal. Animals lacking beta-klotho drank more alcohol 鈥� a finding that took on new significance with the discovery that too. In 2016, a huge genomics study of 100,000 people of European descent looked for genes that affect alcohol consumption in non-addictive drinking. It found that two variants of the beta-klotho gene were associated with how much alcohol people preferred: those with one variant were light drinkers or teetotal whereas those with the other drank more heavily. 鈥淲hat I thought was interesting here was the fact that it was both a liver and brain mechanism,鈥� says Schumann, who was lead author of the study.
The obvious next experiment was to see what happens to our FGF21 levels when we drink alcohol. Eleftheria Maratos-Flier at Harvard Medical School and her colleagues discovered that after drinking alcohol for an hour, volunteers had a 鈥� far bigger, relatively speaking, than the one seen in mice. Kliewer, whose team performed similar experiments, was floored by his findings. 鈥淚n humans, ethanol is by far and away the strongest inducer of FGF21 production,鈥� he says.
The fact that a liver hormone has such a specific effect on the brain came as a big surprise. Scientists already knew of hormones that can reduce appetite generally, including ones that act on the brain鈥檚 reward system. But why is FGF21 so specialised, and why the focus on sugar and alcohol? One possible explanation, says Gillum, is that our evolutionary ancestors probably ate a lot of fruit, including fermented fruit, which would be a diet laden with fructose and ethanol. Dealing with these compounds puts metabolic stress on the liver, which is why drinking too much alcohol can damage this organ. FGF21 is a way for the liver to signal to the brain. 鈥淸It鈥檚 saying:] 鈥榃e鈥檝e got a lot of fructose on board. We have a lot of ethanol on board. We鈥檙e just not doing so well down here. Can we please adopt a more conservative behavioural profile for a few days until we can clear this up?鈥� 鈥� says Gillum. He speculates that our unusually strong FGF21 response to alcohol might be the result of our bodies evolving to cope with our invention of alcohol production, much in the same way that some populations evolved the ability to digest milk beyond infancy following the development of dairy farming.
Brain: copy
Whatever its origin, the hormone seems to have a role in protecting the liver. But, so far, research had only shown that it helps defend against a short binge. Its longer-term action remained unknown 鈥� until Rasmussen cooked up his Oktoberfest jaunt. Following the three-day bender, Gillum and Knop took blood samples from the friends. Sure enough, : they were over twice their baselines on their return to Denmark a couple of days later. 鈥淭hat was the first demonstration, really, that there is some subchronic regulation 鈥� part of the endocrine [hormonal] hangover, as it were,鈥� says Gillum.
These findings don鈥檛 just provide an insight into what鈥檚 going on inside our bodies when we overindulge, as and as many tend to do at this time of year. They also suggest a way to help people who have become dependent on alcohol. Gillum and Knop hypothesise that sustained heavy drinking might blunt the FGF21 response. Just as an overwhelmed pancreas starts struggling to produce insulin in people with type 2 diabetes, so a liver exposed to chronically high levels of ethanol might lose its ability to secrete FGF21. They are now looking at FGF21 secretion in problem drinkers with a view to finding out if giving someone doses of the hormone might help them cut down their alcohol consumption. 鈥淭hat would be my hope,鈥� says Gillum.
To investigate this idea, he has moved on from studying carousing journalists to another kind of party animal, the vervet monkeys of the West Indies island of St Kitts, notorious for swiping cocktails from tourists. 鈥淚t鈥檚 a fantastic feral population of primates that exhibits a fairly human-like distribution of alcohol drinking proclivities,鈥� he says. His focus is on individuals that drink heavily but steadily. 鈥淭hey have the monkey equivalent of about three bottles of wine a day,鈥� says Gillum. His team is testing to see whether giving the monkeys FGF21 can reduce their alcohol consumption. The results, though not yet published, look promising.
鈥淎fter a three-day bender, levels of the hormone were over twice the baseline鈥�
But when it comes to how much alcohol a person drinks, and why, FGF21 is only part of a much more complex picture. And there is another reason to be cautious about FGF21-based therapies: drugs that interact with the brain鈥檚 reward system run the risk of creating psychiatric problems such as depression, says Kliewer. However, Gillum is optimistic that such treatments, used judiciously, might help people with drinking problems, and even repair liver damage.
That would be quite an achievement. But whatever happens, we are still left with the discovery that our livers influence our behaviour in unexpected ways. 鈥淚t鈥檚 a thinking organ,鈥� says Gillum, 鈥渁t least in terms of what it knows, and communicating that to the brain.鈥� By pumping out its hormone, it drains the pleasure we get from alcohol even as we drain our glasses. Knowing that, we can start to listen more carefully to its message. You might even take a cue from one fictional boozer, James Bond, who in Casino Royale observed that his champagne 鈥渢asted bitter, as the first glass too many always does鈥�. If your booze loses its allure, then it鈥檚 time to stop drinking.
