Liver-brain pathway may regulate alcohol consumption

A liver hormone called 'FGF21' may regulate alcohol drinking by acting directly on a receptor in the brain, according to a new study by researchers from King's College London, Imperial College London and UT Southwestern Medical Center.

For the first time this study highlights a liver-brain axis which plays an important role in regulating the consumption of alcohol, raising the possibility of a new therapeutic pathway that could one day be targeted to reduce the desire for alcohol in problem drinkers.

Alcohol drinking is a complex trait that is known to be partly inherited, yet so far there have been few genes associated with it. Genetic influences on brain functions that affect drinking behaviour have been difficult to detect because the effect of individual genes is so small, so large studies are required to detect the genetic signal.

In this new study, published today in Proceedings of National Academy of Sciences (PNAS), researchers carried out the largest-ever genetic analysis of usual (i.e. non-addictive) alcohol consumption in more than 105,000 individuals of European descent. In addition to providing samples for genetic analysis, the participants answered questionnaires on their weekly drinking habits.

They 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 behaviour. The less frequent variant - seen in approximately 40 percent of people in the study - was associated with a decreased desire to drink alcohol.

To examine whether 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.

Under normal conditions FGF21 inhibits alcohol preference in mice. However, when these mice were lacking β-Klotho, FGF21 had no effect on drinking behaviour, 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 behaviour, compared to mice with β-Klotho.

Professor Gunter Schumann from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's College London, said: '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.'

Professor Schumann added: '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.'

Professor Paul Elliott from Imperial College London said: 'Alcohol drinking in excess is a major public health problem worldwide and we need to find new ways of reducing the harmful effects of alcohol in the population. Even small shifts downward in the average amount of alcohol people drink may have major health benefits.'

He added: 'The results of our study point to a previously unrecognised genetic determinant of alcohol drinking among the general population. Our findings may eventually lead to new treatments for people whose health is being harmed by drinking.'

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This study was funded by the Medical Research Council, the European Commission and the Howard Hughes Medical Institute.

For further media information please contact Jack Stonebridge, Press Officer, Institute of Psychiatry, Psychology & Neuroscience, King's College London jack.stonebridge@kcl.ac.uk/ 020 7848 5377.

King's College London is one of the top 25 universities in the world (2016/17 QS World University Rankings) and among the oldest in England. King's has more than 26,500 students (of whom nearly 10,400 are graduate students) from some 150 countries worldwide, and nearly 6,900 staff. The university is in the second phase of a £1 billion redevelopment programme which is transforming its estate.

King's has an outstanding reputation for world-class teaching and cutting-edge research. In the 2014 Research Excellence Framework (REF) King's was ranked 6th nationally in the 'power' ranking, which takes into account both the quality and quantity of research activity, and 7th for quality according to Times Higher Education rankings. Eighty-four per cent of research at King's was deemed 'world-leading' or 'internationally excellent' (3* and 4*). The university is in the top seven UK universities for research earnings and has an overall annual income of more than £600 million.

King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar.

King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King's Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: http://www.kingshealthpartners.org.

Imperial College London is one of the world's leading universities. The College's 16,000 students and 8,000 staff are expanding the frontiers of knowledge in science, medicine, engineering and business, and translating their discoveries into benefits for society.

Founded in 1907, Imperial builds on a distinguished past - having pioneered penicillin, holography and fibre optics - to shape the future. Imperial researchers work across disciplines to improve health and wellbeing, understand the natural world, engineer novel solutions and lead the data revolution. This blend of academic excellence and its real-world application feeds into Imperial's exceptional learning environment, where students participate in research to push the limits of their degrees.

Imperial collaborates widely to achieve greater impact. It works with the NHS to improve healthcare in west London, is a leading partner in research and education within the European Union, and is the UK's number one research collaborator with China.

Imperial has nine London campuses, including its White City Campus: a research and innovation centre that is in its initial stages of development in west London. At White City, researchers, businesses and higher education partners will co-locate to create value from ideas on a global scale.

The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers' money in some of the best medical research in the world across every area of health. Thirty-one MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. http://www.mrc.ac.uk