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Liver-brain pathway may regulate alcohol consumption

Date:
November 28, 2016
Source:
King's College London
Summary:
A liver hormone called ‘FGF21’ may regulate alcohol drinking by acting directly on a receptor in the brain, according to a new study. 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.
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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 in Proceedings of the 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.'


Story Source:

Materials provided by King's College London. Note: Content may be edited for style and length.


Journal Reference:

  1. Gunter Schumann, Chunyu Liu, Paul O’Reilly, He Gao, Parkyong Song, Bing Xu, Barbara Ruggeri, Najaf Amin, Tianye Jia, Sarah Preis, Marcelo Segura Lepe, Shizuo Akira, Caterina Barbieri, Sebastian Baumeister, Stephane Cauchi, Toni-Kim Clarke, Stefan Enroth, Krista Fischer, Jenni Hällfors, Sarah E. Harris, Saskia Hieber, Edith Hofer, Jouke-Jan Hottenga, Åsa Johansson, Peter K. Joshi, Niina Kaartinen, Jaana Laitinen, Rozenn Lemaitre, Anu Loukola, Jian’an Luan, Leo-Pekka Lyytikäinen, Massimo Mangino, Ani Manichaikul, Hamdi Mbarek, Yuri Milaneschi, Alireza Moayyeri, Kenneth Mukamal, Christopher Nelson, Jennifer Nettleton, Eemil Partinen, Rajesh Rawal, Antonietta Robino, Lynda Rose, Cinzia Sala, Takashi Satoh, Reinhold Schmidt, Katharina Schraut, Robert Scott, Albert Vernon Smith, John M. Starr, Alexander Teumer, Stella Trompet, André G. Uitterlinden, Cristina Venturini, Anne-Claire Vergnaud, Niek Verweij, Veronique Vitart, Dragana Vuckovic, Juho Wedenoja, Loic Yengo, Bing Yu, Weihua Zhang, Jing Hua Zhao, Dorret I. Boomsma, John Chambers, Daniel I. Chasman, Toniolo Daniela, Eco de Geus, Ian Deary, Johan G. Eriksson, Tõnu Esko, Volker Eulenburg, Oscar H. Franco, Philippe Froguel, Christian Gieger, Hans J. Grabe, Vilmundur Gudnason, Ulf Gyllensten, Tamara B. Harris, Anna-Liisa Hartikainen, Andrew C. Heath, Lynne Hocking, Albert Hofman, Cornelia Huth, Marjo-Riitta Jarvelin, J. Wouter Jukema, Jaakko Kaprio, Jaspal S. Kooner, Zoltan Kutalik, Jari Lahti, Claudia Langenberg, Terho Lehtimäki, Yongmei Liu, Pamela A. F. Madden, Nicholas Martin, Alanna Morrison, Brenda Penninx, Nicola Pirastu, Bruce Psaty, Olli Raitakari, Paul Ridker, Richard Rose, Jerome I. Rotter, Nilesh J. Samani, Helena Schmidt, Tim D. Spector, David Stott, David Strachan, Ioanna Tzoulaki, Pim van der Harst, Cornelia M. van Duijn, Pedro Marques-Vidal, Peter Vollenweider, Nicholas J. Wareham, John B. Whitfield, James Wilson, Bruce Wolffenbuttel, Georgy Bakalkin, Evangelos Evangelou, Yun Liu, Kenneth M. Rice, Sylvane Desrivières, Steven A. Kliewer, David J. Mangelsdorf, Christian P. Müller, Daniel Levy, Paul Elliott. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proceedings of the National Academy of Sciences, 2016; 201611243 DOI: 10.1073/pnas.1611243113

Cite This Page:

King's College London. "Liver-brain pathway may regulate alcohol consumption." ScienceDaily. ScienceDaily, 28 November 2016. <www.sciencedaily.com/releases/2016/11/161128153908.htm>.
King's College London. (2016, November 28). Liver-brain pathway may regulate alcohol consumption. ScienceDaily. Retrieved May 23, 2017 from www.sciencedaily.com/releases/2016/11/161128153908.htm
King's College London. "Liver-brain pathway may regulate alcohol consumption." ScienceDaily. www.sciencedaily.com/releases/2016/11/161128153908.htm (accessed May 23, 2017).

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