Dataset Information

KLB is associated with alcohol drinking, and its gene product ?-Klotho is necessary for FGF21 regulation of alcohol preference.

ABSTRACT: Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified ?-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). ?-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific ?-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

SUBMITTER: Schumann G

PROVIDER: S-EPMC5167198 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.

Schumann Gunter G Liu Chunyu C O'Reilly Paul P Gao He H Song Parkyong P Xu Bing B Ruggeri Barbara B Amin Najaf N Jia Tianye T Preis Sarah S Segura Lepe Marcelo M Akira Shizuo S Barbieri Caterina C Baumeister Sebastian S Cauchi Stephane S Clarke Toni-Kim TK Enroth Stefan S Fischer Krista K Hällfors Jenni J Harris Sarah E SE Hieber Saskia S Hofer Edith E Hottenga Jouke-Jan JJ Johansson Åsa Å Joshi Peter K PK Kaartinen Niina N Laitinen Jaana J Lemaitre Rozenn R Loukola Anu A Luan Jian'an J Lyytikäinen Leo-Pekka LP Mangino Massimo M Manichaikul Ani A Mbarek Hamdi H Milaneschi Yuri Y Moayyeri Alireza A Mukamal Kenneth K Nelson Christopher C Nettleton Jennifer J Partinen Eemil E Rawal Rajesh R Robino Antonietta A Rose Lynda L Sala Cinzia C Satoh Takashi T Schmidt Reinhold R Schraut Katharina K Scott Robert R Smith Albert Vernon AV Starr John M JM Teumer Alexander A Trompet Stella S Uitterlinden André G AG Venturini Cristina C Vergnaud Anne-Claire AC Verweij Niek N Vitart Veronique V Vuckovic Dragana D Wedenoja Juho J Yengo Loic L Yu Bing B Zhang Weihua W Zhao Jing Hua JH Boomsma Dorret I DI Chambers John J Chasman Daniel I DI Daniela Toniolo T de Geus Eco E Deary Ian I Eriksson Johan G JG Esko Tõnu T Eulenburg Volker V Franco Oscar H OH Froguel Philippe P Gieger Christian C Grabe Hans J HJ Gudnason Vilmundur V Gyllensten Ulf U Harris Tamara B TB Hartikainen Anna-Liisa AL Heath Andrew C AC Hocking Lynne L Hofman Albert A Huth Cornelia C Jarvelin Marjo-Riitta MR Jukema J Wouter JW Kaprio Jaakko J Kooner Jaspal S JS Kutalik Zoltan Z Lahti Jari J Langenberg Claudia C Lehtimäki Terho T Liu Yongmei Y Madden Pamela A F PA Martin Nicholas N Morrison Alanna A Penninx Brenda B Pirastu Nicola N Psaty Bruce B Raitakari Olli O Ridker Paul P Rose Richard R Rotter Jerome I JI Samani Nilesh J NJ Schmidt Helena H Spector Tim D TD Stott David D Strachan David D Tzoulaki Ioanna I van der Harst Pim P van Duijn Cornelia M CM Marques-Vidal Pedro P Vollenweider Peter P Wareham Nicholas J NJ Whitfield John B JB Wilson James J Wolffenbuttel Bruce B Bakalkin Georgy G Evangelou Evangelos E Liu Yun Y Rice Kenneth M KM Desrivières Sylvane S Kliewer Steven A SA Mangelsdorf David J DJ Müller Christian P CP Levy Daniel D Elliott Paul P

Proceedings of the National Academy of Sciences of the United States of America 20161128 50

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10<sup>-12</sup>). β-Klotho is an obligate coreceptor for the hormone FGF21 ...[more]

PMID: 27911795

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Project description:OBJECTIVE:To signal, FGF19 and FGF21 require co-receptor ?Klotho (KLB) to act in concert with FGF receptors, and yet there is appreciable variance in the C-terminal sequences of these two novel metabolic hormones where binding is believed to be primary. We seek to determine the functional consequences for these amino acid differences and determine whether such information can be used to design high potency antagonists and agonists. METHODS:We employed a functional in vitro assay to identify C-terminal protein fragments capable of fully blocking KLB-mediated FGF19 and 21 receptor signaling. The key residues in each hormone responsible for support full bioactivity were identified through peptide-based Ala-scanning. Chemical optimization of the peptides was employed to increase their antagonistic potency. An optimized sequence as a substituted part of a full length FGF21 was assessed for enhanced FGFR/KLB-mediated agonism using tissue culture and obese mice. RESULTS:C-terminal FGF19 and FGF21 peptides of relatively short length were observed to potently inhibit the activity of these two hormones, in vitro and in vivo. These FGFs of different sequence also demonstrated a striking conservation of structural determinants to maintain KLB binding. A single C-terminal amino acid in FGF19 was observed to modulate relative activity through FGFR1 and FGFR4. The substitution of native FGF21 C-terminal sequence with a peptide optimized for the highest antagonistic activity resulted in significantly enhanced FGF potency, as measured by in vitro signaling and improvements in metabolic outcomes in diet-induced obese mice. CONCLUSIONS:We report here the ability of short C-terminal peptides to bind KLB and function as antagonists of FGF19 and 21 actions. These proteins maintain high conservation of sequence in those residues central to KLB binding. An FGF21 chimeric protein possessing an optimized C-terminal sequence proved to be a super-agonist in delivery of beneficial metabolic effects in obese mice.

Project description:ObjectiveExcessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes ?-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1-181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain.MethodsWe recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1-181) measurement in plasma. In addition, we measured circulating FGF21 (1-181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1-181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice.ResultsWe show that alcohol ingestion (25.3 g or ?2.5 standard drinks) acutely increases plasma levels of FGF21 (1-181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1-181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1-181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice.ConclusionsFGF21 (1-181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans.

Dataset Information

KLB is associated with alcohol drinking, and its gene product ?-Klotho is necessary for FGF21 regulation of alcohol preference.

Publications

KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.

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