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

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

doi:10.1073/pnas.1611243113

Cited by 222 publications

(256 citation statements)

References 29 publications

(38 reference statements)

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“…In addition to the regulation of BAT thermogenesis, recent studies indicate that FGF21 can influence central reward circuits and reduce sweet and alcohol consumption via activating KLB complexes expressed in the CNS [59], [61], [62]. Reduction in saccharin-containing water consumption by a FGF21-immunoglobulin G (IgG) fusion protein is conserved in NHPs [61].…”

Section: Metabolic E昀fects In Obese Micementioning

confidence: 99%

“…Reduction in saccharin-containing water consumption by a FGF21-immunoglobulin G (IgG) fusion protein is conserved in NHPs [61]. In addition, a genome-wide association study in humans identified KLB locus as a gene that regulates alcohol consumption [62]. These reports together suggest that the regulation of the central reward circuits is an evolutionarily conserved function of FGF21.…”

Section: Metabolic E昀fects In Obese Micementioning

confidence: 99%

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FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

Sonoda¹,

Chen²,

Baruch

2017

Hormone Molecular Biology and Clinical Investigation

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Abstract:Fibroblast growth factor 21 (FGF21) analogs and FGF21 receptor agonists (FGF21RAs) that mimic FGF21 ligand activity constitute the new "FGF21-class" of anti-obesity and anti-diabetic molecules that improve insulin sensitivity, ameliorate hepatosteatosis and promote weight loss. The metabolic actions of FGF21-class proteins in obese mice are attributed to stimulation of brown fat thermogenesis and increased secretion of adiponectin. The therapeutic utility of this class of molecules is being actively investigated in clinical trials for the treatment of type 2 diabetes and non-alcoholic steatohepatitis (NASH). This review is focused on various FGF21-class molecules, their molecular designs and the preclinical and clinical activities. These molecules include modified FGF21 as well as agonistic antibodies against the receptor for FGF21, namely the complex of FGF receptor 1 (FGFR1) and the obligatory coreceptor βKlotho (KLB). In addition, a novel approach to increase endogenous FGF21 activity by inhibiting the FGF21-degrading protease fibroblast activation protein (FAP) is discussed.

show abstract

Section: Metabolic E昀fects In Obese Micementioning

confidence: 99%

Section: Metabolic E昀fects In Obese Micementioning

confidence: 99%

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

Sonoda¹,

Chen²,

Baruch

2017

Hormone Molecular Biology and Clinical Investigation

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“…The PPARG gene encodes Peroxisome proliferator-activated receptor gamma, an adipocyte transcription factor that upregulates FGF21 in white adipose tissue of db/db mice [20,21]. A common allele in KLB is associated with alcohol intake [22] and a common allele in PPARG, Pro12Ala, is associated with type 2 diabetes [23] and fasting insulin [24]. We reasoned that, if the FGF21 allele's effect acted through its interaction with B-Klotho or PPARG, we would see similar patterns of associations between these alleles and human traits as we did for the FGF21 allele.…”

Section: The Minor Allele At Fgf21 Rs838133 Is Associated With Highermentioning

confidence: 99%

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

et al. 2017

Preprint

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word summaryFibroblast Growth Factor 21 (FGF21) is a hormone that induces weight loss in model organisms. These findings have led to trials in humans of FGF21 analogues with some showing weight loss and lipid lowering effects. Recent genetic studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with body fat distribution, with less fat in the lower body, and higher blood pressure, than it is with BMI, where there is only nominal evidence of an effect. These human phenotypes of naturally occurring variation in the FGF21 gene will inform decisions about FGF21's therapeutic potential. IntroductionFGF21 is a hormone secreted primarily by the liver whose multiple functions include signalling to the paraventricular nucleus of the hypothalamus to suppress sugar and alcohol intake [1,2], stimulating insulin-independent glucose uptake by adipocytes [3] and acting as an insulin sensitizer [4]. These features and several other lines of evidence have prompted the development of FGF21 based therapies as potential treatments for obesity and type 2 diabetes, with consistent effects on triglyceride lowering, some effects on weight loss but little effect on glucose tolerance [5,6]. An early trial showed lipid lowering effects in people with type 2 diabetes and obesity but there was only suggestive evidence for effects on weight and glucose tolerance [7]. A recent study suggested that FGF21 analogues may alter not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/214700 doi: bioRxiv preprint first posted online Nov. 6, 2017; blood pressure in humans [8], although changes in blood pressure were not observed in a previous trial [9]. Pre-clinical evidence of FGF21's potential role in metabolism includes resistance to diet induced obesity in mice overexpressing FGF21 [3] and improved glucose tolerance in obese mice through administration of recombinant FGF21 [3]. Subsequent studies have confirmed these findings in mice [10] and shown similar effects in non human primates, including improvement of glucose tolerance and slight weight loss in diabetic rhesus monkeys [11], but other studies are less conclusive [5].Recent studies have shown that FGF21 affects the balance of macronutrients consumed. Studies in mice and non human primates show that genetically and pharmacologically raising FGF21 levels suppresses sugar and alcohol intake [1,2]. Three human genetic studies have shown that the minor A allele at rs838133 (A/G, Minor Allele Frequency=44.7%), which results in a synonymous change to the first exon of FGF21, is associated with higher carbohydrate and lower...

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“…Upon repeated exposures, flies develop tolerance (Scholz et al, 2000) and preference for alcohol consumption (Devineni and Heberlein, 2009; Peru y Colón de Portugal et al, 2014). Many of the genes regulating ethanol responses in Drosophila are conserved in mammals (Grotewiel and Bettinger, 2015), and a number of genes have been shown to affect alcohol responses in both flies and humans (Gonzalez et al, 2017; Ojelade et al, 2015; Schumann et al, 2016). Histone demethylase genes are also conserved between mammals and Drosophila , with the fly’s genome encoding 13 jumonji C domain-containing demethylases (JmjC-KDMs).…”

Section: Introductionmentioning

confidence: 99%

Alcohol‐Induced Behaviors Require a Subset of Drosophila JmjC‐Domain Histone Demethylases in the Nervous System

Pinzón

Reed

Shalaby

et al. 2017

Alcoholism Clin & Exp Res

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Background Long-lasting transcriptional changes underlie a number of adaptations that contribute to alcohol use disorders (AUD). Chromatin remodeling, including histone methylation, can confer distinct, long-lasting transcriptional changes, and histone methylases are known to play a role in the development of addiction. Conversely, little is known about the relevance of Jumonji (JmjC) domain-containing demethylases in AUDs. We systematically surveyed the alcohol-induced phenotypes of null mutations in all 13 Drosophila JmjC genes. Methods We used a collection of JmjC mutants, the majority of which we generated by homologous recombination, and assayed them in the Booze-o-mat to determine their naïve sensitivity to sedation and their tolerance (change in sensitivity upon repeat exposure). Mutants with reproducible phenotypes had their phenotypes rescued with tagged genomic transgenes, and/or phenocopied by nervous system-specific knock down using RNA interference (RNAi). Results Four of the 13 JmjC genes (KDM3, lid, NO66 and HSPBAP1) showed reproducible ethanol-sensitivity phenotypes. Some of the phenotypes were observed across doses, e.g. the enhanced ethanol-sensitivity of KDM3KO and NO66KO, but others were dose-dependent, such as the reduced ethanol sensitivity of HSPBAP1KO, or the enhanced ethanol tolerance of NO66KO. These phenotypes were rescued by their respective genomic transgenes in KDM3KO and NO66KO mutants. While we were unable to rescue lidk mutants, knock down of lid in the nervous system recapitulated the lidk phenotype, as was observed for KDM3KO and NO66KO RNAi-mediated knock down. Conclusion Our study reveals that the Drosophila JmjC-domain histone demethylases Lid, KDM3, NO66, and HSPBAP1 are required for normal ethanol-induced sedation and tolerance. Three of three tested of those four JmjC genes are required in the nervous system for normal alcohol-induced behavioral responses, suggesting that this gene family is an intriguing avenue for future research.

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

Cited by 222 publications

References 29 publications

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

Alcohol‐Induced Behaviors Require a Subset of Drosophila JmjC‐Domain Histone Demethylases in the Nervous System

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