A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure

Frayling, Timothy M.; Beaumont, Robin N; Jones, Samuel E.; Yaghootkar, Hanieh; Tuke, Marcus A.; Ruth, Katherine S.; Casanova, Francesco; West, Ben C.; Locke, Jonathan M.; Sharp, Seth A.; Ji, Yingjie; Thompson, William E.; Harrison, Jamie; Etheridge, Amy S.; Gallins, Paul J.; Jima, Dereje D.; Wright, Fred A.; Zhou, Yifeng; Innocenti, Federico; Lindgren, Cecilia M.; Grarup, Niels; Murray, Anna; Freathy, Rachel M.; Weedon, Michael N.; Tyrrell, Jessica; Wood, Andrew R.

doi:10.1016/j.celrep.2018.03.070

Cited by 87 publications

(101 citation statements)

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“…Administration of recombinant FGF21 decreased the levels of dopamine and its metabolites in the nucleus accumbens, suggesting that FGF21 acts on the reward system (Talukdar et al 2016). Moreover, a genetic link between alcohol consumption and the FGF21 locus has been demonstrated in human genetic studies (Søberg et al 2017;Frayling et al 2018;Merino et al 2018). It is the same variant that was previously associated with altered macronutrient consumption (rs838133-A) (Chu et al 2013;Tanaka et al 2013).…”

Section: Fgf21 Regulates Alcohol Preferencementioning

confidence: 88%

“…Specifically, two SNPs were associated with higher carbohydrate intake and lower protein and fat intake (rs838133 and rs838145) (Chu et al 2013;Tanaka et al 2013). Several lines of work have since confirmed the association to the same two SNPs in the FGF21 locus (Søberg et al 2017;Frayling et al 2018;Merino et al 2018), and the association has been expanded to include regulation of alcohol (see above). The first reports separated food intake into the three major nutrient classes (protein, fat and carbohydrate), and the newer studies have subdivided them to investigate whether any single component drives the association.…”

Section: Genetics Influences Preference For Sugar and Alcoholmentioning

confidence: 92%

“…the relative proportion of one's diet derived from fat, carbohydrate and protein), it was reported that FGF21, a predominantly liver-derived hormone, suppresses intake of simple sugars and alcohol in mice and consumption of the artificial sweetener saccharin in primates (Talukdar et al 2016;von Holstein-Rathlou et al 2016). Since then, these findings have been replicated and generalized in mice and humans (Evangelou et al 2018;Frayling et al 2018;Meddens et al 2018;Sanchez-Roige et al 2018).…”

Section: Introductionmentioning

confidence: 96%

“…The authors also detected lower physical activity in the cohort, which may itself impact the physiological changes (Frayling et al . ). The described studies show that human genetics might predict our liking of sugar and alcohol, thus suggesting that FGF21 may impact behaviour in humans.…”

Section: Introductionmentioning

confidence: 97%

“…; Frayling et al . ). Genetic associations to higher alcohol consumption in humans with FGF21 have also been found (Schumann et al .…”

Section: Introductionmentioning

confidence: 97%

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Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

Holstein-Rathlou

Gillum

2019

The Journal of Physiology

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Fibroblast growth factor 21 (FGF21) is a liver‐derived hormone with pleiotropic metabolic effects. Its production is induced by various dietary imbalances in mice (including low‐protein and ketogenic diets, fructose feeding and ethanol), hinting that it might influence food preference given the role of the liver in maintaining homeostatic levels of circulating nutrients. In 2016, it was shown that FGF21 selectively inhibits consumption of sugars and the primary product of their fermentation, ethanol, but not intake of fat, protein or complex carbohydrates. Since then, studies have sought to unravel this selectivity, its physiological purpose and translational relevance, as well as delineate the neural mechanisms involved. Initially found to impact ingestive behaviours in mice and non‐human primates, FGF21 is also induced in humans by sugars and, far more dramatically, by acute alcohol intake. Genetic studies have revealed that patterns of weekly candy and alcohol consumption are associated with genetic variants in FGF21 and its co‐receptor β‐klotho (KLB), suggesting that liking for sugar, and fermented sugar, may be influenced by natural variation in FGF21 signal strength in humans. Herein, we discuss our nascent understanding of FGF21 as a selective negative regulator of sugar and alcohol appetite as well as reasons why such a peculiar system may have evolved in mammals. Uncovering the regulatory network governing sugar, and fermented sugar, intake could provide new opportunities to improve dietary choices in a population suffering from Western diet‐induced diseases fuelled in part by a runaway sweet – and alcohol – tooth.

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Section: Fgf21 Regulates Alcohol Preferencementioning

confidence: 88%

Section: Genetics Influences Preference For Sugar and Alcoholmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 97%

“…; Frayling et al . ). Genetic associations to higher alcohol consumption in humans with FGF21 have also been found (Schumann et al .…”

Section: Introductionmentioning

confidence: 97%

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Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

Holstein-Rathlou

Gillum

2019

The Journal of Physiology

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Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus

et al. 2021

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Fibroblast growth factor 21 (FGF21) is a liver‐derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype‐ and context‐dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.

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Fibroblast growth factor 21 is a hepatokine involved in MASLD progression

Gallego‐Durán,

Ampuero,

Maya‐Miles

et al. 2024

UEG Journal

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AimWe aimed to assess the role of FGF21 in metabolic dysfunction‐associated steatotic liver disease (MASLD) at a multi‐scale level.MethodsWe used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte‐derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high‐fat and choline‐deficient diet (CDA‐HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA.ResultsA significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA‐Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A‐allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA‐HFD.ConclusionsHepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA‐HFD animals. The A‐allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.

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A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure

Cited by 87 publications

References 49 publications

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite

Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus

Fibroblast growth factor 21 is a hepatokine involved in MASLD progression

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