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

Abstract

SummaryFibroblast growth factor 21 (FGF21) is a hormone that has insulin-sensitizing properties. Some trials of FGF21 analogs show weight loss and lipid-lowering effects. Recent 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, aiming to use the human allele to inform potential adverse and beneficial effects of targeting FGF21. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with higher blood pressure and waist-hip ratio, despite an association with lower total body-fat percentage, than it is with BMI or type 2 diabetes. These human phenotypes of variation in the FGF21 gene will inform research into FGF21’s mechanisms and therapeutic potential.

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

“…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).…”

“…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.…”

“…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).…”

“…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.…”

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