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

Abstract

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 A recent study suggested that FGF21 analogues may alter not peer-reviewed) is the author/funder.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...

Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis

“…However, while changes in caloric intake can affect body weight and metabolic homeostasis, changes in macronutrient intake alone can affect insulin signaling, cardiometabolic health, and longevity (122). Importantly, an additional study using data from 451,000 individuals in the UK Biobank found that not only is the rs838133 allele associated with higher carbohydrate intake but it is also associated with stronger effects on body fat distribution and higher blood pressure than with effects on body mass (40). Thus, FGF21 may regulate nutrient homeostasis and metabolic health beyond changes in body weight.…”

Evidence of a common causal relationship between body mass index and inflammatory skin disease: a Mendelian Randomization study

“…Sample quality control (QC) measures included removing individuals who were duplicated and highly related (3rd degree or closer), had sex mismatches, as well as those identified to be outliers of heterozygosity and of non-European descent. Further details of the QC measures applied and imputation performed have been described previously [18][19][20][21].…”

“…The standard errors (SE) of these estimates were adjusted using the first term of the delta method expansion for the variance of a ratio, allowing for the uncertainty in the first regression stage to be taken into account [24]. Genetic principal components (as previously described [20][21][22]) were included as covariates in the analysis to control for residual population structure. UK Biobank analysis also controlled for the platform used to genotype the samples.…”

Regulation of glucose homeostasis by FGF21

“…However, while changes in caloric intake can affect body weight and metabolic homeostasis, changes in macronutrient intake alone can affect insulin signaling, cardiometabolic health and longevity [62]. Importantly, an additional study using 451,000 individuals from the UK Biobank found that not only is the rs838133 allele associated with higher carbohydrate intake, but it is also associated with stronger effects on body fat distribution and higher blood pressure than with effects on body mass [63]. Thus, FGF21 may regulate nutrient homeostasis and metabolic health beyond changes in body weight.…”

“…FGF21 also regulates alcohol intake. The FGF21 rs838133 variant associates with increased alcohol intake [63] and the rs11940694 SNP in the β-Klotho (KLB) locus associates with alcohol consumption [76]. Interestingly, administration of recombinant FGF21 [76] or overexpression of FGF21 [71] significantly reduced alcohol preference, but not plasma ethanol concentrations.…”