



A common variant of the gene for the liver hormone fibroblast growth factor 21 (FGF21) genetically predisposes carriers to eat more sugar and consume more alcohol, but it is also, perhaps counterintuitively, associated with lower total body fat, according to the findings of a study headed by researchers at the University of Exeter in the U.K. The scientists’ analysis of genetic, health, and lifestyle data from more than 450,000 individuals also showed that the same FGF21 variant (rs838133, or “A” version) is associated with a particular pattern of fat distribution in the body and higher blood pressure.

The researchers say that the data could offer key insights into the genetic basis of obesity, but could also have implications for the development of new treatments for obesity or type 2 diabetes that target FGF21. “It sort of contradicts common intuition that people who eat more sugar should have less body fat,” comments Niels Grarup, Ph.D., at the Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen in Denmark, who worked alongside the University of Exeter team. “But it is important to remember that we are only studying this specific genetic variation and trying to find connections to the rest of the body. This is just a small piece of the puzzle describing the connection between diet and sugar intake and the risk of obesity and diabetes.”

The University of Exeter researchers and collaborators at the University of Copenhagen, and academic centers in the U.K. and U.S., report on their findings in Cell Reports, in a paper entitled, “A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure.”

Secreted by the liver, FGF21 acts as an insulin sensitizer and also signals to the brain to suppress sugar and alcohol intake. The hormone is the target for potential new treatments for obesity and type 2 diabetes. Human studies have recently suggested that a common variant of the FGF21 gene is also associated with higher carbohydrate intake—specifically sugary products—higher alcohol intake, and lower protein and fat intake, but with no effect on total calories consumed.

The University of Exeter team analyzed data from more than 451,000 individuals in the UK Biobank to further characterize the effects of the FGF21 variant. “We reasoned that genotype-phenotype associations of FGF21 would generate hypotheses for developers of FGF21-based therapies about their potential beneficial and adverse effects,” the researchers write. “Human genotype-phenotype associations will also inform experimental studies of FGF21 function.”

Their results confirmed previous reports that the FGF21 variant was linked with higher carbohydrate, but lower protein and fat intake, and also provided “conclusive evidence” that the same allele increases alcohol intake. The findings also showed an association between the FGF21 variant and lower total body fat percentage. Interestingly, the team points out, “lower levels of body fat are usually associated with a lower waist-hip ratio (WHR), but paradoxically, the FGF21 allele was associated with higher WHR before and after adjusting for BMI [body mass index].” Effectively people had more fat around the waist than at the hips. “… the strongest association, reaching genome-wide levels of statistical confidence, was with lower hip circumference.”

The FGF21 variant was also associated with higher blood pressure, hypertension, and blood pressure medication use, even after adjusting for other factors such as alcohol intake, smoking, and salt consumption, although the effects on blood pressure were very small, just about 0.33 mmHg blood pressure. There was no evidence that the allele was associated with coronary artery disease or type 2 diabetes.

There was also no evidence that the FGF21 allele’s effect on protein, sugar, and carbohydrate consumption directly led to the observed effects on body shape or blood pressure, the researchers point out. “These results suggest that FGF21 has pleiotropic effects, with separate effects on macronutrient intake to those on body shape and blood pressure.”

“We were surprised that the version of the gene associated with eating more sugar is associated with lower body fat,” acknowledges Timothy Frayling, Ph.D., a molecular geneticist at the University of Exeter Medical School in the U.K., who is first author of the team’s published paper. “This goes against the current perception that eating sugar is bad for health. It may reduce body fat because the same allele also results in a lower consumption of protein and fat in the diet. But whilst this version of the gene lowers body fat, it also redistributes fat to the upper body, where it's more likely to cause harm, including higher blood pressure.”

The authors say their findings are important for two primary reasons. First, the genetic association data throw out hypotheses about the potential adverse and beneficial effects of FGF21-based therapies, while second, the associations give researchers advanced knowledge about the range of effects that FGF21 variations can have in the humans. “Our data mean that researchers studying the molecular and therapeutic effects of FGF21 can now hypothesize and study in greater detail a number of potential mechanisms, in both experimental systems and clinical trials.”

“Now that so many people are involved in the study, it gives our conclusions a certain robustness,” Dr. Grarup asserts. “Around 20% of the European population has this genetic predisposition.…Even though the difference in the amount of body fat or blood pressure level is only minor depending on whether or not the person has this genetic variation or not, we are very confident that the results are accurate.”

What the study couldn’t discern is how the variant exerts its effects on phenotypes such as body fat distribution, the researchers note. Also, there is no direct experimental evidence to demonstrate that the variant directly changes FGF21 gene expression or function. However, the team points out, “Although there is no direct evidence for the function of the rs838133 variant (or one in strong linkage disequilibrium), the A allele is very likely to represent lower FGF21 function, because it is very robustly associated with higher sugar and alcohol preference in people, a finding that is completely consistent with the genetic and pharmacological effects of FGF21 lowering in animal models, including non-human primates.”



























