Diet pattern determines circulating FGF21 levels while distinct FGF21 variants influence diet pattern and FGF21 levels

Abstract

Experimental and genetic studies suggest that FGF21 modulates macronutrient and alcohol preferences. However, FGF21's regulation of human appetite remains elusive. To address this gap in translation, we investigated the relationships between plasma FGF21 levels, FGF21 genetic variation and habitual macronutrient intake in a large human population. We show that the main macronutrient-associated variant rs838133 and the FGF21 cis-pQTL rs838131, both in the FGF21 gene, are distinct genetic signals. Effect directions also suggest that the influence of FGF21 variation on macronutrient intake appear more complex than by direct mediation through plasma FGF21. Only when considering this complexity at FGF21, is plasma FGF21 estimated to reduce alcohol and increase protein and fat intake using mendelian randomization. Importantly, plasma FGF21 levels are also markedly elevated by high alcohol and low protein intake. This supports the diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the FGF21 genetic region.