Hepatic lipogenesis marked by GCKR‐modulated triglycerides increases serum FGF21 in children/teens with obesity

Aims: Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase-2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of paradox. We tested the hypothesis that FGF21 is induced by TG in youth with obesity, as a compensatory mechanism. Materials and Methods: We recruited 159 children/adolescents with obesity (80 males, 12.7 ± 2.1 years). Besides serum FGF21 and lipid dosages, we genotyped the Pro446Leu variant at glucokinase regulator (GCKR) as a known marker of genetically increased hepatic de novo lipogenesis, and we used it as an instrumental variable to establish a cause-and-effect relationship between FGF21 and TG, according to a Mendelian randomization analysis. Results: The Pro446Leu variant increased circulating TG (β = +0.35, p < 0.001), which was positively associated with circulating FGF21 (β = +0.42, p < 0.001). The Pro446Leu variant increased FGF-21 (β = +0.14, p = 0.031) with the expected slope (β-coefficient) in case of association entirely mediated by TG: 0.35 (slope between Pro446Ala and TG) × 0.42 (slope between TG and FGF21) = 0.14. Conclusions: Hepatic lipogenesis, marked by GCKR-modulated triglycerides, is significantly associated with increased serum FGF-21 in children/adolescents with obesity.