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

Maffeis, Claudio; Morandi, Anita; Zusi, Chiara; Olivieri, Francesca; Fornari, Elena; Cavarzere, Paolo; Piona, Claudia; Corradi, Massimiliano; Emiliani, Federica; Da Ros, Alessandro; Berni Canani, Roberto; Mantovani, Alessandro; Targher, Giovanni

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.

FIBROBLAST growth factors; ADOLESCENT obesity; MENDELIAN randomization; INSULIN resistance; BLOOD lipids

Diabetes, Obesity & Metabolism, 2025, Vol 27, Issue 2, p825

1462-8902

Academic Journal

10.1111/dom.16081