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

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2025-02, Vol.27 (2), p.825-834
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adolescents; Animal models; Children; Fibroblast growth factors; Glucokinase; insulin resistance; lipid‐lowering therapy; Lipogenesis; Liver; Obesity; obesity care; Original; Teenagers; Triglycerides
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/dom.16081

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