ESPE Abstracts

Background and aim: Fibroblast growth factor 21 (FGF21) is produced and expressed in several tissues but mainly in the liver and adipose tissue, where it has endocrine and paracrine functions. Several experimental studies reported that FGF21 decreases lipogenesis, triggers beta oxidation of fatty acids, reduces hepatic ER stress and VLDL release and reduces fasting and postprandial triacylglycerols (TG). Consistently, several phase 2 trials with FGF21-agonists have already been conducted in adults with very encouraging results on the lipid profile. In contrast, FGF21 has been found positively associated with TG in both adults and children with obesity. In line with some evidence in animals, we hypothesized that also in children with obesity FGF21 be induced by hepatic lipogenesis as a compensatory mechanism and we tested our hypothesis in 159 children/adolescents with obesity (80 males, age 12.69 ± 2.09 years).

Methods: As the Pro446Leu variant at GCKR is known to increase hepatic lipogenesis and circulating triglycerides and has been found associated with FGF21 concentration in adults, we used it as instrumental variable to establish the cause to effect relationship between FGF21 and TG, according to a classical Mendelian Randomization (MR) analysis. FGF21 was measured by Multi Plex Human immunoassay kits for use on Ella instrument ELISA kit (Bio-techne, USA). The genotype of Pro446Leu at GCKR was determined by TaqMan allelic discrimination assay (Applied Biosystems, USA) according to manufacturer’s protocol using QuantStudio TM 5 Real-Time PCR (Applied Biosystems, USA). The associations were assessed by general linear models without inserting co-variates, because the associations between genetic variants and phenotypes are free from confounders.

Results: The 446Leu variant increased TG (β=+0.35, P < 0.001) and FGF21 (β=+0.14, P = 0.031), and TG was associated with FGF21 (β=+0.47, P < 0.001). After adjusting for TG, the association between 446Leu and FGF21 disappeared and only TG was associated with FGF21. The association coefficient between 446Leu and FGF21 before adjusting for TG (+0.14[0.10- 0.90], P = 0.031), was consistent with the expected coefficient based on the hypothesis of complete mediation of TG between 446Leu and FGF21: 0.35 * 0.47 = 0.16.

Conclusion: Hepatic lipogenesis, marked by GCKR-modulated triglycerides, increases the FGF21 concentration in children/adolescents with obesity.