Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Feb;27(2):825-834.
doi: 10.1111/dom.16081. Epub 2024 Nov 29.

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

Claudio Maffeis  1   2 , Anita Morandi  1   2 , Chiara Zusi  1 , Francesca Olivieri  2 , Elena Fornari  2 , Paolo Cavarzere  2 , Claudia Piona  1   2 , Massimiliano Corradi  1 , Federica Emiliani  1 , Alessandro Da Ros  3 , Roberto Berni Canani  4 , Alessandro Mantovani  5 , Giovanni Targher  5   6
Affiliations

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

Claudio Maffeis et al. Diabetes Obes Metab. 2025 Feb.

Abstract

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.

Keywords: insulin resistance; lipid‐lowering therapy; liver; obesity care.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

FIGURE 1
FIGURE 1
Associations of FGF21 with TG, the Matsuda‐index and the GCKR Pro446Leu variant.
FIGURE 2
FIGURE 2
Models predicting FGF21. Grey = univariate associations. Black = Multivariate model. Dashed = not statistically significant. Continuous = statistically significant. (A) The Mendelian randomization highlights that triglycerides are causally associated with FGF21. (B) The Matsuda index is inversely associated with FGF21. The association is slightly attenuated by adjusting for the age confounder and for the BMI confounder. The association between age and FGF21 is attenuated by adjusting for the Matsuda mediator and the association between BMI and FGF21 is attenuated by adjusting for the age confounder and for the Matsuda mediator. (C) The mediation analysis suggests that the association between Matsuda and FGF21 is mediated by the triglycerides.
See this image and copyright information in PMC

References

    1. Prevalence of Obesity|World Obesity Federation . Accessed March 17, 2024. https://www.worldobesity.org/about/about-obesity/prevalence-of-obesity
    1. NCD Risk Factor Collaboration (NCD‐RisC) . Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population representative studies with 222 million children, adolescents, and adults. Lancet. 2024;403:1027‐1050. - PMC - PubMed
    1. Tirosh A, Shai I, Afek A, et al. Adolescent BMI trajectory and risk of diabetes versus coronary disease. Physiol Behav. 2017;176(10):139‐148. - PMC - PubMed
    1. Bjørge T, Engeland A, Tverdal A, Smith GD. Body mass index in adolescence in relation to cause‐specific mortality: a follow‐up of 230,000 Norwegian adolescents. Am J Epidemiol. 2008;168(1):30‐37. - PubMed
    1. Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Looker HC. Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med. 2010;62(6):687‐696. - PMC - PubMed