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

IF 5.4 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes, Obesity & Metabolism Pub Date : 2024-11-29 DOI:10.1111/dom.16081

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

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引用次数: 0

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.

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来源期刊

Diabetes, Obesity & Metabolism 医学-内分泌学与代谢

CiteScore

10.90

自引率

6.90%

发文量

319

审稿时长

3-8 weeks

期刊介绍： Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.