Free Fatty Acids Link Metabolism and Regulation of the Insulin-sensitizing Fibroblast Growth Factor-21

Overview

Journal Diabetes

Specialty Endocrinology

Date 2009 Apr 30

PMID 19401423

Citations 66

Authors

Knut Mai

Janin Andres

Katrin Biedasek

Jessica Weicht

Thomas Bobbert

Markus Sabath

Sabine Meinus

Franziska Reinecke

Matthias Mohlig

Martin O Weickert

Markus Clemenz

Andreas F H Pfeiffer

Ulrich Kintscher

Simone Spuler

Joachim Spranger

Affiliations

Soon will be listed here.

Abstract

Objective: Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator-activator receptor (PPAR) alpha-dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARalpha, might modify FGF-21 levels.

Research Design And Methods: The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARgamma activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks.

Results: Oleate and linoleate increased FGF-21 expression and secretion in a PPARalpha-dependent fashion, as demonstrated by small-interfering RNA-induced PPARalpha knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect.

Conclusions: The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.

Citing Articles

The Impact of Human Liver Transplantation on the Concentration of Fibroblast Growth Factors: FGF19 and FGF21.

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

Maffeis C, Morandi A, Zusi C, Olivieri F, Fornari E, Cavarzere P Diabetes Obes Metab. 2024; 27(2):825-834.

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Signals of energy availability in sleep: consequences of a fat-based metabolism.

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Relationship of postprandial fibroblast growth factor 21 with lipids, inflammation and metabolic dysfunction-associated fatty liver disease during oral fat tolerance test.

Li X, Zheng K, Liu L, Zhang T, Gu W, Hou X Front Endocrinol (Lausanne). 2024; 15:1343853.

PMID: 38828414 PMC: 11140040. DOI: 10.3389/fendo.2024.1343853.

FGF21 alleviates endothelial mitochondrial damage and prevents BBB from disruption after intracranial hemorrhage through a mechanism involving SIRT6.

Wang R, Wang J, Zhang Z, Ma B, Sun S, Gao L Mol Med. 2023; 29(1):165.

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