Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21 - PubMed (original) (raw)

doi: 10.2337/db08-1775. Epub 2009 Apr 28.

Janin Andres, Katrin Biedasek, Jessica Weicht, Thomas Bobbert, Markus Sabath, Sabine Meinus, Franziska Reinecke, Matthias Möhlig, Martin O Weickert, Markus Clemenz, Andreas F H Pfeiffer, Ulrich Kintscher, Simone Spuler, Joachim Spranger

Affiliations

Knut Mai et al. Diabetes. 2009 Jul.

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.

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Figures

FIG. 1.

FIG. 1.

Protein levels of FGF-21 in the supernatant of HepG2 cells after stimulation with palmitate (A), oleate (B), linoleate (C), and an FFA mixture (D) for 1, 2, 4, 8, and 24 h. Results are expressed as means ± SE. *P < 0.05 vs. BSA at the same time point, P = 0.072 for FGF-21 protein levels during linoleate stimulation at 2 h vs. BSA, P = 0.069 for FGF-21 protein levels during linoleate stimulation at 8 h vs. BSA, respectively.

FIG. 2.

FIG. 2.

mRNA Expression of FGF-21 in HepG2 cells after stimulation with linoleate for 1, 2, 4, and 8 h. Results are expressed as means ± SE. *P < 0.05 vs. BSA at the same time point.

FIG. 3.

FIG. 3.

A: Gene expression of FGF-21, CPT1A, and PPARα in HepG2 cells in BSA medium after siRNA knockdown of PPARα compared with control siRNA (100%). Results are expressed as means ± SE. *P < 0.05 vs. expression during control siRNA, respectively. B: FGF-21 mRNA expression in HepG2 cells during linoleate or FFA mixture stimulation after siRNA knockdown of PPARα (compared with control siRNA and BSA stimulation [100%]). Results are expressed as means ± SE. *P < 0.05 vs. expression during control siRNA, respectively. C: Concentration of FGF-21 in the supernatant of HepG2 cells after siRNA knockdown of PPARα and subsequent stimulation by linoleate or FFA mixture compared with control siRNA and BSA medium. Results are expressed as means ± SE. *P < 0.05 vs. control siRNA and BSA medium.

FIG. 4.

FIG. 4.

Concentrations of FFAs (A), triacylglycerols (B), and FGF-21 (C) during SHI (○) and LHI (●). y-Axis in Fig. 2_C_ does not start at 0. Results are expressed as means ± SE. **P < 0.01; *P < 0.05.

FIG. 5.

FIG. 5.

Correlation between changes of FGF-21 and FFAs during LHI and SHI. The saline group (○) and the lipid group (●) were included in the correlation analysis. Correlation after adjustment for sex, age, BMI, and change in insulin levels (r = 0.474, P < 0.005).

FIG. 6.

FIG. 6.

Effect of insulin on FGF-21 levels in subjects with impaired glucose tolerance. Results are expressed as means ± SE.

FIG. 7.

FIG. 7.

Effect of PPARγ stimulation by rosiglitazone treatment on FGF-21 levels in subjects with impaired glucose tolerance. Results are expressed as means ± SE.

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