The metabolic regulator FGF-21 is induced by free fatty acids but not by PPARχ stimulation in man: Results of two randomized, controlled trials

Objective: Fibroblast growth factor 21 (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 PPARα-dependent regulator of fasting metabolism, we hypothesized that free fatty acids, natural agonists of PPARα, might modify FGF-21 levels. Furthermore we aimed to evaluate the effect of PPARχ-stimulation on FGF-21 levels.

Research design and methods: HepG2 cells were incubated with different fatty acids. Within a randomized controlled trial a 240min 20% lipid/heparin or a saline/heparin infusion was administered in random order in 21 healthy subjects (13 women and 8 men). Furthermore a subsequent insulin infusion using an euglycemic hyperinsulinemic clamp was performed in a subgroup of 6 men. In addition we studied the effect of a 8 week rosiglitazone treatment in 7 male and 10 female volunteers with impaired glucose tolerance.

Results: Oleate (141.1 vs. 100%; p<0.05), and especially linoleate (209.6 vs. 100%; p<0.05) increased FGF-21 secretion in cell culture while no change was observed during palmitate stimulation. Indeed lipid infusion induced an increase of circulating FGF-21 in-vivo in humans (treatment-vs.-time interaction: p<0.05.; AUC: 1191±91 vs. 1090±86ng/ml*min, p<0.05) and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed (r=0.446, P<0.05). In contrast, a subsequent infusion of insulin did not further modulate the FGF-21 levels in healthy humans. In contrast to these findings during PPARα stimulation by FFAs, the rosiglitazone treatment had no effect on FGF-21 levels in humans.

Conclusions: The here presented results of in-vitro experiments and of two randomized-controlled trial offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation, but also in type 2 diabetes and obesity. Given existing experimental data, our findings offer a potential mechanism linking FFA-induced regulation of FGF-21 to the switch of metabolism during starvation. Although this might be caused by PPARα stimulation by FFAs, a stimulation of PPARχ seems not to modify the FGF-21 levels in humans. Further studies are warranted to clarify, whether this is an adaptive response to counteract the LHI induced metabolic disturbances, which might contribute to the elevated FGF-21 levels seen in type 2 diabetes and obesity.