The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue

Abstract

FGF21 is a multifunctional metabolic regulator. The co-factor βKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.

Keywords: ACADL, Long chain acetyl-CoA dehydrogenase; ACADVL, Very long chain acetyl-CoA dehydrogenase.; Adipose tissue; BAT, Brown adipose tissue; DIO, Diet induced obese; EGR1, Early growth response protein 1; FFA, Free fatty acids; FGF19; FGF19, Fibroblast growth factor 19; FGF21; FGF21, Fibroblast growth factor 21; FGFR, Fibroblast growth factor receptor; FGFR1; KLB, βKlotho; PGC1α, PPARγ coactivator 1α; SCD1, Stearoyl-Coenzyme A desaturase 1; TG, Triglycerides; UCP1, Uncoupling protein 1; WAT, White adipose tissue; βHB, β-HydroxyButyrate.

Figure 1

Panel 1. Immediate early gene (EGR-1) expression was examined in WAT (A) and liver (B) of WT and FR1KO animals following acute FGF21 treatment. Additionally we examined the effects of a single dose of FGF21 on serum glucose (C), insulin (D), triglycerides (E), free fatty acids (F) and adiponectin (G). Panel 2. Following chronic FGF21 treatment we assessed weight loss (H and I), energy expenditure (J and K), glucose (L) and insulin (M) in addition to hepatic TG (N) and FFA (O) levels. Statistical analysis was performed using one-way ANOVA, followed by Dunnett's multiple comparisons test where appropriate. Differences were considered significant when P≤0.05.

Figure 2

Panel 1. Following acute administration of FGF19 we examined EGR-1 in liver (A) and WAT (B). We then measured both serum glucose (C) and insulin (D) in the acute dosing paradigm. Panel 2. Following chronic administration we assessed effects of FGF19 on glucose (E), insulin (F) and body mass (G and H). Statistical analysis was performed using one-way ANOVA, followed by Dunnett's multiple comparisons test where appropriate. Differences were considered significant when P≤0.05.