title: 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.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Yang
authors.forename: Tamer
authors.initials: T
authors.lastname: Coskun
authors.forename: Christine C
authors.initials: CC
authors.lastname: Cheng
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Gimeno
authors.forename: Yongde
authors.initials: Y
authors.lastname: Luo
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
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
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