FGF21 Requires βklotho to Act In Vivo 英文参考文献.docVIP

FGF21RequiresbklothotoActInVivo AndrewC.Adams,ChristineC.Cheng,TamerCoskun,AlexeiKharitonenkov* LillyResearchLaboratories,LillyCorporateCenter,Indianapolis,Indiana,UnitedStatesofAmerica Abstract FGF21hasgraduallybecomeafocalpointinmetabolicresearchgivenitsintriguingandcomplexbiologyandrelevanceto drug discovery. Despite the large amount of accumulated data, there remains a dearth of understanding of FGF21 physiologyatthemolecular/wholeorganismlevel.Thescaffoldproteinbklotho(KLB)haspreviouslybeendemonstrated invitrotofunctionasaco-factorpermittingFGF21mediatedFGFreceptoractivation.However,therequirementforKLBin thepropagationofFGF21actioninlivinganimalshasyettobeevaluated.Toanswerthisquestion,wetestedFGF21inmice withtotalbodyablationofKLB(KLBKO)andfoundnodetectableactivity.Firstly,wedemonstratethatthedisruptionofKLB entirelyabrogatesacuteFGF21signalinginadiposetissue.Wegoontoshowthatthissignalingdefecttranslatestothe absence of FGF21 mediated metabolic improvements in DIO mice. Indeed, KLBKO mice are totally refractory to FGF21- induced normalization ofglucose homeostasis, attenuation ofdyslipidemia, elevation of energyexpenditure andweight loss. The lack of FGF21-driven effects was further substantiated at the transcriptional level with no FGF21 target gene signature detectable in adipose tissue and liver of KLBKO animals. Taken together our data show that KLB is a vital componentoftheFGF21invivosignalingmachineryandiscriticallyrequiredforFGF21actionatthewholeorganismlevel. Citation: Adams AC, Cheng CC, Coskun T, Kharitonenkov A (2012) FGF21 Requires bklotho to Act In Vivo. PLoS ONE 7(11): e49977. doi:10.1371/ journal.pone.0049977 Editor:MichaelMu¨ller,WageningenUniversity,TheNetherlands ReceivedAugust30,2012;AcceptedOctober15,2012;PublishedNovember27,2012 Copyright: ? 2012 Adams etal. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,provide