A Mouse Model for the Metabolic Effects of the Human Fat Mass and Obesity Associated FTO Gene 英文参考文献.docVIP

AMouseModelfortheMetabolicEffectsoftheHuman FatMassandObesityAssociatedFTOGene ChrisChurch1,SheenaLee2.,EleanorA.L.Bagg3.,JamesS.McTaggart2.,RobertDeacon4 ,Thomas Gerken3,AngelaLee1,LeeMoir1,JasminMecinovic′3,MohamedM.Quwailid1,ChristopherJ.Schofield3, FrancesM.Ashcroft2,RogerD.Cox1* 1MRC Harwell, Metabolism and Inflammation, Harwell Science and Innovation Campus, Harwell, United Kingdom, 2Henry Wellcome Centre for Gene Function, DepartmentofPhysiology,Anatomy,andGenetics,UniversityofOxford,Oxford,UnitedKingdom, 3ChemistryResearchLaboratoryandOxfordCentreforIntegrative SystemsBiology,UniversityofOxford,Oxford,UnitedKingdom,4DepartmentofExperimentalPsychology,UniversityofOxford,Oxford,UnitedKingdom Abstract HumanFTOgenevariantsareassociatedwithbodymassindexandtype2diabetes.Becausetheobesity-associatedSNPs areintronic,itisunclearwhetherchangesinFTOexpressionorsplicingarethecauseofobesityorifregulatoryelements withinintron1influenceupstreamordownstreamgenes.WetestedtheideathatFTOitselfisinvolvedinobesity.Weshow that a dominant point mutation in the mouse Fto gene results in reduced fat mass, increased energy expenditure, and unchangedphysicalactivity.Exposuretoahigh-fatdietenhancesleanmassandlowersfatmassrelativetocontrolmice. Biochemical studies suggest the mutation occurs in a structurally novel domain and modifies FTO function, possibly by altering its dimerisation state. Gene expression profiling revealed increased expression of some fat and carbohydrate metabolismgenesandanimprovedinflammatoryprofileinwhiteadiposetissueofmutantmice.Thesedataprovidedirect functional evidence that FTO is a causal gene underlying obesity. Compared to the reported mouse FTO knockout, our model more accurately reflects the effect of human FTO variants; we observe a heterozygous as well as homozygous phenotype, asmallerdifference inweightandadiposity, andourmice donotshowperinatal lethalityor anage-related reductioninsizeandlength.Ourmodelsuggeststhatasearchforhumancodingmut