Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure 英文参考文献.docVIP

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Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure 英文参考文献.doc

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Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure 英文参考文献

BileAcidBindingResinImprovesMetabolicControl throughtheInductionofEnergyExpenditure MitsuhiroWatanabe1,6*,KohkichiMorimoto1,SanderM.Houten2,NaoKaneko-Iwasaki1, TaichiSugizaki1,YasushiHorai1,ChikageMataki3,HiroyukiSato4,KarinMurahashi1,EriArita1, KristinaSchoonjans3,TatsuyaSuzuki5,HiroshiItoh1,JohanAuwerx3* 1DepartmentofInternalMedicine,SchoolofMedicine,KeioUniversity,Tokyo,Japan,2LaboratoryGeneticMetabolicDiseases,AcademicMedicalCenter,Amsterdam, TheNetherlands,3EcolePolytechniqueFe′de′raledeLausanne,Lausanne,Switzerland,4DepartmentofBioscience,EhimeUniversityGraduateSchoolofMedicine,Ehime, Japan,5NipponMedicalSchool,Tokyo,Japan,6GraduateSchoolofMediaandGovernance,KeioUniversity,Fujisawa-shi,Kanagawa,Japan Abstract Background:Besideswell-establishedrolesofbileacids(BA)indietarylipidabsorptionandcholesterolhomeostasis,ithas recentlybecomeclearthatBAisalsoabiologicalsignalingmolecule.Wehaveshownthatstrategiesaimedatactivating TGR5byincreasingtheBApoolsizewithBAadministrationmayconstituteasignificanttherapeuticadvancetocombatthe metabolicsyndromeandsuggestthatsuchstrategiesareworthtestinginaclinicalsetting.Bileacidbindingresin(BABR)is knownnotonlytoreduceserumcholesterollevelsbutalsotoimproveglucosetoleranceandinsulinresistanceinanimal modelsandhumans.However,themechanismsbywhichBABRaffectsglucosehomeostasishavenotbeenestablished.We investigatedhowBABRaffectsglycemiccontrolindiet-inducedobesitymodels. MethodsandFindings:WeevaluatedthemetaboliceffectofBABRbyadministratingcolestimidetoanimalmodelsforthe metabolic syndrome. Administrationof BABR increased energy expenditure, translating into significant weightreduction andinsulinsensitization.ThemetaboliceffectsofBABRcoincidewithactivationofcholesterolandBAsynthesisinliverand thermogenesis in brown adipose tissue. Interestingly, these effects of BABR occur despite normal food intake and triglyceride absorption. Administration of BABR and BA had similar effects on BA composition and thermogenesis, suggestingthattheybothare