Disruption of Growth Hormone Receptor Prevents Calorie Restriction from Improving Insulin Action and Longevity 英文参考文献.docVIP

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Disruption of Growth Hormone Receptor Prevents Calorie Restriction from Improving Insulin Action and Longevity 英文参考文献.doc

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Disruption of Growth Hormone Receptor Prevents Calorie Restriction from Improving Insulin Action and Longevity 英文参考文献

DisruptionofGrowthHormoneReceptorPrevents CalorieRestrictionfromImprovingInsulinActionand Longevity MichaelS.Bonkowski1,2,FernandoP.Dominici3,OgeArum1,JulianaS.Rocha1,4,KhalidA.AlRegaiey1,5 ReyhanWestbrook1,AdamSpong1,JacobPanici1,MichalM.Masternak1,JohnJ.Kopchick6 ,Andrzej , Bartke1,2 * 1DepartmentofInternalMedicine–GeriatricsResearch,SouthernIllinoisUniversitySchoolofMedicine,Springfield,Illinois,UnitedStatesofAmerica,2Departmentof Pharmacology, and Physiology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America, 3Instituto de Qu?′mica y Fisicoqu?′mica Biolo′gicas (IQUIFIB), Facultad de Farmacia y Bioqu?′mica, Universidad de Buenos Aires, Buenos Aires, Argentina, 4Department of Morphology, Laboratory of Cellular Biology,InstituteofBiologicalSciences,FederalUniversityofMinasGerais,BeloHorizonte,Brazil,5DepartmentofPhysiology,CollegeofMedicine,KingSaudUniversity, Riyadh,SaudiArabia,6DepartmentofBiomedicalSciences,EdisonBiotechnologyInstitute,OhioUniversity,Athens,Ohio,UnitedStatesofAmerica Abstract Mostmutationsthatdelayagingandprolonglifespaninthemousearerelatedtosomatotropicand/orinsulinsignaling. Calorie restriction (CR) is theonly interventionthat reliably increases mouse longevity. There is considerable phenotypic overlapbetweenlong-livedmutantmiceandnormalmiceonchronicCR.Therefore,weinvestigatedtheinteractiveeffects ofCRandtargeteddisruptionorknockoutofthegrowthhormonereceptor(GHRKO)inmiceonlongevityandtheinsulin signalingcascade.Everyotherdayfeedingcorrespondstoamild(i.e.15%)CRwhichincreasedmedianlifespaninnormal micebutnotinGHRKOmicecorroboratingourpreviousfindingsontheeffectsofmoderate(30%)CRonthelongevityof theseanimals.TodeterminewhyinsulinsensitivityimprovesinnormalbutnotGHRKOmiceinresponseto30%CR,we conducted insulin stimulation experiments after one year of CR. In normal mice, CR increased the insulin stimulated activationoftheinsulinsignalingcascade(IR/IRS/PI3K/AKT)inliverandmuscle.LiversofGHRKOmicerespon