Early Metabolic Defects in Dexamethasone-Exposed and Undernourished Intrauterine Growth Restricted Rats 英文参考文献.docVIP

EarlyMetabolicDefectsinDexamethasone-Exposedand UndernourishedIntrauterineGrowthRestrictedRats EmmanuelSomm1*,DelphineM.Vauthay1,AudreyGue′rardel1,AudreyToulotte1,PhilippeCettour- Rose1,PhilippeKlee1,PaoloMeda2,MichelL.Aubert1,PetraS.Hu¨ppi1,Vale′rieM.Schwitzgebel1 1DepartmentofPaediatrics,UniversityofGenevaSchoolofMedicine,Geneva,Switzerland,2DepartmentofCellPhysiologyandMetabolism,UniversityofGenevaSchool ofMedicine,Geneva,Switzerland Abstract Poorfetalgrowth,alsoknownasintrauterinegrowthrestriction(IUGR),isaworldwidehealthconcern.IUGRiscommonly associated with both an increased risk in perinatal mortality and a higher prevalence of developing chronic metabolic diseaseslaterinlife.Obesity,type2diabetesormetabolicsyndromecouldresultfromnoxious‘‘metabolicprogramming.’’ In order to betterunderstand early alterations involved in metabolic programming, we modeled IUGR rat pups through eitherprenatalexposuretosyntheticglucocorticoid(damsinfusedwithdexamethasone100mg/kg/day,DEX)orprenatal undernutrition (dams feeding restricted to 30% of ad libitum intake, UN). Physiological (glucose and insulin tolerance), morphometric(automatedtissueimageanalysis)andtranscriptomic(quantitativePCR)approacheswerecombinedduring early life of these IUGR pups with a special focus on their endocrine pancreas and adipose tissue development. In the absence of catch-up growth before weaning, DEX and UN IUGR pups both presented basal hyperglycaemia, decreased glucose tolerance, and pancreatic islet atrophy. Other early metabolic defects were model-specific: DEX pups presented decreased insulin sensitivity whereas UN pups exhibited lowered glucose-induced insulin secretion and more marked alterationsingeneexpressionofpancreaticisletandadiposetissuedevelopmentregulators.Inconclusion,theseresults showthatbeforeanycatch-upgrowth,IUGRratspresentearlyphysiologic,morphologicandtranscriptomicdefects,which canbeconsideredasinitialmechanisticbasisofmetabolicprogramming. Citation:SommE,VauthayDM,Gue′rard