Obesityisassociatedwithmanyadversehealtheffects,includinganincreasedriskofdiabetesandheartdisease.Thecombinedconditionofobesity,diabetesandheartdiseaseissometimesreferredtoasthemetabolicsyndrome.Oneofthefactorsthatbestcorrelatesobesitywiththerestofthemetabolicsyndromeisnotoverallbodymass,butthedistributionofADIposetissueintheaBDominalregion,visceralobesity.Glucocorticoidshavebeenassociatedasariskfactorforthemetabolicsyndrome,butmostobeseindividualshavenormallevelsofcirculatingcorticosteroids.Activecorticosteroidssuchascortisolandcorticosteroneactivatetheglucocorticoidreceptor,anuclearhormonereceptorandtranscriptionfactor.Obeseindividualshaveelevatedlevelsinadiposetissueofakeyenzymeinglucocorticoidmetabolism,11betahydroxysteroiddehydrogenasetype1(11betaHSD-1).11betaHSD-1interconvertsinactivecorticosteroidsandtheactiveform.Whenpresentincells,11betaHSD-1canconvertinactivecorticosteroidsfromthebloodtocreatelocallyhighconcentrationsinatissuesuchasadiposetissue.Whenactivatedinadiposetissue,GRincreasesthelevelofvisceralfat,inducesinsulinresistanceanddyslipidemiasthatincreasetheriskofheartdisease.ThemechanismsbywhichGRmightinducethevariousaspectsofthemetabolicsyndromeareakeyareaofresearch.OneofthegenesactivatedbyGRislipoproteinlipase.WhenGRisactivatedinvisceraladiposetissue,itwillincreasetheexpressionoflipoproteinlipase(LPL).Thisenzymehydrolyzestriglyceridesinplasma,releasingfreefattyacidsintotissues,wheretheycanbereassembledintotriglycerides.Invisceraladipose,thisGR-drivenoverexpressionoflipoproteinlipasewillresultintheincreaseddepositsofvisceralfatthatareobserved.Genesthoughttobeinvolvedininsulinresistancealsoappeartobeaffectedbyaltered11betaHSD-1corticosteroidmetabolisminvisceralfat.ThisincludesdownregulationofresistinandadipoQ,andinductionofTNF-alpha.Theelevatedfreefattyacidsandactivecorticosteroidsreleasedfromvisceralfatmayaccountforthemetabolicchangesinliverassociatedwiththemetabolicsyndrome.AntidiabeticthiazoidinedionedrugssuchastroglitazoneandAvandiaactasagoNISTsofanothernuclearreceptor,PPAR-gamma.ThesedrugsactivatePPAR-gammaandrepressexpressionof11betaHSD-1invisceraltissue,perhapsaccountinginpartfortheantidiabeticinsulinsensitizingpropertiesofthesedrugs.

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REFERENCES:Combs,T.P.etal.(2002)Inductionofadipocytecomplement-relatedproteinof30kilodaltonsbyPPARgammaagonists:apotentialmechanismofinsulinsensitization.Endocrinology143(3),998-1007E.Rask,etal.(2001)Tissue-SpecificDysregulationofCortisolMetabolisminHumanObesity.J.Clin.Endocrinol.Metab.86,1418Gura,T.(2001)Obesityresearch.Pot-belliedmicepointtoobesityenzyme.Science294(5549),2071-2MasuzakiH.etal.(2001)Atransgenicmodelofvisceralobesityandthemetabolicsyndrome.Science294(5549),2166-70Y.Kotelevtsev,etal.(1997)11beta-hydroxysteroiddehydrogenasetype1knockoutmiceshowattenuatedglucocorticoid-inducIBLeresponsesandresisthyperglycemiaonobesityorstress.PNASU.S.A.94,14924

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