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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