OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP1OMIMUniSTS0*109691LinksBETA3ADRENERGICRECEPTORADRB3Genemaplocus8p12p112TEXTCLONINGEmorineetal(1989)isolatedathirdbetaadrenergicreceptorbeta3adrenergicreceptor(ADRB3)(SeeADRB1(109630)andADRB2(109690))Exposureofeukaryoticcellstransfectedwiththisgenetoadrenalineornoradrenalinepromotedtheaccumulationofadenosine3prime5primemonophosphateThepotencyofbetaARagonistsandinhibitorswasdescribedVanSpronsenetal(1993)demonstratedthatthetranscriptionstartsitesofthemouseandhumanADRB3mRNAarelocatedinaregioncomprisedbetween150and200nucleotides5primefromtheATGtranslationstartcodonMotifspotentiallyimplicatedinheterologousregulationofADRB3expressionbyglucocorticoidsandbybetaadrenergicagonistswereidentifiedupstreamfromthesecapsitesGENESTRUCTUREVanSpronsenetal(1993)describedtheexon/intronstructureofthemouseandhumanADRB3genesTheirresultssuggestedthatutilizationofalternatepromotersand/or3primeuntranslatedregionsmayallowtissuespecificregulationoftheexpressionofADRB3MAPPINGWilkieetal(1993)presentedalistofGproteincoupledreceptorgenes(theirTable3)indicatingthattheADRB3genehadbeenmappedto8p12p112andthehomologousgenetomousechromosome8MOLECULARGENETICSThebeta3adrenergicreceptorlocatedmainlyinadiposetissueisinvolvedintheregulationoflipolysisandthermogenesisThepotentialrelevanceofthisreceptortoobesity(see601665)inhumansledClementetal(1995)toscreenobesepatientsforthemutationintheADRB3genethatresultsinreplacementoftryptophanbyarginineatposition64(W64R1096910001)TheystudiedDNAextractedfromleukocytesof94normalsubjectsand185unrelatedpatientswithmorbidobesityasdefinedbyabodymassindex(BMItheweightinkilogramsdividedbythesquareoftheheightinmeters)greaterthan40ThemutationwasdetectedbyanalysisofRFLPswiththerestrictionenzymeBstNIwhichdiscriminatesbetweenthenormalandmutantsequencesThefrequencyoftheW64Rvariantwassimilarinthemorbidlyobesepatientsandthenormalsubjects008and010respectivelyHoweverpatientswithmorbidobesitywhowereheterozygousfortheallelehadanincreasedcapacitytogainweightthemeanweightinthe14heterozygouspatientswas140kgascomparedwith126kginthe171patientswithoutthemutation(P=003)TherewerenohomozygotesinthissampleThecumulative25yearchangeinweight(fromtheageof20years)was67kginW64Rheterozygotesascomparedwith51kginthosewithoutthemutationThemaximumweightdifferential(themaximallifetimeweightminustheweightat20yearsofage)intheheterozygoteswas74kgascomparedwith59kginthepatientswithoutthemutation(P=002)Clementetal(1995)interpretedthefindingsasindicatingthattheADRB3genemutationW64RincreasesthecapacitytogainweightANIMALMODELTodeterminewhetherthesympatheticnervoussystemistheefferentarmofdietinducedthermogenesisBachmanetal(2002)createdmicethatlackedthebetaadrenergicreceptorsADRB1ADRB2andADRB3BetalessmiceonachowdiethadareducedmetabolicrateandwereslightlyobeseOnahighfatdietbetalessmiceincontrasttowildtypemicedevelopedmassiveobesitythatwasdueentirelytoafailureofdietinducedthermogenesisBachmanetal(2002)concludedthatthebetaadrenergicreceptorsarenecessaryfordietinducedthermogenesisandthatthisefferentpathwayplaysacriticalroleinthebody'sdefenseagainstdietinducedobesity(selectedexamples)0001OBESITYSUSCEPTIBILITYTO[ADRB3TRP64ARG]Usingacandidategeneapproachtostudythegeneticsofobesity(601665)Clementetal(1995)foundevidencesuggestingthatthetrp64toarg(W64R)variantoftheADRB3geneincreasesthecapacitytogainweightGagnonetal(1996)failedtofindanassociationbetweenW64Randobesityinstudiesin2cohortstheQuebecFamilyStudy(QFS)andtheSwedishObeseSubjects(SOS)Walstonetal(1995)foundthatPimaIndianshomozygousfortheW64RADRB3mutationhadanearlieronsetofnoninsulindependentdiabetesmellitus(NIDDM125853)andtendedtohavealowerrestingmetabolicrateTheauthorssuggestedthatthemutationmayacceleratetheonsetofNIDDMbyalteringthebalanceofenergymetabolisminvisceraladiposetissueElbeinetal(1996)testedthehypothesisthatthebeta3adrenergicreceptorlocusaffectsdiabetessusceptibilityobesityasmeasuredbybodymassindex(BMI)andcomponentsoftheinsulin(176730)resistancesyndromebyexaminingADRB3allelesharinginfamiliesascertainedfor2ormoresibswithNIDDMTheyfoundnoevidenceforlinkagetoNIDDMasadichotomoustraitandnoevidenceforlinkagetoBMIwaist/hipratioinsulinlevelsorglucoselevelsasquantitativetraitsortoreportedageofonsetamongNIDDMindividualsTheW64Rmutationpresentin11%ofthepopulationalsodidnotshowlinkageorassociationTheyconcludedthatthebeta3adrenergicreceptorlocusdoesnotplayanimportantroleinNIDDMsusceptibilityorintheinsulinresistancesyndromeamongmembersoffamilieswithastrongpredispositiontoNIDDMKimMotoyamaetal(1997)examinedthefrequencyoftheW64Rvariantin278JapanesemeninrelationtovisceralobesityassessedbycomputerizedtomographyTheyfoundthatthemutationwasmorefrequentinsubjectswithhigherBMIInsubjectswithamoderatedegreeofobesitythemutation(homozygotesandheterozygotes)wasassociatedwithvisceralobesity(higherratioofvisceraltosubcutaneousfatarea)FurthermoretheW64RvariantwasmorefrequentinsubjectswithlowerserumtriglyceridelevelsandhomozygotesbutnotheterozygotesexhibitedlowertriglyceridelevelsKimMotoyamaetal(1997)suggestedthatthemutationmaydescribeasubsetofsubjectscharacterizedbydecreasedlipolysisinvisceraladiposetissueToexaminetheeffectofW64RonbodyweightduringadultlifetheADRB3genotypesof186unselectedJapanesemenmostofwhomhadrecordsofbodyweightmeasuredyearlyfrom25to53yearsofageweredeterminedbyNagaseetal(1997)Ofthesesubjects26werediagnosedashavingnoninsulindependentdiabetesmellitus(NIDDM)and41ashavingimpairedglucosetoleranceTheresultssuggestedthatADRB3isnotamajorcontributingfactortoobesityorNIDDMinJapanesemenBuettneretal(1998)examinedtheprevalenceofthe2ADRB3allelesinGermanyandlookedforassociationsbetweentheADRB3genotypeandobesityandNIDDMThefrequenciesofthedifferentgenotypesintheexaminedcohortwereasfollowstrp64/trp64883%trp64/arg64108%andarg64/arg6408%TheauthorsfoundnosignificantdifferencesbetweenthedifferentgenotypeswhencomparingageBMIweighttotalandhighdensitylipoproteincholesterolfastinginsulinHbA1candbloodpressureTheyconcludedthattheNIDDMphenotypedidnotdiffersignificantlybetweenthedifferentgenotypegroupsintermsofageofdiabetesonsetorHbA1cUsinghyperinsulinemic/euglycemicclampmethodologyGarciaRubietal(1998)measuredinsulinsensitivityin13obesewomenheterozygousfortheW64RADRB3variantandin14womenhomozygousforthenormalgeneExogenousglucoseinfusionduringtheclampwassignificantlylower(P=003)inW64Rheterozygotes(241+/135mg/min)comparedwithnormalhomozygotes(379+/172mg/min)TheyconcludedthatobesepostmenopausalwomenwhoareheterozygousfortheW64RvarianthavegreaterinsulinresistancethanwomenhomozygousforthenormalgenematchedforagebodycompositionandphysicalactivityMitchelletal(1998)detectedaneffectoftheW64RvariantonobesityinaMexicanAmericanpopulationTheyhadpreviouslyidentifiedamajorquantitativetraitlocus(QTL)influencingtheserumconcentrationsofleptinon2pinaMexicanAmericanpopulationinsouthTexas(Comuzzieetal1997)Theystudied45sibpairswhowereconcordant(identicalbydescent)forthislocusonchromosome2whichhadbeenshownpreviouslytobetightlylinkedtoobesityinthispopulationTheW64RvariantdetectedbyPCRRFLPanalysiswaspresentin1sibwithineachofthe45sibpairsPresenceofthevariantwasassociatedwithasignificantlyhighervaluesinbodymassindexfatmassandwaistcircumferenceThepairedsibdesignenhancedtheirabilitytodetecttheeffectsofthisvariantbyallowingthemtoaccountforvariationattributabletoanotherobesitysusceptibilitylocusandtobackgroundgenesSinceADRB3playsasignificantroleinthecontroloflipolysisandthermogenesisinbrownadiposetissuethroughautonomicnervoussystem(ANS)activityShiharaetal(1999)investigatedtheassociationoftheW64RpolymorphismwithANSactivitySubjectswiththepolymorphismdidnotdifferfromsubjectswithoutitinBMIplasmaglucoseplasmainsulinorfamilyhistoryofdiabetesorobesityThetotalpowerofheterozygotesatsupinerestwaslowerthanthatofnormalsubjects(11246+/1916vs30298+/7588ms2mean+/SE)Withaposturalchangetostandingtheparasympatheticandsympatheticnervoussystemactivityindexesofheterozygotesshowedahigherresponsethanthoseofnormalsubjects(parasympatheticnervoussystemindex010+/002vs017+/002sympatheticnervoussystemindex1055+/147vs626+/109)andthedifferenceintotalpowerdisappearedTheauthorsconcludedthatsubjectswiththepolymorphismevenheterozygoteshadlowerrestingANSactivitythandidnormalsubjectsHoffstedtetal(1999)studied208healthySwedishsubjectsTwentytwopercentofthosewithahighBMI(definedasgreaterthan31kg/m(2))carriedtheW64RADRB3variantcomparedwith11%ofthosewhohadalowerBMIFurthermoreBMIwasapproximately2kg/m(2)higherinargcarrierscomparedwithsubjectswhoweretrphomozygousinthelowerBMIgroupNoassociationoftheW64RhaplotypewithmetabolicparametersorbloodpressurewasidentifiedWhencomparingsensitivityforCPG12177aselectivebeta3receptoragonistHoffstedtetal(1999)observeda10folddecreaseinbeta3argcomparedwithbeta3trpsubjectsFestaetal(1999)studiedtherelationshipbetweenADRB3genotypeandglucosetoleranceduringpregnancyastateofphysiologicinsulinresistanceThefrequencyoftheW64Rallelewas915%in179pregnantwomenIn70womenwithmildgestationaldiabetesasdefinedby60minutepostloadglucosevaluestheW64Rgenotypewasmorefrequentthanin109womenwithnormalglucosetolerance(26%vs11%Pof001)FurthermoretheW64Rgenotypewasassociatedwithincreasedweightgainduringpregnancy(baselinetogestationalweeks20to31)andincreasedpostloadglucoseinsulinandCpeptidevaluesduringtheoralglucosetolerancetestThisapparentassociationwithmildgestationaldiabetessuggestedtotheauthorsthattheimpactofthepolymorphismmaybeclinicallyimportantduringpregnancyThestudyofUrhammeretal(2000)failedtodemonstrateanadditiveorsynergisticeffectoftheW64RvariantoftheADRB3geneandthe3826AGvariantoftheUCP1gene(1137300001)onthedevelopmentofobesityandinsulinresistanceamongrandomlyrecruitedDanishCaucasiansubjectsWalstonetal(2000)foundthatarg64/arg64homozygotessecretesignificantlylessinsulininresponsetoaglucoseinfusionhavehigherfastingglucoselevelsandhavelowerglucoseeffectivenesscomparedwithtrp64/trp64homozygotesTheyconcludedthattheirdatamayhelpexplaintheearlieronsetoftype2diabetesmellitus(NIDDM)observedinseveralpopulationsofindividualswiththearg64ADRB3variantalleleWangetal(2004)evaluatedwhethertheW64RpolymorphismintheADRB3geneisassociatedwithdecreasedbirthweightandmightaccountforsomeoftheassociationbetweenbirthweightandimpairedinsulinsensitivityFrequencyoftheW64Rallelewassimilaringroupsofneonatesclassifiedasappropriateforgestationalage(AGA)andsmallforgestationalage(SGA)(015and017respectively)MoreoverafteradjustmentforsexandgestationalagetherewasnosignificantdifferenceinbirthweightfastingglucoseinsulinlevelsorinsulintoglucoseratiobetweenthosewithandwithoutthemutationHoweverintheSGAgroupcarriersoftheW64RallelehadsignificantlyhigherfastinginsulinlevelsandinsulintoglucoseratiosthannoncarrierswhereasnoassociationwasdetectedforthispolymorphismintheAGAgroupREFERENCES1BachmanESDhillonHZhangCYCintiSBiancoACKobilkaBKLowellBBBetaARsignalingrequiredfordietinducedthermogenesisandobesityresistanceScience2978438452002PubMedID121616552BuettnerRSchafflerAArndtHRoglerGNusserJZietzBEngerIHuglSCukAScholmerichJPalitzschKDThetrp64argpolymorphismofthebeta3adrenergicreceptorgeneisnotassociatedwithobesityortype2diabetesmellitusinalargepopulationbasedCaucasiancohortJClinEndocrMetab83289228971998PubMedID97099653ClementKVaisseCManningBSJBasdevantAGuyGrandBRuizJSilverKDShuldinerARFroguelPStrosbergADGeneticvariationinthebeta3adrenergicreceptorandanincreasedcapacitytogainweightinpatientswithmorbidobesityNewEngJMed3333523541995PubMedID76097524ComuzzieAGHixsonJEAlmasyLMitchellBDMahaneyMCDyerTDSternMPMacCluerJWBlangeroJAmajorquantitativetraitlocusdeterminingserumleptinlevelsandfatmassislocatedonhumanchromosome2NatureGenet152732761997PubMedID90549405ElbeinSCHoffmanMBarrettKWegnerKMilesCBachmanKBerkowitzDShuldinerARLeppertMFHasstedtSRoleofthebeta3adrenergicreceptorlocusinobesityandnoninsulindependentdiabetesamongmembersofCaucasianfamilieswithadiabeticsiblingpairJClinEndocrMetab81442244271996PubMedID89540536EmorineLJMarulloSBriendSutrenMMPateyGTateKDelavierKlutchkoCStrosbergADMolecularcharacterizationofthehumanbeta3adrenergicreceptorScience245111811211989PubMedID25704617FestaAKruglugerWShnawaNHopmeierPHaffnerSMSchernthanerGTrp64Argpolymorphismofthebeta3adrenergicreceptorgeneinpregnancyassociationwithmildgestationaldiabetesmellitusJClinEndocrMetab84169516991999PubMedID103234028GagnonJMauriegePRoySSjostromDChagnonYCDionneFTOppertJMPerusseLSjostromLBouchardCThetrp64argmutationofthebeta3adrenergicreceptorgenehasnoeffectonobesityphenotypesintheQuebecFamilyStudyandSwedishObeseSubjectscohortsJClinInvest98208620931996PubMedID89033289GarciaRubiEStarlingRDTchernofAMatthewsDEWalstonJDShuldinerARSilverKPoehlmanETCallesEscandonJTrp64Argvariantofthebeta3adrenoceptorandinsulinresistanceinobesepostmenopausalwomenJClinEndocrMetab83400240051998PubMedID981448310HoffstedtJPoirierOThorneALonnqvistFHerrmannSMCambienFArnerPPolymorphismofthehumanbeta3adrenoceptorgeneformsawellconservedhaplotypethatisassociatedwithmoderateobesityandalteredreceptorfunctionDiabetes482032051999PubMedID989224411KimMotoyamaHYasudaKYamaguchiTYamadaNKatakuraTShuldinerARAkanumaYOhashiYYazakiYKadowakiTAmutationofthebeta3adrenergicreceptorisassociatedwithvisceralobesitybutdecreasedserumtriglycerideDiabetologia404694721997PubMedID911202512MitchellBDBlangeroJComuzzieAGAlmasyLAShuldinerARSilverKSternMPMacCluerJWHixsonJEApairedsiblinganalysisofthebeta3adrenergicreceptorandobesityinMexicanAmericansJClinInvest1015845871998PubMedID944969113NagaseTAokiAYamamotoMYasudaHKadoSNishikawaMKugaiNAkatsuTNagataNLackofassociationbetweenthetrp64argmutationinthebeta3adrenergicreceptorgeneandobesityinJapanesemenalongitudinalanalysisJClinEndocrMetab82128412871997PubMedID910060814ShiharaNYasudaKMoritaniTUeHAdachiTTanakaHTsudaKSeinoYTheassociationbetweenTrp64Argpolymorphismofthebeta3adrenergicreceptorandautonomicnervoussystemactivityJClinEndocrMetab84162316271999PubMedID1032339015UrhammerSAHansenTBorchJohnsenKPedersenOStudiesofthesynergisticeffectofthetrp/arg64polymorphismofthebeta3adrenergicreceptorgeneandthe3826AGvariantoftheuncouplingprotein1geneonfeaturesofobesityandinsulinresistanceinapopulationbasedsampleof379youngDanishsubjectsJClinEndocrMetab85315131542000PubMedID1099980116VanSpronsenANahmiasCKriefSBriendSutrenMMStrosbergADEmorineLJThepromoterandintron/exonstructureofthehumanandmousebeta3adrenergicreceptorgenesEuropJBiochem213111711241993PubMedID838929317WalstonJSilverKBogardusCKnowlerWCCeliFSAustinSManningBStrosbergADSternMPRabenNSorkinJDRothJShuldinerARTimeofonsetofnoninsulindependentdiabetesmellitusandgeneticvariationinthebeta3adrenergicreceptorgeneNewEngJMed3333433471995PubMedID760975018WalstonJSilverKHilfikerHAndersenRESeibertMBeamerBRothJPoehlmanEShuldinerARInsulinresponsetoglucoseislowerinindividualshomozygousforthearg64variantofthebeta3andrenergicreceptorJClinEndocrMetab85401940222000PubMedID1109542619WangXCuiYTongXYeHLiSEffectsofthetrp64argpolymorphisminthebeta3adrenergicreceptorgeneoninsulinsensitivityinsmallforgestationalageneonatesJClinEndocrMetab89498149852004PubMedID1547219420WilkieTMChenYGilbertDJMooreKJYuLSimonMICopelandNGJenkinsNAIdentificationchromosomallocationandgenomeorganizationofmammalianGproteincoupledreceptorsGenomics181751841993PubMedID8288218CONTRIBUTORSJohnAPhillipsIIIupdated10/26/2005AdaHamoshupdated8/7/2002JohnAPhillipsIIIupdated8/9/2001JohnAPhillipsIIIupdated3/16/2001JohnAPhillipsIIIupdated3/20/2000AdaHamoshupdated5/18/1999JohnAPhillipsIIIupdated3/19/1999JohnAPhillipsIIIupdated3/3/1999VictorAMcKusickupdated3/31/1998VictorAMcKusickupdated3/25/1998VictorAMcKusickupdated8/7/1997JohnAPhillipsIIIupdated4/17/1997JohnAPhillipsIIIupdated12/20/1996CREATIONDATEVictorAMcKusick12/14/1993EDITHISTORYalopez10/26/2005carol6/1/2005alopez8/8/2002terry8/7/2002alopez8/9/2001alopez3/16/2001mgross4/12/2000terry3/20/2000alopez5/25/1999terry5/18/1999mgross3/23/1999mgross3/19/1999mgross3/11/1999mgross3/3/1999dkim12/11/1998psherman3/31/1998terry3/26/1998alopez3/25/1998terry3/20/1998terry8/11/1997terry8/7/1997terry8/7/1997alopez7/30/1997alopez7/30/1997alopez7/9/1997jenny5/21/1997jenny5/21/1997jenny5/21/1997jenny5/21/1997jenny12/12/1996terry12/6/1996mark2/22/1996terry2/19/1996mark9/7/1995carol12/14/1993Copyright©19662007JohnsHopkinsUniversityDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardDisclaimerWritetotheHelpDeskPrivacyPolicyNCBINLMNIH