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Review series

Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome
Takashi Kadowaki,1,2 Toshimasa Yamauchi,1,3 Naoto Kubota,1,2,3 Kazuo Hara,1,2 Kohjiro Ueki,1 and Kazuyuki Tobe1
1Department

of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. 2Division of Applied Nutrition, National Institute of Health and Nutrition, Tokyo, Japan. 3Department of Integrated Molecular Science on Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
Theprevalenceofobesityhasincreaseddramaticallyinrecent years(1,2).Itiscommonlyassociatedwithtype2diabetes,coronaryarterydisease,andhypertension,andthecoexistenceofthese diseaseshasbeentermedthemetabolicsyndrome(37).Insulin resistanceisakeyfeatureofthesediseasesandisdefinedasastate thatrequiresmoreinsulintoobtainthebiologicaleffectsachieved byaloweramountofinsulininthenormalstate.Thus,anydefects intheinsulinsignalingcascadecancauseinsulinresistance.Insulinstimulatesasignalingnetworkcomposedofanumberofmolecules,initiatingtheactivationofinsulinreceptortyrosinekinase andphosphorylationoftheinsulinreceptorsubstrate(IRS)proteins(e.g.,IRS-1andIRS-2)(8).Amongseveralcomponentsof thenetwork,thesignalingaxisofIRSproteinsandPI3K,which activatesdownstreamserine/threoninekinasesincludingAkt, regulatesmostofthemetabolicactionsofinsulin,suchassuppressionofhepaticglucoseproductionandactivationofglucose transportinmuscleandadipocytes(9).Itisknownthatthispathwayisimpairedatthemultiplestepsthroughalterationsinthe proteinlevelsandactivitiesofthesignalingmolecules,enzymes, andtranscriptionfactorsininsulinresistancecausedbyobesity,a stateofincreasedadiposity(9). Whiteadiposetissue(WAT)isamajorsiteofenergystorage andisimportantforenergyhomeostasis:itstoresenergyinthe formoftriglyceridesduringnutritionalabundanceandreleases itasFFAsduringnutritionaldeprivation(10,11).WhileWAT providesasurvivaladvantageintimesofstarvation,excessWAT isnowlinkedtoobesity-relatedhealthproblemsinthecurrent nutritionallyrichenvironment.Regulatedbymultiplehormonal signals,nuclearhormonereceptors(12,13),andtheCNS(14),
Nonstandard abbreviations used:AdipoR,adiponectinreceptor;AMPK,AMP-activatedproteinkinase;APPL,adaptorproteincontainingpleckstrinhomologydomain, phosphotyrosine-bindingdomain,andleucinezippermotif;GPCR,Gproteincoupledreceptor;HMW,highmolecularweight;IRS,insulinreceptorsubstrate; LMW, lowmolecularweight;MMW,middlemolecularweight;PR-5,pathogenesisrelated-5; TZD,thiazolidinedione;WAT,whiteadiposetissue. Conflict of interest:Theauthorshavedeclaredthatnoconflictofinterestexists. Citation for this article:J. Clin. Invest.116:17841792(2006).doi:10.1172/JCI29126.
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WAThasbeenincreasinglyrecognizedasanimportantendocrine organthatsecretesanumberofbiologicallyactiveadipokines (1519).Someoftheseadipokineshavebeenshowntodirectlyor indirectlyaffectinsulinsensitivitythroughmodulationofinsulin signalingandthemoleculesinvolvedinglucoseandlipidmetabolism(20).Oftheseadipokines,adiponectinhasrecentlyattracted muchattentionbecauseofitsantidiabeticandantiatherogenic effectsandisexpectedtobeanoveltherapeutictoolfordiabetes andthemetabolicsyndrome(21).Indeed,adecreaseinthecirculatinglevelsofadiponectinbygeneticandenvironmentalfactorshasbeenshowntocontributetothedevelopmentofdiabetes andthemetabolicsyndrome.Thethiazolidinedione(TZD)class ofantidiabeticdrugs,whichalsohavepleiotropiceffectsoncardiovasculardiseasesandlipidmetabolism,isknowntoexertits effectspartlythroughincreasingthelevelsoftheactiveformof adiponectin,asdescribedbelow. InthisReview,wedescriberecentprogressinresearchonthe pathophysiologicalroleofadiponectinandadiponectinreceptors ininsulinresistance,type2diabetes,andthemetabolicsyndrome. SincethelengthofthisReviewislimited,werecommendthatreaders alsoconsultotherrecentreviewsonadiponectinresearch(2123). Association of hypoadiponectinemia with insulin resistance, diabetes, and the metabolic syndrome Adiponectin,alsotermedAcrp30(24),AdipoQ(25),apM1(26),or GBP28(27),wasoriginallyidentifiedindependentlyby4groups usingdifferentapproaches.TheAdiponectin geneencodesasecretedproteinexpressedexclusivelyinbothWATandbrownadipose tissue.Adiponectinhasacarboxyl-terminalglobulardomainand anamino-terminalcollagendomainandisstructurallysimilar tocomplement1q(28,29),whichbelongstoafamilyofproteins thatformcharacteristicmultimers(30,31).Adiponectinexistsina widerangeofmultimercomplexesinplasmaandcombinesviaits collagendomaintocreate3majoroligomericforms:alowmolecularweight(LMW)trimer,amiddlemolecularweight(MMW) hexamer,andhighmolecularweight(HMW)12-to18-meradiponectin(32,33).Incontrasttotheexpressionofadipokinessuch

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Table 1 Physiological and pathophysiological conditions and treatment modalities associated with either decrease or increase in plasma adiponectin levels
Pathophysiological conditions or treatment modality Hypoadiponectinemia is associated with: Genetic variation in Adiponectin gene Obesity Insulin resistance Type 2 diabetes Metabolic syndrome Dyslipidemia Cardiovascular disease Hypertension Sex hormones (androgen, testosterone) Oxidative stress Carbohydrate-rich diet Increase in adiponectin levels is observed following: Administration of: TZDs 58, 79, 104108 Angiotensin II receptor blocker (ARB) 110 Angiotensin-converting enzyme inhibitors (ACEIs) 111 Heart failure 114 Renal failure 115 Weight loss 112, 113 Dietary factors: Soy protein 53 Oils 54, 55 33, 7277 3537 37, 38 37, 3944 45 45 46, 47 48, 49 51, 52 57 56 Ref.

moresensitivetoinsulinthanmales.Somedietaryfactors,such assoyprotein(53),fishoils(54),andlinoleicacid(55),arealso suggestedtoincreaseplasmaadiponectinlevels,whichisconsistentwiththefactthatintakeofthesefactorsisthoughttohave aprotectiveeffectonthedevelopmentofdiabetes.Ontheother hand,acarbohydrate-richdietappearstodecreaseplasmaadiponectinlevel(56).Oxidativestresshasalsobeensuggestedto inhibittheexpressionofadiponectin(57).Althoughthemechanismunderlyingthisregulationisunclear,thismaycontributeto thedecreaseinplasmaadiponectininobesity,whichisassociated withincreasedoxidativestressinadiposetissue.Thus,theplasma adiponectinlevelisaffectedbymultiplefactors,includinggender, aging,andlifestyle. Discovery of the insulin-sensitizing action of adiponectin Theinsulin-sensitizingeffectofadiponectinwasfirstidentified by3independentgroupsin2001(5860).Weassessedwhether adiponectinwasabletoimproveinsulinresistanceinKKAymice (KKmiceoverexpressingtheagoutiprotein),asamodelofthe metabolicsyndromeandtype2diabeteslinkedtoobesity.Plasma adiponectinlevelsweredecreasedinKKAymicefedahigh-fatdiet. Replenishmentofadiponectinsignificantlyamelioratedhigh-fat dietinducedinsulinresistanceandhypertriglyceridemia,which ledustoproposethatadiponectinisaninsulin-sensitizingadipokine(58).Thesedataalsostronglysuggestedthatthehigh-fat dietinduced,obesity-linkeddecreaseinadiponectinleveliscausallyinvolvedinobesity-linkedinsulinresistanceandthemetabolic syndrome.Schererandcolleaguesreportedthatanacuteincrease inthelevelofcirculatingadiponectintriggersatransientdecrease inbasalglucoselevelbyinhibitingboththeexpressionofhepaticgluconeogenicenzymesandtherateofendogenousglucose productioninbothwild-typeandtype2diabeticmice,andthey proposedthatadiponectinsensitizesthebodytoinsulin(59).A truncatedformofadiponectinthatincludestheglobulardomain cleaved proteolytically from full-length adiponectin has been reportedtoexistinplasma,althoughinverysmallamounts(60). Lodishandcolleaguesreportedthataproteolyticcleavageproduct ofadiponectin,whichstructurallyresemblesglobularadiponectin, increasesfatty-acidoxidationinmuscle,decreasesplasmaglucose, andcausesweightlossinmice(60). Subsequently,thechroniceffectsofadiponectinoninsulinresistanceinvivowereinvestigatedbygenerationofadiponectintransgenicmice(61,62)oradiponectin-deficientmice(6366).Globularadiponectintransgenicob/obmiceshowedpartialamelioration ofinsulinresistanceanddiabetes(61).Full-lengthadiponectin transgenicmiceshowedsuppressionofinsulin-mediatedendogenousglucoseproduction(62).Ouradiponectin-deficientmice showedmildinsulinresistancewithglucoseintolerancewhileon astandarddiet(63).Theadiponectin-deficientmiceexaminedby Maedaetal.exhibitedanear-normalinsulinsensitivitywhenfed astandardlaboratorydietbutdevelopedsevereinsulinresistance, especiallyinskeletalmuscle,inasfewas2weeksonahigh-fat, high-sucrosediet(64).Maetal.reportedthatadiponectin-deficientmicedisplayedincreasedfatty-acidoxidationinskeletalmusclebutshowednoeffectoneitherinsulinsensitivityorglucose tolerancewhetheronastandardorahigh-fatdiet(65).Scherers groupreportedthatadiponectin-deficientmiceshowedmildinsulinresistanceintheliverwhileonastandarddiet(66),andtheir phenotypewasverysimilartothoseofouradiponectin-deficient mice.Ontheotherhand,somediscrepanciesinphenotypesthat
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asTNF-andresistin,whichcauseinsulinresistance,adiponectin expressionisreducedinobese,insulin-resistantrodentmodels (25).Plasmaadiponectinlevelsarealsodecreasedinanobeserhesusmonkeymodelthatfrequentlydevelopstype2diabetes(34). Importantly,a decreaseinplasmaadiponectinlevelsprecededthe onsetofdiabetesintheseanimals,inparallelwiththeobservationofdecreasedinsulinsensitivity(34).Plasmaadiponectinlevels havealsobeenreportedtobereducedinobesehumans,particularlythosewithvisceralobesity,andtocorrelateinverselywith insulinresistance(3538) (Table1).Prospectiveandlongitudinal studies(37,3944)haveshownthatloweradiponectinlevelsare associatedwithahigherincidenceofdiabetes.Adiponectin,but notinflammatorymarkerssuchasC-reactiveproteinandIL-6, hasbeenshowntobesignificantlyrelatedtothedevelopmentof type2diabetesinPimaIndians(44).Hypoadiponectinemiahas alsobeendemonstratedtobeindependentlyassociatedwiththe metabolicsyndromeindeed,morestronglythanareanyother inflammatorymarkers(45). Reducedplasmaadiponectinlevels arealsocommonlyobservedinavarietyofstatesfrequentlyassociatedwithinsulinresistance,suchascardiovasculardisease(46, 47)andhypertension(48,49). Howisthelevelofplasmaadiponectinphysiologicallyregulated?Thereisasexualdimorphisminthecirculatinglevelsofadiponectin.Indeed,femalehumansandrodentshavehigherplasma adiponectinlevelsthanmales,suggestingthatsexualhormones regulatetheproductionofadiponectin,althoughitiscontroversialhowthesehormones,suchasestrogenandtestosterone,are involvedintheregulationofplasmaadiponectinlevel(5052). Nevertheless,thismaypartlyaccountforthefactthatfemalesare

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Figure 1
Adiponectin hypothesis for insulin resistance, the metabolic syndrome, and atherosclerosis. Reduced adiponectin levels can be caused by interactions of genetic factors such as SNP 276 in the Adiponectin gene itself and environmental factors, i.e., lifestyle changes that cause obesity, such as a high-fat diet and sedentary lifestyle. This reduction in adiponectin levels in turn appears to play an important causal role in the development of insulin resistance, type 2 diabetes (T2D), and metabolic disease, thereby indirectly causing atherosclerosis. Moreover, reduced adiponectin levels also directly play a causal role in the development of atherosclerosis.

havebeendescribedamongadiponectin-deficientmicearemost likelyduetodifferencesingeneticbackground.Adiponectin-deficientmiceexhibitedotherfeaturesofthemetabolicsyndrome, suchashyperlipidemiaandhypertension(48,63). Withrespecttothemolecularmechanismsunderlyingtheinsulin-sensitizingactionofadiponectin,wefoundthatfull-length adiponectinstimulatedAMP-activatedproteinkinase(AMPK) phosphorylationandactivationintheliver,whileglobularadiponectindidsoinbothskeletalmuscleandtheliver(67).Blocking AMPKactivationbyuseofadominant-negativemutantinhibited theseeffectsoffull-lengthorglobularadiponectin,indicatingthat stimulationofglucoseutilizationandfatty-acidcombustionby adiponectinoccursthroughactivationofAMPK(67).Thus,an adipocyte-derivedantidiabetichormone,adiponectin,activates AMPK,therebydirectlyregulatingglucosemetabolismandinsulinsensitivity(67).Thesedataalsosuggestedthattheremaybe2 distinctreceptorsforadiponectinintheliverandskeletalmuscle, withdifferentbindingaffinitiesforglobularandfull-lengthadiponectin.Lodish,Ruderman,andcolleaguesalsoshowedthatthe adiponectinglobulardomaincouldenhancemusclefatoxidationandglucosetransportviaAMPKactivationandacetyl-CoA carboxylaseinhibition(68).Schereretal.reportedthatinadiponectintransgenicmice(62),reducedexpressionofgluconeogenic enzymessuchasphosphoenolpyruvatecarboxylaseandglucose6-phosphataseisassociatedwithelevatedphosphorylationof hepaticAMPK,whichmayaccountforinhibitionofendogenous glucoseproductionbyadiponectin(59,67,69). Adiponectinalsoincreasedfatty-acidcombustionandenergy consumption,inpart viaPPARactivation,whichledtodecreased triglyceridecontentintheliverandskeletalmuscle,andtherebya coordinatedincreaseofinvivoinsulinsensitivity(61). Adiponectin gene SNPs in human insulin resistance and type 2 diabetes TheAdiponectingeneislocatedonchromosome3q27,whichhas beenreportedtobelinkedtotype2diabetesandthemetabolic syndrome(7072).Therefore,theAdiponectingeneappearstobe apromisingcandidatesusceptibilitygenefortype2diabetes. AmongtheSNPsintheAdiponectingene,1SNPlocated276bp downstreamofthetranslationalstartsite(SNP276)wasconcomitantlyassociatedwithdecreasedplasmaadiponectinlevel,greater insulinresistance,andanincreasedriskoftype2diabetes(73). Thesubjects,bothofwhose2allelesofSNP276aretheG(G/G
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genotype),hadanapproximatelydoubledriskfordevelopingtype 2diabetesascomparedwiththosewiththeT/Tgenotype(73).It isnoteworthythatmorethan40%ofJapaneseindividualshavethe at-riskG/Ggenotype,whichmakessubjectspronetogenetically decreasedadiponectinlevelsandthussusceptibletotype2diabetes(73).SubjectswithanI164Tmissensemutationintheglobular domainofadiponectinhadsignificantlylowerplasmaadiponectin levelsthanthosewithout,independentlyofBMI(74). SimilarassociationsoftheAdiponectin genewithsusceptibility totype2diabeteshavealsobeenreportedinotherethnicgroups. InwhiteGermanandNorthAmericansubjects,SNP276,either independentlyorasahaplotypetogetherwithSNP45inexon2, wasshowntobeassociatedwithobesityandinsulinresistance (75,76).InwhiteFrenchsubjects,2SNPsinthepromoterregion oftheAdiponectin gene,SNP11377andSNP11391,weresignificantlyassociatedwithhypoadiponectinemiaandtype2diabetes (72).Takentogether,thesedatastronglysupportthehypothesis thatadiponectinplaysapivotalroleinthepathogenesisoftype2 diabetes.ArecenthaplotypeanalysisbasedonadenseSNPmap inalargesampleclarifieda2-blocklinkagedisequilibriumstructureoftheAdiponectin gene,thefirstblockincludingthepromoter SNPsandthesecondspanningtheexonsandintrons(77).Itis noteworthythatneitherblockhasmorethan1SNPsignificantly associatedwiththeplasmaadiponectinlevel.Thehaplotypesin thefirstblockwereassociatedwithincreasedadiponectinlevel, whereasthehaplotypesinthesecondblockwereassociatedwith decreasedadiponectinlevel.Thisresultindicatedtheexistenceof atleast2causalhaplotypesorSNPsintheAdiponectingene. Basedonthesignificantbodyofevidencediscussedabove,we haveproposedtheadiponectinhypothesis,inwhichreduced plasmaadiponectinlevelscausedbyinteractionsbetweengenetic factors,suchasSNPsintheAdiponectingeneitself,andenvironmentalfactorscausingobesity,suchasasedentarylifestyle,may playacrucialroleinthedevelopmentofinsulinresistance,type2 diabetes,andthemetabolicsyndrome(21)(Figure1). Role of HMW adiponectin in insulin resistance and type 2 diabetes SeveralobservationssupportthehypothesisthatHMWadiponectinisthemoreactiveformoftheproteinandhas amorerelevant roleininsulinsensitivityandinprotectingagainstdiabetes.First, raremutationsG84RandG90Sinthecollagendomainare closelyassociatedwithtype2diabetes(33,73,78).Subjectswith

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Figure 2
Structure of adiponectin receptors. AdipoR1 and AdipoR2 (66.7% amino acid identity with AdipoR1) are predicted to contain 7 transmembrane domains but are structurally and topologically distinct from GPCRs. Redrawn with permission from Endocrine Reviews (21); copyright 2005, The Endocrine Society.

eitherofthese2mutationshaveextremelylowlevelsofHMWadiponectin(Table1).Moreover,the2mutantadiponectinsrecombinantlyexpressedinNIH-3T3fibroblastswerenotabletoform theHMWformofadiponectin.Second,increasesintheratioof plasmaHMWadiponectinlevelstototaladiponectinlevelscorrelatewithimprovementininsulinsensitivityduringtreatment withaninsulin-sensitizingdrug,TZD,inbothmiceandhuman diabeticpatients,whereasincreasesintotalserumadiponectin levelsdonotshowgoodcorrelationswithimprovementininsulin sensitivityduringtreatmentwithTZDattheindividuallevel(79). Third,thelevelofplasmaHMWadiponectinwasreportedtobe associatedwithparametersrelatedtoglucosehomeostasisina cohortstudy(80).ItisnoteworthythattheratioofplasmaHMW adiponectintototaladiponectincorrelatedmoresignificantly withglucoseandinsulinlevelsthandidthetotaladiponectin level(80),suggestingthatalterationsinplasmaHMWadiponectinlevelmaybemorerelevanttothepredictionofinsulinresistancethanaretotalplasmaadiponectinalterations.Consistent withthis,levelsoftotaladiponectin,HMWadiponectin,LMW adiponectin,andtheHMW-to-totaladiponectinratioallcorrelatedsignificantlywithkeyfeaturesofcentralobesityandthe insulin-stimulatedglucosedisposalrate(81).However,HMWadiponectinlevels,nottotaladiponectinlevels,areprimarilyresponsiblefortheserelationships,suggestingthatmeasurementofthe HMWadiponectinlevelmaybesuperiortomeasurementoftotal adiponectin(81).UsinganELISAsystemforselectivemeasurementofHMWadiponectin(82),wealsofoundHMWadiponectin andtheHMW-to-totaladiponectinratiotohavesignificantlybetterpowerforthepredictionofinsulinresistanceandthemetabolicsyndrome inhumans (83).Thus,HMWadiponectinlevelmay bethesuperiorbiomarkerforinsulinresistance,themetabolic syndrome,andtype2diabetes. Cloning, function, and regulation of adiponectin receptors Inordertofurtherdeterminethepathophysiologicalsignificance andmolecularmechanismofadiponectinaction,weisolated cDNAforadiponectinreceptorsmediatingtheantidiabeticeffects ofadiponectinfromahumanskeletalmusclecDNAlibraryby screeningforglobularadiponectinbinding(84).ThecDNAana

lyzedencodedaproteindesignatedhumanadiponectinreceptor1 (AdipoR1)(84).Thisproteinisstructurallyconservedfromyeast tohumans(especiallyinthe7transmembranedomains).Interestingly,theyeasthomologue(YOL002c)playsakeyroleinmetabolicpathwaysthatregulatelipidmetabolism,suchasfatty-acid oxidation(85).Sinceatthattimetheremayhavebeen2distinct adiponectinreceptors,aswasdescribedabove(67),wesearchedfor ahomologousgeneinthehumanandmousedatabases.Wefound only1genethatwassignificantlyhomologous(67%aminoacid identity)withAdipoR1,whichwastermedAdipoR2(84).AdipoR1 is ubiquitously expressed, including abundant expression in skeletalmuscle,whereasAdipoR2ismostabundantlyexpressed inthemouseliver.AdipoR1andAdipoR2appeartobeintegral membraneproteins;theN-terminusisinternalandtheC-terminusisexternaloppositetothetopologyofallotherreported Gproteincoupledreceptors(GPCRs)(84)(Figure2).ExpressionofAdipoR1andAdipoR2orsuppressionofAdipoR1and AdipoR2expressionsupportsourconclusionthatAdipoR1and AdipoR2serveasreceptorsforglobularandfull-lengthadiponectinandmediateincreasedAMPK,PPARligandactivities,fattyacidoxidation,andglucoseuptakebyadiponectin(Figure3). LodishsgroupreportedthatT-cadherinwascapableofbindingadiponectininC2C12myoblasts;however,T-cadherinwas notexpressedinhepatocytesortheliver(86),themostimportanttargetorgan(66,69,87).Moreover,T-cadherinbyitselfwas thoughttohavenoeffectonadiponectincellularsignalingor function,sinceT-cadheriniswithoutanintracellulardomain. ThesedataraisedthepossibilitythatT-cadherinmaybeoneof theadiponectin-bindingproteins. Most recently, a 2-hybrid study revealed that the C-terminal extracellulardomainofAdipoR1interactedwithadiponectin,whereastheN-terminalcytoplasmicdomainofAdipoR1interactedwith APPL(adaptorproteincontainingpleckstrinhomologydomain, phosphotyrosine-bindingdomain,andleucinezippermotif)(88). Moreover,interactionofAPPLwithAdipoR1inmammaliancells wasstimulatedbyadiponectinbinding,andthisinteractionplayed importantrolesinadiponectinsignalingandadiponectin-mediated downstreameventssuchaslipidoxidationandglucoseuptake.These dataclearlyindicatedthatadiponectinreceptors directlyinteracted withadiponectinandmediatedadiponectineffects.Furthermore,
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Figure 3
Signal transduction by adiponectin receptors. Globular adiponectin exists as a trimer, whereas full-length adiponectin exists as at least 3 species of multimers: an LMW trimer, an MMW hexamer, and an HMW multimer. Suppression of AdipoR1 by RNA interference markedly reduces globular adiponectin binding, whereas suppression of AdipoR2 by RNA interference largely reduces full-length adiponectinspecific binding (21, 84). The dotted line between AdipoR2 and globular adiponectin reflects that AdipoR2 is a relatively low-affinity receptor for globular adiponectin. AdipoR1 and AdipoR2 do not seem to be coupled with G proteins, since overexpression of AdipoR1/R2 has little effect on cAMP, cGMP, and intracellular calcium levels, but instead these receptors activate unique sets of signaling molecules such as PPAR, AMPK, and p38 MAPK. In C2C12 myocytes overexpressing AdipoR1/R2, adiponectin stimulates PPAR, AMPK, and p38 MAPK activation, glucose uptake, and fatty-acid oxidation (84). Suppression of AMPK or PPAR partially reduces adiponectin-stimulated fatty-acid oxidation, and suppression of AMPK or p38 MAPK partially reduces adiponectin-stimulated glucose uptake. In hepatocytes overexpressing AdipoR1/R2, adiponectin stimulates PPAR or AMPK and fattyacid oxidation (84). Suppression of AMPK or PPAR in these hepatocytes partially reduces adiponectin-stimulated fatty-acid oxidation. Moreover, treatment with adiponectin reduces plasma glucose levels and molecules involved in gluconeogenesis in the liver, and dominant-negative AMPK partly reduces these effects. These data support the conclusion that AdipoR1 and AdipoR2 serve as receptors for globular and full-length adiponectin and mediate increased AMPK, PPAR ligand activities, p38 MAPK, and adiponectin-induced biological functions. T-cadherin is capable of binding adiponectin but is thought to have no effect on adiponectin cellular signaling, since T-cadherin lacks an intracellular domain (86). Interaction of APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif 1) with AdipoR1 appears to play important roles in adiponectin signaling and adiponectin-mediated downstream events such as lipid oxidation and glucose uptake (88). S-S, disulfide bond. Adapted with permission from Endocrine Reviews (21); copyright 2005, The Endocrine Society.

thesedatastronglysupportedthattheN-terminusofadiponectin receptorsisinternalandtheC-terminusisexternal(88). TheexpressionlevelsofbothAdipoR1andAdipoR2weresignificantlydecreasedinmuscleandadiposetissueofinsulin-resistant ob/obmice,probablyinpartbecauseofobesity-linkedhyperinsulinemia(89).Moreover,adiponectin-inducedactivationofAMPK wasimpairedintheskeletalmuscleofob/obmice.Thesedatasuggest thatadiponectinresistanceispresentinob/obmice,presumablydue todecreasedexpressionofAdipoR1andAdipoR2(89).Thus,obesity decreases notonlyplasmaadiponectinlevelsbutalsoAdipoR1/R2 expression,therebyreducingadiponectinsensitivityandleadingto insulinresistance,whichinturnaggravateshyperinsulinemia,creatingaviciouscycle(89).Adiponectinreceptorexpressioninthe skeletalmuscleoftype2diabeticpatientshasbeenreportedtobe
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decreased(90).Inaddition,acorrelationhasbeenreportedbetween adiponectinreceptorgeneexpressionandinsulinsensitivityinnondiabeticMexicanAmericanswithorwithoutafamilyhistoryoftype 2diabetes(91).Moreover,AdipoR1mRNAexpressionwaspositively correlatedwithinvivoinsulinandC-peptideconcentrations,firstphaseinsulinsecretion,andplasmatriglycerideandcholesterol concentrationsbeforeandafteradjustmentforsex,age,waist-to-hip ratio,andbodyfat.ExpressionofAdipoR2mRNAwasclearlyassociatedonlywithplasmatriglycerideconcentrations.Inmultivariate linearregressionmodels,mRNAexpressionofAdipoR1,butnot AdipoR2,wasadeterminantoffirst-phaseinsulinsecretionindependentlyofinsulinsensitivityandbodyfat(92).SinceAdipoR1 andAdipoR2areexpressedinpancreaticcells,thesereceptors may playaroleininsulinsecretion(93).

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Figure 4
TZDs ameliorate insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. We propose that there are 2 different pathways in the amelioration of insulin resistance induced by the PPAR agonists TZDs, such as pioglitazone and probably rosiglitazone. One involves an adiponectin-dependent pathway and the other an adiponectin-independent pathway. TZDs increase adiponectin levels, ameliorating insulin resistance, increasing AMPK activation, and decreasing gluconeogenesis in the liver. On the other hand, independently of adiponectin, TZDs decrease adipocyte size, serum FFA levels, and expression of TNF- and resistin, thus contributing to amelioration of insulin resistance in skeletal muscle.

Adiponectin and adiponectin receptors as therapeutic targets Accordingtoouradiponectinhypothesis(21),atherapeuticstrategy forthetreatmentofinsulinresistance,type2diabetes,themetabolic syndrome,andcardiovasculardiseasemayincludetheupregulation ofplasmaadiponectinlevels,theupregulationofadiponectinreceptors,orthedevelopmentofadiponectinreceptoragonists. TZD-mediatedupregulation of plasma adiponectin level. TZDsare knowntoimprovesystemicinsulinsensitivityinanimalmodels ofobesity-linkedinsulinresistanceanddiabetes,byenhancing glucosedisposalinskeletalmuscleandsuppressinggluconeogenesisintheliver.TZDshavebeenwidelyusedastherapeuticagents forthetreatmentoftype2diabetes(9499).TZDshavebeen proposedtoameliorateinsulinresistancebybindingtoandactivatingPPARinadiposetissue,therebypromotingadipocytedifferentiationandincreasingthenumberofsmalladipocytesthat aremoresensitivetoinsulin(100103). Plasmaadiponectinlevels havebeenshowntobeupregulatedbyTZDs(58,79,104108) (Table1),andHMWadiponectinisapredominantformofadiponectinupregulatedbyTZDs(89).TZDsmayupregulateadiponectinbygeneratingsmalladipocytesthatabundantlyexpress andsecreteadiponectin(100,102,109)and/ordirectlyactivating Adiponectingenetranscription(106).TZDsmayalsodirectlyfacilitatethegenerationofHMWadiponectin.Sinceadiponectinisan insulin-sensitizingadipokine,itisreasonabletospeculatethat theactionwherebyTZDsincreaseinsulinsensitivityismediated, atleastinpart,byincreasedplasmaadiponectinlevels.However, whethertheTZD-inducedincreaseinplasmaadiponectinlevel iscausallyinvolvedinTZD-mediatedinsulin-sensitizingeffects hasnotbeenaddressedexperimentally.Adiponectin-deficient (Adipo/)ob/obmicewithaC57BL/6backgroundwereusedto investigatewhetherthePPARagonistpioglitazoneiscapableof amelioratinginsulinresistanceintheabsenceofadiponectin(63, 87).Theabsenceofadiponectinhadnoeffectoneithertheobesi

tyorthediabeticphenotypeofthesemice.Theseverityofinsulin resistanceanddiabetesobservedinob/obmicewassignificantly reduced inassociationwithsignificantupregulationofserum adiponectinlevelsbylow-dose(10mg/kg)pioglitazonetreatment. Ameliorationofinsulinresistanceinob/obmicewasattributedto decreasedglucoseproductionandincreasedAMPKlevelsinthe liver,butnottoincreasedglucoseuptakeinskeletalmuscle.In contrast,theseverityofinsulinresistanceanddiabeteswasnot reduced inAdipo/ob/obmice(87).Withhigh-dosepioglitazone treatment,theinsulinresistanceanddiabetesofob/obmicewere againsignificantlyameliorated;thiswasattributednotonlyto decreasedglucoseproductionintheliverbutalsotoincreased glucoseuptakeinskeletalmuscle.Interestingly,Adipo/ob/ob micealsodisplayedsignificantameliorationofinsulinresistance anddiabetes.TheserumFFAandtriglyceridelevelsaswellasadipocytesizesinob/obandAdipo/ob/obmicewereunchangedafter low-dosepioglitazonetreatmentbutweresignificantlyreduced toasimilardegreeafterhigh-dosepioglitazonetreatment.Moreover,theexpressionofTNF-andresistininadiposetissues ofob/obandAdipo/ob/obmicewereunchangedafterlow-dose pioglitazonebutweredecreasedafterhigh-dosepioglitazone. Althoughbothhighandlowdosesofpioglitazoneameliorated insulinresistanceanddiabetes,theunderlyingmechanismsmay bedifferent(87).Weproposethatthereare2differentpathways intheameliorationofinsulinresistanceinducedbyTZDssuch aspioglitazone,andprobablyrosiglitazone.Oneinvolvesanadiponectin-dependentpathwayandtheotheranadiponectin-independentpathway(Figure4).TZDsincreaseadiponectinlevelsvia activationofAdiponectingenetranscriptionwithoutstimulating adipocytedifferentiation(58,106),therebyincreasingAMPKactivation,decreasinggluconeogenesisintheliver,andameliorating insulinresistanceandtype2diabetes.Ontheotherhand,independentlyofadiponectin,TZDsinduceadipocytedifferentiation, leadingtoanincreaseinthenumberofsmalladipocytes,whichis
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associatedwithdecreasedserumFFAlevelsanddecreasedTNF- andresistinexpression,togethercontributingtoameliorationof insulinresistanceinskeletalmuscle(87). Scherersgroupdemonstratedthatob/obmiceshowedsignificantlyimprovedglucosetoleranceafterrosiglitazonetreatment, whereasAdipo/ob/obmicerespondedonlypartiallytothistreatmentandremainedseverelyglucoseintolerant(66),suggesting thatrosiglitazoneamelioratedglucoseintoleranceviabothadiponectin-dependentand-independentpathways.Moreover,rosiglitazonesignificantlyincreasedAMPKactivityintheliversofwildtypemice,whereasithadnoeffectonAdipo/mice.Inskeletal muscle,AMPKactivitywasalsosignificantlyincreasedinwildtypemice,whilenoincreasewasdetectableinAdipo/mice.These dataareincompleteagreementwithourdata.Otherpharmacologicalagentsaswellaslifestylechangeshavealsobeenreported tobeassociatedwithupregulationofplasmaadiponectinlevels (53,55,110115)(Table1). Upregulation of adiponectin receptors and development of adiponectin receptor agonists.SinceAdipoR1andAdipoR2aredownregulated in obesity-linked insulin resistance and diabetes, both upregulationofAdipoR1andAdipoR2expressionandagonism ofAdipoR1andAdipoR2maybealogicalapproachtoproviding anoveltreatmentmodalityforinsulinresistanceandtype2diabetes(84,89).Previously,Staelssgroupreportedthatadiponectinreceptorsareexpressedinhumanmacrophagesandthatadiponectin receptorexpressionlevelsmayberegulatedbyagonistsof thenuclearreceptorsPPAR,PPAR,andliverXreceptor(116). Wehaverecentlyshownthat,inKKAymice,aPPARagonist reverseddecreasesinAdipoR1andAdipoR2expression,which was lowerinwhiteandbrownadiposetissueofKKAymicethan inthatofwild-typecontrolKKmice(117).Thesedatasuggested thatdualactivationofPPARandPPARenhancedtheactionof adiponectinbyincreasingbothtotalandHMWadiponectinlevel andadiponectinreceptornumber,whichcanameliorateobesitylinkedinsulinresistance. Osmotinisamemberofthepathogenesisrelated-5(PR-5)familyofplantdefenseproteins(24membersinArabidopsis thaliana) thatinduceapoptosisinyeast.Itisubiquitousinfruitsandvegetables,etc.,andthegenesencodingthePR-5proteinsequenced frommanydifferentspeciesareabout5095%identical.PR-5familyproteinsarealsoextremelystableandmayremainactiveeven whenincontactwiththehumandigestiveorrespiratorysystem. Bressansgroupisolatedayeastclonethatexhibitedhypersensitivitytoosmotin,sequencedthecDNAinserts,andfoundthat PHO36/YOL002c,theyeasthomologueofAdipoR1,isareceptorforosmotin(118).X-raycrystallographicstudiesrevealedthat bothglobularadiponectinandosmotinconsistofantiparallel -strandsarrangedintheshapeofa-barrel.DomainI(lectinlike
1.Flier,J.S.2004.Obesitywars:molecularprogressconfrontsanexpandingepidemic.Cell.116:337350. 2.Friedman,J.M.2000.Obesityinthenewmillennium. Nature.404:632634. 3.Reaven,G.M.1998.Roleofinsulinresistancein humandisease.Diabetes.37:15951607. 4.Kaplan,N.M.1989.Thedeadlyquartet.Upper-body obesity,glucoseintolerance,hypertriglyceridemia, andhypertension.Arch. Intern. Med.149:15141520. 5.Matsuzawa,Y.1997.Pathophysiologyandmolecularmechanismsofvisceralfatsyndrome:theJapaneseexperience.Diabetes Metab. Rev.13:313. 6.NationalCholesterolEducationProgram.2001. ExecutiveSummaryoftheThirdReportofthe
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domain)ofosmotinshowedsimilaritytoglobularadiponectinin 3Dstructure,suggestingthatthese2proteinssharethelectinlikedomain(118).Interestingly,osmotinactivatesAMPKviaadiponectinreceptorsinmammalianC2C12myocytes(118).These dataraisethepossibilitythatfurtherresearchexaminingsimilaritiesinadiponectinandosmotinmayfacilitatethedevelopmentofpotentialadiponectinreceptoragonists(118).Although furtherstudieswillbeneededtodeterminethephysiologicaland pathophysiologicalrolesofAdipoR1andAdipoR2,theenhancementormimickingofadiponectinactionthroughmodulation ofexpressionand/orfunctionofAdipoR1andAdipoR2canbea noveltherapeuticstrategyforthetreatmentofinsulinresistance, themetabolicsyndrome,andtype2diabetes. Insummary,adiponectinisanadipokinethatexertsapotentinsulin-sensitizingeffectbybindingtoitsreceptorssuchasAdipoR1 andAdipoR2,leadingtoactivationofAMPK,PPAR,andpresumablysomeotherunknownsignalingpathways.Indeed,circulatinglevelsofadiponectin,especiallyHMWadiponectin,are positivelycorrelatedwithinsulinsensitivityandalteredbyvarious geneticandenvironmentalfactors,pathologicalconditions,and medications.Thus,monitoringthelevelsofHMWadiponectinis agoodpredictablemarkerfortype2diabetesandthemetabolic syndrome.Moreover,methodstoincreaseadiponectinlevels, suchasTZDadministration,areexpectedtobeeffectiveforthe treatmentofthesediseases.Inthefuture,enhancingormimickingadiponectinactionthroughmodulationofexpressionand/or functionoftheadiponectinreceptorsmaybeanovelandpromisingtherapeuticstrategyforinsulinresistance,type2diabetes,and themetabolicsyndrome. Acknowledgments ThisworkwassupportedbytheProgramforPromotionofFundamental Studies in Health Sciences of the Organization for PharmaceuticalSafetyandResearchofJapan,agrantfromthe HumanScienceFoundation(toT.Kadowaki),aGrant-in-Aidfor theDevelopmentofInnovativeTechnologyfromtheMinistry ofEducation,Culture,Sports,Science,andTechnologyofJapan (toT.Kadowaki),aGrant-inAidforCreativeScientificResearch (10NP0201)fromtheJapanSocietyforthePromotionofScience (toT.Kadowaki),andbyHealthScienceResearchGrants(Research onHumanGenomeandGeneTherapy)fromtheMinistryof Health,LabourandWelfareofJapan(toT.Kadowaki). Addresscorrespondenceto:TakashiKadowaki,Departmentof MetabolicDiseases,GraduateSchoolofMedicine,Universityof Tokyo,7-3-1Hongo,Bunkyo-ku,Tokyo113-8655,Japan.Phone: 81-3-5800-8818;Fax:81-3-5800-9797;E-mail:kadowaki-3im@ h.u-tokyo.ac.jp.
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The Journal of Clinical Investigation http://www.jci.org Volume116 Number7 July2006