ARTICLENATURECOMMUNICATIONS|DOI:10.1038/ncomms7618 8.Challis,B.G.etal.Micelackingpro-opiomelanocortinaresensitivetohigh-38.Mirshamsi,S.etal.Leptinandinsulinstimulationofsignallingpathwaysin fatfeedingbutrespondnormallytotheacuteanorecticeffectsofpeptide-arcuatenucleusneurones:PI3KdependentactinreorganizationandKATP YY(3-36).Proc.NatlAcad.Sci.USA101,4695–4700(2004).channelactivation.BMCNeurosci.5,54(2004). 9.Huszar,D.etal.Targeteddisruptionofthemelanocortin-4receptorresultsin39.Smith,M.A.etal.Melanocortinsandagouti-relatedproteinmodulatethe obesityinmice.Cell88,131–141(1997).excitabilityoftwoarcuatenucleusneuronpopulationsbyalterationofresting 10.Butler,A.A.etal.Auniquemetabolicsyndromecausesobesityinthepotassiumconductances.J.Physiol.578,425–438(2007). melanocortin-3receptor-de?cientmouse.Endocrinology141,3518–352140.Pennock,R.L.&Hentges,S.T.Differentialexpressionandsensitivityof (2000).presynapticandpostsynapticopioidreceptorsregulatinghypothalamic 11.Krude,H.etal.Severeearly-onsetobesity,adrenalinsuf?ciencyandredhairproopiomelanocortinneurons.J.Neurosci.31,281–288(2011). pigmentationcausedbyPOMCmutationsinhumans.Nat.Genet.19,155–15741.Yee,C.L.,Wang,Y.,Anderson,S.,Ekker,M.&Rubenstein,J.L.Arcuate (1998).nucleusexpressionofNKX2.1andDLXandlineagesexpressingthese 12.Jackson,R.S.etal.ObesityandimpairedprohormoneprocessingassociatedtranscriptionfactorsinneuropeptideY(t),proopiomelanocortin(t),and withmutationsinthehumanprohormoneconvertase1gene.Nat.Genet.16,tyrosinehydroxylase(t)neuronsinneonatalandadultmice.J.Comp.Neurol. 303–306(1997).517,37–50(2009). 13.Yeo,G.S.etal.AframeshiftmutationinMC4Rassociatedwithdominantly42.Hentges,S.T.,Otero-Corchon,V.,Pennock,R.L.,King,C.M.&Low,M.J. inheritedhumanobesity.Nat.Genet.20,111–112(1998).ProopiomelanocortinexpressioninbothGABAandglutamateneurons.J. 14.Vaisse,C.,Clement,K.,Guy-Grand,B.&Froguel,P.AframeshiftmutationinNeurosci.29,13684–13690(2009). humanMC4Risassociatedwithadominantformofobesity.Nat.Genet.20,43.Collin,M.etal.Plasmamembraneandvesicularglutamatetransporter 113–114(1998).mRNAs/proteinsinhypothalamicneuronsthatregulatebodyweight.Eur.J. 15.Qiu,J.,Fang,Y.,Ronnekleiv,O.K.&Kelly,M.J.LeptinexcitesNeurosci.18,1265–1278(2003). proopiomelanocortinneuronsviaactivationofTRPCchannels.J.Neurosci.30,44.Bodnar,R.J.Endogenousopioidsandfeedingbehavior:a30-yearhistorical 1560–1565(2010).perspective.Peptides25,697–725(2004). 16.Plum,L.etal.EnhancedPIP3signalinginPOMCneuronscausesKATP45.Glass,M.J.,Billington,C.J.&Levine,A.S.Opioidsandfoodintake:distributed channelactivationandleadstodiet-sensitiveobesity.J.Clin.Invest.116,functionalneuralpathways?Neuropeptides33,360–368(1999). 1886–1901(2006).46.Kalra,S.P.&Horvath,T.L.Neuroendocrineinteractionsbetweengalanin, 17.Hill,J.W.etal.AcuteeffectsofleptinrequirePI3Ksignalinginhypothalamicopioids,andneuropeptideYinthecontrolofreproductionandappetite.Ann. proopiomelanocortinneuronsinmice.J.Clin.Invest.118,1796–1805(2008).N.Y.Acad.Sci.863,236–240(1998). 18.Al-Qassab,H.etal.Dominantroleofthep110betaisoformofPI3Kover47.Aponte,Y.,Atasoy,D.&Sternson,S.M.AGRPneuronsaresuf?cientto p110alphainenergyhomeostasisregulationbyPOMCandAgRPneurons.Cellorchestratefeedingbehaviorrapidlyandwithouttraining.Nat.Neurosci.14, Metab.10,343–354(2009).351–355(2011). 19.Ernst,M.B.etal.EnhancedStat3activationinPOMCneuronsprovokes48.Williams,K.W.etal.Segregationofacuteleptinandinsulineffectsindistinct negativefeedbackinhibitionofleptinandinsulinsignalinginobesity.populationsofarcuateproopiomelanocortinneurons.J.Neurosci.30, J.Neurosci.29,11582–11593(2009).2472–2479(2010). 20.Reed,A.S.etal.Functionalroleofsuppressorofcytokinesignaling349.Xu,A.W.,Ste-Marie,L.,Kaelin,C.B.&Barsh,G.S.Inactivationofsignal upregulationinhypothalamicleptinresistanceandlong-termenergytransducerandactivatoroftranscription3inproopiomelanocortin(Pomc) homeostasis.Diabetes59,894–906(2010).neuronscausesdecreasedpomcexpression,mildobesity,anddefectsin 21.Bates,S.H.etal.STAT3signallingisrequiredforleptinregulationofenergycompensatoryrefeeding.Endocrinology148,72–80(2007). balancebutnotreproduction.Nature421,856–859(2003).50.Strubing,C.,Krapivinsky,G.,Krapivinsky,L.&Clapham,D.E.TRPC1and 22.Minokoshi,Y.etal.AMP-kinaseregulatesfoodintakebyrespondingtoTRPC5formanovelcationchannelinmammalianbrain.Neuron29,645–655 hormonalandnutrientsignalsinthehypothalamus.Nature428,569–574(2001). (2004).51.Lin,S.,Thomas,T.C.,Storlien,L.H.&Huang,X.F.Developmentofhighfat 23.Dagon,Y.etal.p70S6kinasephosphorylatesAMPKonserine491tomediatediet-inducedobesityandleptinresistanceinC57Bl/6Jmice.Int.J.Obes.Relat. leptin’seffectonfoodintake.CellMetab.16,104–112(2012).Metab.Disord.24,639–646(2000). 24.Martin,T.L.etal.Diet-inducedobesityaltersAMPkinaseactivityin52.Munzberg,H.,Flier,J.S.&Bjorbaek,C.Region-speci?cleptinresistancewithin hypothalamusandskeletalmuscle.J.Biol.Chem.281,18933–18941(2006).thehypothalamusofdiet-inducedobesemice.Endocrinology145,4880–4889 25.Claret,M.etal.AMPKisessentialforenergyhomeostasisregulationand(2004). glucosesensingbyPOMCandAgRPneurons.J.Clin.Invest.117,2325–233653.El-Haschimi,K.,Pierroz,D.D.,Hileman,S.M.,Bjorbaek,C.&Flier,J.S.Two (2007).defectscontributetohypothalamicleptinresistanceinmicewithdiet-induced 26.Parton,L.E.etal.GlucosesensingbyPOMCneuronsregulatesglucoseobesity.J.Clin.Invest.105,1827–1832(2000). homeostasisandisimpairedinobesity.Nature449,228–232(2007). 27.Enriori,P.J.etal.Diet-inducedobesitycausesseverebutreversibleleptin Acknowledgements resistanceinarcuatemelanocortinneurons.CellMetab.5,181–194(2007). WethankDrGarySchwartzforhisvaluablefeedbackanddiscussionsthroughoutthe 28.Cowley,M.A.etal.LeptinactivatesanorexigenicPOMCneuronsthrougha yearandDrChristophBuettnerforcommentsonthemanuscript.WealsothankDr neuralnetworkinthearcuatenucleus.Nature411,480–484(2001). Shun-MeiLiufortechnicalsupports.ThisworkwassupportedbyNIDDK 29.Vong,L.etal.LeptinactiononGABAergicneuronspreventsobesityand (RO1DK092246)toY.-H.J. reducesinhibitorytonetoPOMCneurons.Neuron71,142–154(2011). 30.Ha,S.etal.Somato-dendriticlocalizationandsignalingbyleptinreceptorsin hypothalamicPOMCandAgRPneurons.PLoSONE8,e77622(2013). Authorcontributions 31.Balthasar,N.etal.LeptinreceptorsignalinginPOMCneuronsisrequiredfor Y.-H.J.designedresearch,performedtheexperiments,analysedthedataandwrotethe normalbodyweighthomeostasis.Neuron42,983–991(2004). manuscript.D.K.L.performedelectrophysiologicalandimmunocytochemicalanalysesof 32.Chun,S.K.&Jo,Y.H.LossofleptinreceptorsonhypothalamicPOMC POMCneurons.S.-K.C.performedinitialelectrophysiologicalrecordings.J.H.J.per- neuronsalterssynapticinhibition.J.Neurophysiol.104,2321–2328(2010). formedimmunocytochemistryandsingle-cellreal-timeqRT–PCRanalysis.S.C.designed 33.Knight,Z.A.etal.Molecularpro?lingofactivatedneuronsbyphosphorylated research. ribosomecapture.Cell151,1126–1137(2012). 34.Munzberg,H.etal.Appropriateinhibitionoforexigenichypothalamicarcuate Additionalinformation nucleusneuronsindependentlyofleptinreceptor/STAT3signaling.J.Neurosci. 27,69–74(2007).SupplementaryInformationaccompaniesthispaperathttp://www.nature.com/ naturecommunications 35.Munsch,T.,Freichel,M.,Flockerzi,V.&Pape,H.C.Contributionoftransient receptorpotentialchannelstothecontrolofGABAreleasefromdendrites. Competing?nancialinterests:Theauthorsdeclarenocompeting?nancialinterests. Proc.NatlAcad.Sci.USA100,16065–16070(2003). 36.Qiu,J.etal.Insulinexcitesanorexigenicproopiomelanocortinneuronsvia Reprintsandpermissioninformationisavailableonlineathttp://npg.nature.com/ activationofcanonicaltransientreceptorpotentialchannels.CellMetab.19, reprintsandpermissions/ 682–693(2014). 37.Yang,Y.,Atasoy,D.,Su,H.H.&Sternson,S.M.Hungerstatesswitcha?ip-Howtocitethisarticle:Lee,D.K.etal.Interplaybetweenglucoseandleptinsignalling ?opmemorycircuitviaasynapticAMPK-dependentpositivefeedbackloop.determinesthestrengthofGABAergicsynapsesatPOMCneurons.Nat.Commun. Cell146,992–1003(2011).6:6618doi:10.1038/ncomms7618(2015). 12NATURECOMMUNICATIONS|6:6618|DOI:10.1038/ncomms7618|www.nature.com/naturecommunications &2015MacmillanPublishersLimited.Allrightsreserved. |
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