Action of Neurotransmitter: A Key to Unlock the AgRP Neuron Feeding Circuit.

0.67 MB·English

by  Liu, Tiemin

REVIEWARTICLE
published:21January2013
doi:10.3389/fnins.2012.00200
Action of neurotransmitter: a key to unlock the AgRP
neuron feeding circuit
TieminLiu1,QianWang1,EricD.Berglund1 andQingchunTong2*
1DivisionofHypothalamicResearch,DepartmentofInternalMedicine,TheUniversityofTexasSouthwesternMedicalCenteratDallas,Dallas,TX,USA
2TheBrownFoundationInstituteofMolecularMedicine,TheUniversityofTexasHealthScienceCenteratHouston,Houston,TX,USA
Editedby: Thecurrentobesityepidemicandlackofefficienttherapeuticsdemandaclearunderstand-
KevinW.Williams,TheUniversityof ingofthemechanismunderlyingbodyweightregulation.Despiteintensiveresearchfocus
TexasSouthwesternMedicalCenter,
onobesitypathogenesis,aneffectivetherapeuticstrategytotreatandcureobesityisstill
USA
lacking.Excitingstudiesinlastdecadeshaveestablishedtheimportanceofhypothalamic
Reviewedby:
SergeH.Luquet,UniversityParis agouti-relatedprotein-expressingneurons(AgRPneurons)intheregulationofbodyweight
Diderot-Paris7,France homeostasis. AgRP neurons are both required and sufficient for feeding regulation.The
ScottSternson,HowardHughes activityofAgRPneuronsisintricatelyregulatedbynutritionalhormonesaswellassynap-
MedicalInstitute,USA
ticinputsfromupstreamneurons.ChangesinAgRPneuronactivityleadtoalterationsin
QiWu,UniversityofIowa,USA
the release of mediators, including neuropeptides NeuropeptideY (NPY) and AgRP, and
*Correspondence:
QingchunTong,TheBrown fast-actingneurotransmitterGABA.Recentstudiesbasedonmousegenetics,novelopto-
FoundationInstituteofMolecular genetics,anddesignerreceptorexclusivelyactivatedbydesignerdrugshaveidentifieda
Medicine,TheUniversityofTexas criticalroleforGABAreleasefromAgRPneuronsintheparabrachialnucleusandparaven-
HealthScienceCenteratHouston,
tricularhypothalamusinfeedingcontrol.Thisreviewwillsummarizerecentfindingsabout
1825PresslerStreet,Houston,TX
77030,USA. AgRPneuron-mediatedcontroloffeedingcircuitswithafocusontheroleofneurotrans-
e-mail:[email protected] mitters. Given the limited knowledge on feeding regulation, understanding the action of
neurotransmittersmaybeakeytounlockneurocircuitrythatgovernsfeeding.
Keywords:AgRPneurons,parabrachialnucleus,paraventricularhypothalamus,feeding
INTRODUCTION In regard to feeding control, emerging results demonstrate
Theabilitytoharnessenergyfromavarietyofmetabolicpathways orexigenicAgouti-relatedprotein(AgRP)neuronsinthearcuate
is a property of all living organisms. For a multi-organ system nucleus(Arc)ofthehypothalamusarecriticalregulatorsoffeed-
likerodentsandmammals,differentorganshaveevolvedtoper- ingandfood-seekingbehavior(Ollmannetal.,1997;Cone,2005;
formdistinctfunctionstomaintainenergybalance.Forexample, Flier,2006).ActivationofAgRPneuronsinmicecauseshyperpha-
thebraincontrolstheintakeofenergy(mostlycarbohydrates,fats, gia,increases motivation to work for food,and initiates intense
andproteins),whichisabsorbedbythedigestivesystem,trafficked food-seekingbehavior(Aponteetal.,2011;Krashesetal.,2011),
bytheliver,anddistributedtothebodyviathecirculationsystem while inhibition of AgRP activity or ablation of AgRP neurons
(Schwartzetal.,2000;Saperetal.,2002;ElmquistandFlier,2004). leadstoreducedfeedingorstarvation(Bewicketal.,2005;Gropp
Adisturbanceinthedelicatebalancebetweenenergyintakeand etal.,2005;Luquetetal.,2005;Xuetal.,2005a;Wuetal.,2009).
energy requirements in the body will lead to changes in metab- SincetheactivitylevelofAgRPneuronsisadeterminantforfeed-
olism and body growth (body weight). During evolution when ing,itwillbeimportanttounderstandhowtheactivityofAgRP
foodisnotalwaysavailable,excessenergyisstoredasfat,which neurons is controlled. The ultimate result of changes in AgRP
canbeusedwhenfoodisscarce.Thus,foragivenlivingsubject, neuronactivityisalterationsinneurotransmitterrelease,whichis
energy balance is depicted as energy intake=internal heat pro- theonlywayforneuronstotransmitsignalstodownstreamtar-
duced+external work+energy storage (fat; Saper et al.,2002). gets.Decipheringthefunctionofneurotransmittersreleasedfrom
Obesityisdefinedastheexcessivefataccumulation.Thecurrent AgRPneuronsandtheirdownstreamtargetsrepresentsacritical
obesityepidemicandlackofefficienttherapeuticsdemandaclear steptowardunderstandingtheAgRPneuralpathwayforfeeding
understanding of the mechanisms underlying body weight reg- control.Thisreviewdiscussesrecentfindingsonthecontrolthe
ulation. It is now well established that the brain, especially the AgRPactivityandthefunctionof neurotransmittersfromAgRP
hypothalamus,maintainsbodyweighthomeostasisbyeffectively neurons.
adjustingfoodintakeandenergyexpenditure(internalheatpro-
ductionandexternalwork)inresponsetochangesinthelevelsof UPSTREAMREGULATORSOFAgRPNEURONS
variousnutritionalstatusindicatorssuchasleptin,insulin,ghre- UPSTREAMHUMORALREGULATORSOFAgRPNEURONS–LEPTIN,
lin,andothers(Elmquistetal.,1999;Pintoetal.,2004;Nogueiras GHRELIN,INSULIN
etal.,2008;Friedman,2009;Yangetal.,2011;Heppneretal.,2012; Agouti-relatedproteinneuronsinthehypothalamicArcarecrucial
Liuetal.,2012).Recentstudieshaveidentifiedimportantgroups targets of feeding hormones. One of these hormones is ghre-
of neurons and genes in the hypothalamus for energy balance lin,whichpromotespositiveenergybalance(Tschopetal.,2000;
regulation(Cone,2005;Elmquistetal.,2005). Nakazato et al., 2001; Nogueiras et al., 2008). Ghrelin was first
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Liuetal. NeurotransmitteractionandAgRPneuronregulation
identifiedin1999asanendogenousligandofthegrowthhormone suggestedtoinhibitPOMCneuronsindirectlybyactivatingAgRP
secretagogue receptor (GHSR) and is synthesized and secreted neurons(Cowleyetal.,2003;Tongetal.,2008;Wuetal.,2008a;
mainlyfromendocrinecellsofthestomachandintestine(Kojima Atasoyetal.,2012).Feedingstimulationbyghrelinisabolishedin
et al., 1999; Wierup et al., 2007). Both central and peripheral AgRP/NeuropeptideY(NPY)doubleknockoutmiceandablation
administrations of ghrelin stimulate appetite and food intake, ofAgRPneuronsinadulthoodindicatingthatghrelinsignalingin
increasebodyweight,andpromoteadiposityanddecreaseenergy AgRP neurons is important for controlling feeding (Chen et al.,
expenditure in rodents indicating an orexigenic impact via cen- 2004;Bewicketal.,2005).
tral signaling (Tschop et al., 2000; Wren et al., 2000; Asakawa Leptin, which counter-acts the effects of ghrelin to regulate
et al., 2001; Nakazato et al., 2001). Histological examination of energybalanceandfoodintake,isahormoneproducedbyfattis-
GHSRshoweditspresenceinseveralhypothalamicnucleiinclud- sue. The gene for leptin was first cloned in 1994 (Zhang et al.,
ingArcandparaventricularnucleusofthehypothalamus(PVH) 1994) followed by the gene for the leptin receptor (LEPR) in
anddirectbindingof ghrelininthesehypothalamicregionswas 1995(Tartagliaetal.,1995).Micewithleptindeficiency(ob/ob)or
also found (Cowley et al., 2003; Zigman et al., 2006). In these deficitsinitsreceptor(db/db)showsevereobesityphenotypethus
potential sites of ghrelin action,theArc where GHSR mRNA is supporting a crucial role for leptin signaling to regulate feeding
abundantlyexpressed,isthoughttocontaintheprimaryghrelin- andenergyexpenditure(Friedman,1998;FriedmanandHalaas,
responsiveneuronsmediatingeffectsonfeedingandbodyweight. 1998).LEPRmRNAishighlyexpressedwithinthehypothalamus
GHSRsarepredominantlyexpressedintheorexigeniccellpopula- includingtheventromedialnucleusofthehypothalamus(VMH),
tionintheArc,AgRPneurons(Figure1),incontrasttofewGHSRs thedorsomedialnucleusofthehypothalamus(DMH),andtheArc
inproopiomelanocortin(POMC)neurons,theanorexigenicpop- whereLEPRisdenselyexpressedinbothAgRPandPOMCneu-
ulationintheArc(Willesenetal.,1999;Nogueirasetal.,2008). rons(Figure1;Merceretal.,1996a,b;Elmquistetal.,1998,1999;
TheneuronalactivityofAgRPneuronsistriggeredbyghrelinindi- Eliasetal.,1999).Indeed,directleptinactiononAgRPneurons
catedbyincreasedelectricalactivityandc-fosimmunoreactivity has been revealed by the obesity phenotype caused by specific
(Cowley et al.,2003;Andrews et al.,2008). Therefore,ghrelin is deletion of LEPR in AgRP neurons (van de Wall et al., 2008).
FIGURE1|ModelunderlyingtheAgRPNeuronFeedingCircuit.AsummaryaboutupstreamanddownstreammediatorsofAgRPneuronsincluding(1)
neuronalregulators-glutamate,GABA,AgRP,NPY,andβ-endorphin;(2)humoralregulators–leptin,ghrelin,insulin.
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Liuetal. NeurotransmitteractionandAgRPneuronregulation
Activationofleptin-responsiveneuronsinvolvesinductionofthe Inaseriesofelegantinvitroelectrophysiological,pharmacoge-
JAK-STAT3 signaling pathway,which regulates the gene expres- netic,andoptogeneticexperimentsonacutebrainslicesinfedand
sion(Batesetal.,2003;BatesandMyers,2004).Consistentwithits food-deprivedmice,Yangetal.(2011)foundthatfastingactivation
anorexigenicrole,leptinadministrationdirectlyinhibitsneuronal ofAgRPneuronsdoubledthefrequencyofexcitatorypostsynap-
activityofAgRPneuronsanddepolarizesPOMCneurons(Span- tic currents, but not amplitude. They also investigated in great
swicketal.,1997;Cowleyetal.,2001;Elmquistetal.,2005).The detail the paired-pulse ratio (PPR) in wild-type mice and con-
directbutoppositeactionsofleptininAgRPandPOMCneurons cludedthattheverylowPPRofglutamatergicinputsontoAgRP
arefurtherconfirmedby(1)inductionof STAT3inbothpopu- neurons in ad libitum fed mice limits the capability to observe
lations;(2)increasedc-fosimmunoreactivityinPOMCneurons, anyfurtherreductionof PPRafterfooddeprivation.Consistent
butnotinAgRPneuronsafterleptintreatment(Eliasetal.,1999). with this, they showed a dissociation of PPR in fed and fasted
Although GHSR and LEPR are co-expressed in the medial part miceuponloweringextracellularcalcium(acommonmethodfor
of the Arc, the function of LEPR is likely to be independent of revealingchangesinpresynapticreleasepropertiesofhighrelease
GHSRindicatedbytheevidencethatanorecticeffectsof exoge- probability synapses). Together, these lines of evidence suggest
nouslyadministratedleptinweresimilarinwild-typeandGHSR aghrelin/ghrelinreceptor/AMP-activatedproteinkinasepathway
knockoutmice(Perelloetal.,2012). operatinginpresynapticglutamatergicneurons(Figure1).
Insulinisahormonemadeandsecretedbybetacellsinthepan- Other potential mechanisms have also been suggested. Pinto
creasandplaysapivotalroleinregulatingbloodglucose.Anele- and colleagues measured EPSCs on AgRP neurons (via in vitro
vationofbloodglucosestimulatespancreaticbetacellstosecrete electrophysiologicalrecordings)andanalyzedexcitatorysynapses
insulin.Theincreaseincirculatinginsulinleadstoacceleratedglu- on perikarya (using electron microscopic stereology) and pro-
coseuptakeintoperipheraltissues,whichisessentialtomaintain videddatasuggestingapostsynapticmechanism.Specifically,they
glucose homeostasis (Shepherd and Kahn,1999). In addition to foundthatincreasedfrequencyofEPSCsonNPY/AgRPneurons
wellknowngluco-regulatoryactionsofinsulinonperipheraltis- inleptin-deficientob/obmicewasassociatedwithincreasedexci-
sues,insulinsignalinginthebrain(especiallythehypothalamus) tatory synapses on the perikarya of NPY/AgRP neurons (Pinto
alsocriticallyregulatesbloodglucose(Obicietal.,2002;Plumetal., etal.,2004).
2006; Paranjape et al., 2010; Levin and Sherwin, 2011). Insulin Thereis additionalsupportforapostsynaptic mechanism.A
receptors (INSR) are expressed in many CNS regions including recentstudybyLiuetal.(2012)evaluatedtheroleofglutamatergic
the hypothalamus (Figure 1; Werther et al., 1987; Unger et al., inputtoAgRPneuronsandexcitatorysynapsesonthedendritic
1991).Amongthesehypothalamicneurons,insulin/PI3Ksignal- spinesofAgRPneurons.Theirstrategywastodecreaseglutamate
inginbothAgRPandPOMCneuronsisrequiredformaintaining inputtoAgRPneuronsbyselectivelydeletingtheionotropicglu-
glucose homeostasis (Konner et al., 2007; Hill et al., 2010; Lin tamatereceptor,NMDARs(MalenkaandNicoll,1999;Kesselsand
et al., 2010). As early as 1979, intracerebroventricular infusion Malinow, 2009; Collingridge et al., 2010). Using Cre-loxP tech-
of insulin was shown to reduce body weight and food intake in nology,theauthorscrossedAgrp-ires-Cremice(Tongetal.,2008)
baboons,afeatureofanorexigenichormone(Woodsetal.,1979). with lox-NR1 mice (Tsien et al., 1996; NR1 is a required sub-
RecentstudiessuggestthatinsulinactsonAgRPneuronstoexert unitoftheNMDAreceptor,deletionofNR1subunitscausestotal
this anorexigenic role,which is mediated by activation of phos- loss of NMDAR activity) to generate Agrp-ires-Cre, NR1lox/lox
phatidylinositol 3-kinases (PI3K) and the nuclear export of the mice (Voglis and Tavernarakis,2006; Higley and Sabatini,2008;
forkheadtranscriptionfactor(Foxo1;Kimetal.,2006;Renetal., Bito,2010).TheyfoundthatdecreasedglutamateinputtoAgRP
2012).Likeleptin,insulinhyperpolarizesAgRPneurons,whichis neuronswasassociatedwithdecreasedbodyweight,foodintake,
consistent with its role to reduce food intake and body weight ratesofre-feeding,EPSCfrequency,anddendriticspinenumber.
(Spanswick et al., 2000; Konner et al., 2007). Although LEPR Importantly,fastingdidnotalterthePPRinwild-typemice.Liu
andINSRco-expressinbothAgRPandPOMCcellpopulations, andcolleaguessuggestedthatpostsynapticNMDARsarerequired
theactionsof LEPRandINSRareintegratedbyPI3KinPOMC forthefasting-inducedincreaseinEPSCfrequencythatisparal-
neurons,butnotinAgRPneurons(Xuetal.,2005b). leled by dendritic spinogenesis. They propose a tentative model
toexplainhowfastingregulatestheactivationofAgRPneurons:
UPSTREAMNEURONALREGULATORSOFAgRP fasting→dendritic spinogenesis→formation of new excitatory
NEURONS–GLUTAMATE synapses→increasedglutamatergictransmission→activationof
Agouti-related protein neurons are regulated by numerous AgRPneurons.
humoralandneuralinputs.Whileintensefocushasbeenplaced However, the findings of Liu et al. could not rule out the
onidentifyingandunderstandinghumoralinputstoAgRPneu- possibilityofapresynapticmechanism,suggestingthatpresynap-
rons(e.g.,leptin,ghrelin,insulin;Elmquistetal.,1999;Belgardt tic and/or postsynaptic mechanisms may apply concurrently or
etal.,2009;Friedman,2009;Castanedaetal.,2010;PerelloandZig- assumedominancedependingonnutritionalstatus.
man,2012),verylittleisknownaboutneuralregulationofAgRP The obvious question is to identify the source(s) of gluta-
neurons. Recent findings that neurotransmitter inputs to AgRP matergicinputtoAgRPneurons.Candidateswillbeglutamatergic
neurons(e.g.,glutamateandGABA)regulatefoodintakesuggest neuronsexpressingghrelinreceptors(Atasoyetal.,2012)including
thatabnormaleatingbehaviorsanddramaticweightchangemay theArc,VMH,DMH,PVH,basolateralnucleusof theamygdala
be linked to disturbances in neural regulation of AgRP neurons (BLA),andventralpremammillarynucleus(PMv;Figure1;Zig-
(Pintoetal.,2004;Yangetal.,2011;Liuetal.,2012). man et al.,2006; Johnson et al.,2009;Vong et al.,2011; Perello
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Liuetal. NeurotransmitteractionandAgRPneuronregulation
et al., 2012). One possible method is to use a monosynaptic othermodulatorsmentionedabove,NPYistheonlyonewidely
rabiesapproachtodeterminethesource(s)ofpresynapticinputto expressedthroughoutthebody,boththeCNSandPNSinmam-
AgRPneurons.Rabiesvirus,aneuronalcircuittracerintheretro- mals (Lundberg et al.,1982;Tatemoto et al.,1982). It is present
gradedirection,canbeusedtotargetthemonosynapticinputto in many brain regions including the hippocampus, hypothala-
AgRPneurons(Marsheletal.,2010;Walletal.,2010).Compared mus,amygdala,cortex(GrayandMorley,1986;Wahlestedtetal.,
to standard electrophysiological techniques, this approach will 1989),andtheperipheralnervoussystemincludingsympathetic
reveal direct monosynaptic inputs toAgRP neurons by control- post-ganglionicneuronsandtheadrenalmedulla,andperipheral
lingtheinitialrabiesvirusinfectionandsubsequentmonosynaptic organssuchasthepancreasandspleen(Lundbergetal.,1982;Eric-
retrograde spread. These studies should identify glutamatergic ssonetal.,1987;Klimaschewskietal.,1996;Whim,2006,2011).
neurons directly projecting to AgRP neurons to drive feeding TheknownNPYreceptorsincludeY1,Y2,Y4,andY5aswellas
behavior. Y6inthemouse.AllYreceptorsareGproteincoupledreceptors
and their activation usually causes inhibitory responses such as
DOWNSTREAMMEDIATORSOFAgRPNEURONS inhibitionofcAMPaccumulation(Micheletal.,1998).
Agouti-related protein neurons directly sense changes in nutri- IntheCNS,NPYismosthighlyco-expressedwithAgRPinthe
tionalstatushormonessuchasleptin,insulin,ghrelin,andothers, ArcandsubstantialamountsofNPYarealsofoundinotherhypo-
and neurotransmitters such as glutamate, GABA, and others to thalamicnucleiincludingthedorsomedialnucleus,andnumerous
modulate energy homeostasis. As a result, AgRP neuron activ- NPYergicneuronsprojectintothePVH(Chronwalletal.,1985;
itydramaticallyincreasesinresponsetofasting,signalinganeed vandenPoletal.,2009).NPYwasfirstfoundtopromotehyper-
to eat (Takahashi and Cone, 2005). AgRP neurons also release phagiabasedonevidencethatintraventricularadministrationof
downstream effectors (neural-GABA, AgRP, and NPY) to drive thispeptidesignificantlyinducedfeedingbehaviorinrats(Clark
feeding(Figure1).Interestingly,comparedtocontrols,increasing etal.,1984,1985;LevineandMorley,1984;StanleyandLeibowitz,
theactivitylevelof AgRPneuronsinduceshyperphagiawhereas 1984). Moreover,central administration of NPY reduces energy
reducing the activity level of those neurons induces hypophagia expenditure and chronic infusion of NPY can induce obesity
(Krashes et al.,2011),suggesting that the activity level of AgRP duetoovereating(Billingtonetal.,1991;FlierandMaratos-Flier,
neurons correlates with the level of feeding. These data suggest 1998).
that AgRP neurons are both sufficient and required for feeding Surprisingly,NPYknockoutmiceona129/SvCp-Jbackground
regulation. didnotshowaphenotypeofreducedfeeding,bodyweight,oradi-
posityundernormalconditions(Ericksonetal.,1996a).However,
DOWNSTREAMNEUROPEPTIDEMEDIATORSOFAgRP geneticremovalofNPYattenuatedhyperphagiaandobesityphe-
NEURONS–AgRPANDNPY notypeinleptin-deficientmice(Ericksonetal.,1996b).Inaddi-
NeuropeptideY andAgRP are two neuropeptides released from tion,whenNPYknockoutmicewerebackcrossedontoaC57BL/6
AgRP neurons that potently induce feeding,consistent with the background,theyshoweddecreasedre-feedingafterfasting(Ban-
roleofAgRPneuronstopromotefeeding(Elmquistetal.,2005). nonetal.,2000).ThisissimilartoY1knockoutmicethatdisplay
Ghrelinincreasesfeedingbehaviorbystimulatingproductionof slightlydiminishedfeedingandstronglyreducedfasting-induced
NPY and AgRP in AgRP neurons whereas leptin and insulin re-feeding(Pedrazzinietal.,1998).TheY2knockoutmousemodel
inhibitsfoodintakeandbodyweightbydecreasingtheirexpres- exhibits decreased body weight gain and deletion of Y2 recep-
sion (Schwartz et al., 1992; Korner et al., 2001; Zigman and torsintheadultmousehypothalamusledtotransientlydecreased
Elmquist, 2003; Chen et al., 2004; Morrison et al., 2005; Goto body weight, but increased food intake indicating a functional
etal.,2006). roleof hypothalamicY2receptorstocontrolfeeding(Sainsbury
Ectopicexpressionofagoutiproteininmice(Ay/a)causesan etal.,2002a,b).Inaddition,Y5-deficientmiceshownormalfood
obese phenotype (Bultman et al., 1992). AgRP, a homology of intakeandbodyweight,butdevelopobesityafter30weeksofage
Agouti,wasidentifiedtobeup-regulatedinobesemicesuggesting (Marsh et al., 1998). Collectively, this literature studying roles
apotentialroleofAgRPinfeedingandenergybalanceregulation of NPY and NPY receptors in feeding and energy balance sup-
(Shutteretal.,1997).IntrocerebroventricularinjectionofAgRPor portstheimportanceofcentralNPYsignalinginregulatingenergy
itsexpressioninatransgenicmousemodelbothleadtohyperpha- homeostasis.
gia,loweredenergyexpenditure,andobesity(Grahametal.,1997;
Rossietal.,1998;Smalletal.,2001).Theeffectofasingleinjection DOWNSTREAMNEURONALMEDIATORSOFAgRPNEURONS-GABA
ofAgRPtopromotefeedingislong-lasting,whichisdifferentfrom Asreviewedabove,extensivestudieshavebeenfocusedontherole
otherorexigenichormonesincludingghrelinandNPY(Schwartz of neuropeptides NPY andAgRP fromAgRP neurons. The role
etal.,2000;Haganetal.,2001).AgRPaffectsfeedingbehaviorand of fast-acting neurotransmitter GABA has also been speculated
metabolism by antagonizing the melanocortin receptors,MC3R to be important (Horvath et al., 1997; van den Pol, 2003), but
and MC4R, which are stimulated by POMC cleavage products waslargelyneglecteduntilrecently.Todirectlyexaminetherole
(Fan et al.,1997; Ollmann et al.,1997). Besides the mechanism ofGABAreleasefromAgRPneurons,Tongetal.(2008)generated
of competitive antagonism, AgRP is also suggested to regulate micewithdisruptionofGABAreleasespecificallyfromAgRPneu-
feedingbehaviorandenergybalanceasaninverseagonistof the rons by inactivating vesicular GABA transporter (VGAT). Tong
centralmelanocortinsystem(Haskell-LuevanoandMonck,2001; et al. (2008) found that GABA release from AgRP neurons is
Nijenhuis et al., 2001; Tolle and Low, 2008). Distinctive from required for normal body weight regulation, and disruption of
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Liuetal. NeurotransmitteractionandAgRPneuronregulation
GABA leads to increased energy expenditure and resistance to directlytesteduntilrecently.Usingacombinationofoptogenetic
diet induced obesity. However, the degree in change of body and designer receptor exclusively activated by designer drugs
weightduetodisruptionofGABAreleaseismild,suggestingthat (DREADD) approaches, Sternson laboratory elegantly demon-
either other neurotransmitters released from AgRP neurons are stratedthat,indeed,AgRPneuronssenddirectGABAergicprojec-
importantorthatdisruptionofGABAreleaseduringearlyembry- tions to POMC neurons; however,surprisingly,POMC neurons
onic phases invokes developmental compensation which masks play a minimal role in mediating AgRP neurons on acute feed-
physiological effects of GABA release. Consistent with the lat- ing (Atasoy et al., 2012). Consistently with this finding, results
ter hypothesis, mice with lesions of AgRP neurons in neonates fromPalmiterlaboratorysuggestedthatstarvationresultedfrom
exhibitamildreductioninbodyweightwhilethosewithlesions AgRPneuronsisindependentofthemelanocortinpathway(Wu
of AgRP neurons in adults exhibit significantly reduced food et al., 2009). These data demonstrate that POMC neurons are
intake or starved to death (Bewick et al., 2005; Gropp et al., not a major part of AgRP neuron feeding pathway, at least in
2005; Luquet et al., 2005; Xu et al., 2005a; Wu et al., 2009). acute hyperphagia response. Strikingly, there is no direct pro-
It is interesting to point out that mice with lesions of AgRP jectionfromPOMCneuronstoAgRPneurons,ornoreciprocal
neurons have been made in several laboratories, and the phe- projectionsbetweenPOMCorAgRPneurons,suggestingarather
notypes of these mice range from mild reduction, more pro- simple, one way circuit from AgRP to POMC neurons (Atasoy
nounced reduction in body weight,or starvation-induced death etal.,2012).WhetherthephysiologicalsignificanceofGABAergic
(Bewick et al.,2005; Gropp et al., 2005; Luquet et al., 2005; Xu regulationof POMCneuronsbyAgRPneuronliesinlongterm
et al., 2005a). These variant results might be due to different regulationoffeedingorinenergyexpenditureregulationremains
approaches used to lesion AgRP neurons. Lesion of AgRP neu- tobeestablished.Likewise,thefunctionof potentialGABAergic
rons through inactivating mitochondria might take more time projectionfromAgRPneuronstonon-POMCneuronsintheArc
tokillAgRPneurons,allowingfordevelopmentalcompensation, isunknown.
resultinginmildeffectsonbodyweight(Xuetal.,2005a).Lesion Previous data also suggest the importance of Arc projections
ofAgRPneuronsmediatedbydiphtheriatoxin(DTX)isarapid to the PVH in energy balance (Elmquist et al., 2005) including
process, resulting in more pronounced effects on body weight feeding and energy expenditure. For example,the melanocortin
and feeding (Gropp et al., 2005; Luquet et al., 2005). Nonethe- pathwayfromPOMCneuronstothePVHhasbeensuggestedto
less,thesestudiesdemonstratepowerfuldevelopmentalcompen- selectivelycontrolfeeding(Balthasaretal.,2005).Ithasalsobeen
sation in response to loss of AgRP neurons in neonatal stages. speculated that GABAergic neurons in theArc mediate a major
Mice with AgRP neuron lesions exhibit abundant c-fos expres- part of leptin action on body weight through projections to the
sioninknownAgRPneuronprojectionsitesincludingthePVH PVH (Cone and Simerly, 2011). Recent data from Lowell labo-
and parabrachial nucleus (PBN;Wu et al.,2008b). Strong c-fos ratory demonstrated that direct GABAergic projections from a
expressionisconsistentwithlossof GABAprojection.However, novel subset of Arc neurons expressing Cre in Rip-Cre mice to
accompanyingwiththec-fosexpression,therearealsoabundant thePVHplayaselectiveroleinenergyexpenditure(Kongetal.,
gliosis responses in both Arc and AgRP neuron projection sites 2012).ItiswellacceptedthatthePVHisonemajordownstream
(Wu et al.,2008b).Whether the gliosis contributes to hypopha- site of AgRP neurons (Cone,2005;Elmquist et al.,2005). How-
giainthese micehasnotbeen explored.It wouldbeinteresting ever,adirectdemonstrationofaroleofAgRPneuronprojection
to directly examine the role of GABA release from AgRP neu- tothePVHinfeedingregulationislackinguntilrecently.Basedon
ronsinadultmicethroughinducibledeletionofVGAT.Notably, similarsetsof elegantexperimentstothoseforPOMCneurons,
mildphenotypesbyNPYknockoutmightnotbeduetodevelop- Sternson laboratory demonstrated a critical role for GABAergic
mental compensations since mice with NPY deletion in adults projectionsfromAgRPneuronstothePVHinpromotingfeeding
show minimal phenotype in energy balance (Ste Marie et al., byAgRP neuron activation (Atasoy et al.,2012). Specifically,by
2005). concurrent activation of PVH neurons andAgRP neurons,they
GiventheestablishedimportanceofAgRPneuronsinfeeding showedthatactivationofPVHneuronseffectivelyreverseshyper-
regulation,intense interests have been generated to look for the phagic effects by AgRP neurons activation (Atasoy et al.,2012),
responsibleneurotransmittersfromtheseneurons.Recentexcit- suggesting that AgRP neuron induced hyperphaga is due to a
ing results from Sternson and Palmiter laboratories suggest that heightened GABAergic tone to the PVH and that suppression
GABAistheresponsibleneurotransmitterandmoreimportantly, of PVH neurons is required for AgRP neuron-mediated hyper-
they have identified that the neurons in the PVH and PBN,but phagia.Furthermore,byselectivelyphotostimulatingAgRPfibers
notPOMCneurons,arethedirectdownstreamsitesthatreceive thePVH,theirresultsshowedthatsuppressionof PVHneurons
GABAtomediatefeedingregulationbyAgRPneurons(Wuetal., byAgRPneuronsissufficienttomediateAgRPneuron-mediated
2009;Atasoyetal.,2012). hyperphagia.Thus,suppressionofPVHneuronsisbothsufficient
Previous electrophysiological data suggest that AgRP neu- andnecessaryforAgRPneuron-mediatedhyperphagia.Interest-
rons send direct GABAergic projections to nearby POMC neu- ingly, a marked strengthening of GABAergic innervations from
rons (Cowley et al., 2001). Coupled with an important role of AgRPneuronstoPVHneuronswasfoundtobeassociatedwith
the melanocortin system in feeding regulation (Elmquist et al., NPYdeficiency.GiventheimportancetoGABAergicinnervations
2005), these results triggered the speculation that POMC neu- fromAgRP neurons to PVH neurons in feeding regulation,this
rons are one of downstream sites to mediate AgPR neuron plasticchangesinGABAergicactionmayprovideanexplanation
action on feeding (Cone, 2005). This speculation has not been forlackofphysiologicphenotypesbyNPYdeficiency.Consistently,
www.frontiersin.org January2013|Volume6|Article200|5
Liuetal. NeurotransmitteractionandAgRPneuronregulation
NPYreceptorblockagesignificantlybluntedthehyperphagiaeffect Caution should be exercised to directly compare the results
causedbyphotostimulationofeitherAgRPfibersinthePVHor betweenSternsonandPalmitergroupssincetheformerdealswith
AgRP neurons, suggesting that both GABA and NPY signaling rapid changes in neuronal activity with acute feeding and the
appeared to be necessary for feeding evoked by the GABAergic latterdealswithslowalterationsinneuronalcircuitrywithlong
projection from AgRP neurons to PVH neurons (Atasoy et al., termfeedingeffects.Nonetheless,theresultsfromthetwogroups
2012). It would be interesting to identify how NPY deficiency taken together suggest that GABAergic action from AgRP neu-
causeschangesinGABAergicaction. rons to the PVH may preferentially mediate hyperphagic effects
GiventhestrongfeedinginhibitioninducedbyAgRPneuron byAgRP neuron excitation,and that to the PBN may preferen-
inhibition(Aponteetal.,2011;Krashesetal.,2011),itwouldbe tiallymediatehypophagiceffectsbyAgRPneuroninhibition.This
interesting to examine whether PVH neurons mediate feeding- speculation is in line with the minimal phenotypes observed in
reducing effects by AgRP neurons. A direct testing of this has micewithAgRPandNPYdeficiency(Qianetal.,2002),although
notbeenreported.However,usingaextremecaseofAgRPneu- thelattercanbeexplainedbypotentialcompensatorychangesin
rons inhibition,i.e.,AgRP neuron lesion,Palmiter group found GABAergic action (Atasoy et al., 2012). It may be the case that
thatPVHspecificadministrationofGABA-Aagonistfailedtores- GABAergic projection from AgRP neurons to the PVH projec-
cuethestarvationphenotypebyAgRPneuronlesion,suggesting tion is more engaged during fasting whereas that to the PBN
that GABAergic projection fromAgRP neurons to the PVH has is more engaged during fed states. In addition to the PVH and
nocontributiontothestarvationphenotypeproducedbyAgRP PBN,AgRP neurons also send GABAergic projections to several
neuron lesion (Wu et al.,2009). Of note,the failure in rescuing other brain sites, and some of these sites might be important
is not due to insignificant GABAergic input from AgRP neu- to mediate AgRP neuron feeding effects (Atasoy et al., 2012),
rons since abundant c-fos expression, an indicator of neuronal but still await further demonstration. Further studies stemmed
activation, was observed in the PVH as a result of AgRP neu- fromtheseresultswillshednewlightsonAgRPneuronfeeding
ron lesion,and importantly,the increased c-fos expression were circuits.
blunted by the application of GABA-A receptor. This data sug-
gestthatexcitationofPVHneuronscontributesminimallytothe SUMMARY
starvation phenotype by AgRP neurons lesion. Since PVH neu- Several laboratories have used a combination of mouse genet-
ronexcitationbyGABA-Aantagonistssuppressesfeeding(Kelly ics and pharmacology to achieve specific lesion of adult AgRP
et al., 1979), this result suggests that GABAergic action in the neurons, state-of-the-art optogenetics, and DREADD (Alexan-
PVH from non-AgRP neurons might mediate feeding suppres- der et al., 2009; Wu et al., 2009; Krashes et al., 2011; Atasoy
sion.InpursuitofdownstreamtargetstoGABAergicprojections et al., 2012) to achieve specific manipulation of adult AgRP
fromAgRP neurons that mediate the starvation effects of AgRP neurons. Given the complexity of feeding behavior, these stud-
neuron lesion, Palmiter group found that the starvation phe- ies represent a significant leap in understanding of brain feed-
notype can be rescued by specific delivery of GABA-A receptor ing circuits. It appears that AgRP neurons have evolved to
agonist in the PBN (Wu et al., 2009), highlighting an impor- be one of major determinants for an individual to harness
tant role for GABAergic projections from AgRP neurons to the energy from the environment. With this in mind, modulating
PBN. Consistently,adult lesion of AgRP neurons increases PBN the activity of AgRP neurons represents one strategy to control
neuron activity (Wu et al., 2008b). Taken together, these data appetite in contexts of the current obesity epidemic (Ren et al.,
suggest a role for a decreased GABAergic tone fromAgRP neu- 2012).
ronstothePBNinmodulatinghypophagiaresponse(Figure1). It is certain thatAgRP neurons are not the only key neurons
The PBN is traditionally viewed as a center for taste aversion controllingfeedingbecauselesionoftheArcincludingAgRPneu-
regulation, which, if activated by sensory inputs from the gut, ronsleadstohyperphagiaandobesity.Thus,intheArc,theremust
induces taste aversion, serving as a general protective mecha- beotherfoodintake-inhibitingneurons,lesionofwhichoverrides
nismtoavoidunpleasantfoodexperiencedbefore(Reilly,1999). theactionofAgRPneuronlesion.Nonetheless,basedontheexcit-
Thus,itappearsthatbothhypophagiaandtasteaversionresponses ingresultsfocusingonAgRPneuronsandusingnewlydeveloped
sharethesameneuralpathway.InadditiontoGABAergicinputs andhighlyinformativetechniques(mousegenetics,optogenetics,
fromAgRP neurons,it appears that PBN neurons are also con- andDREADD),futurestudieswillprovidemoreinsightsonbrain
trolledbyglutamatergicinputsfromthenucleusofsolitarytracts, circuitscontrollingfoodintake.
which might mediate inputs from other neurons such as sero-
toninergic neurons as well as sensory inputs from the gut (Wu ACKNOWLEDGMENTS
et al., 2012). An interesting question is whether this projection Tiemin Liu was supported by the ADA mentor-based postdoc-
also mediates hyperphagic effects produced by increased AgRP toral fellowship from theAmerican DiabetesAssociation (7-11-
neuron activity. Surprisingly, Sternson group found that spe- MN-16 to Joel K. Elmquist). Eric D. Berglund was supported
cificphotostimulationofAgRPfibersinthePBNfailstoinduce byNationalResearchServiceAward(5TL1DK081181).Qingchun
theacutehyperphagiceffectsbyAgRPneuronactivation(Atasoy TongwassupportedbyaScientistDevelopmentAwardfromthe
etal.,2012),suggestingthatacutehyperphagiainducedbyAgRP AmericanHeartAssociation(10SDG3280017),NationalInstitute
neuron activation is not due to heightened GABAergic tone to of Health (1R01DK092605),and the Juvenile Diabetes Research
thePBN. Foundation.
FrontiersinNeuroscience|NeuroendocrineScience January2013|Volume6|Article200|6
Liuetal. NeurotransmitteractionandAgRPneuronregulation
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