Central Control of Body Weight and Appetite

14 Pages·2008·0.31 MB·English

S U P P L E M E N T
R e v i e w
Central Control of Body Weight and Appetite
Stephen C. Woods and David A. D’Alessio
DepartmentsofPsychiatry(S.C.W.)andMedicine(D.A.D.),UniversityofCincinnati,Cincinnati,Ohio45237
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Context:Energybalanceiscriticalforsurvivalandhealth,andcontroloffoodintakeisanintegral w
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part of this process. This report reviews hormonal signals that influence food intake and their loa
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clinicalapplications. e
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EvidenceAcquisition:Arelativelynovelinsightisthatsatiationsignalsthatcontrolmealsizeand m
adipositysignalsthatsignifytheamountofbodyfataredistinctandinteractinthehypothalamus http
andelsewheretocontrolenergyhomeostasis.Thisreviewfocusesuponrecentliteratureaddress- s
ingtheintegrationofsatiationandadipositysignalsandtherapeuticimplicationsfortreatment ://ac
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ofobesity. d
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EvidenceSynthesis:Duringmeals,signalssuchascholecystokininariseprimarilyfromtheGItract ic.o
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tocausesatiationandmealtermination;signalssecretedinproportiontobodyfatsuchasinsulin p
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andleptininteractwithsatiationsignalsandprovideeffectiveregulationbydictatingmealsizeto o
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amountsthatareappropriateforbodyfatness,orstoredenergy.Althoughsatiationandadiposity /jc
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signalsaremyriadandredundantandreducefoodintake,therearefewknownorexigenicsignals; m
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thus,initiationofmealsisnotsubjecttothedegreeofhomeostaticregulationthatcessationofeating rtic
is.Therearenowdrugsavailablethatactthroughreceptorsforsatiationfactorsandwhichcause le
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weightloss,demonstratingthatthissystemisamenabletomanipulationfortherapeuticgoals. b
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Conclusions:Althoughprogressoneffectivemedicaltherapiesforobesityhasbeenrelativelyslow c
incoming,advancesinunderstandingthecentralregulationoffoodintakemayultimatelybe t/93
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turnedintousefultreatmentoptions.(JClinEndocrinolMetab93:S37–S50,2008) 1
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Thepastdecadehasseenanincreasingrecognitionthatacom- beingeatenandabsorbed,andaboutbasalandsituationalen- m
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plex interplay exists between the central nervous system ergyneedsbytissues.Thebraininturncontrolstissuesthathave t_
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(CNS)andtheactivityofnumerousorgansinvolvedinenergy importantrolesinenergyhomeostasis,liketheliverandmus- /s
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homeostasis.Thisrequiresthetransmissionofkeyinformation culoskeletalsystem,aswellasthesecretionofkeymetabolically 7/2
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to the brain, and control of food intake is one component of activehormones,primarilythroughtheautonomicnervoussys- 2
7
2
energybalancewhereendocrinesignalingfromtheperipheryto tem. The brain is thus able to respond to ongoing as well as 1
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theCNShasaparticularlyimportantrole.Consideredbroadly, unanticipated demands via well-coordinated responses to pre- b
y
energy homeostasis consists of the interrelated processes inte- vent shortfalls in energy stores while maintaining biochemical gu
e
grated by the brain to maintain energy stores at appropriate homeostasis.Thisreviewfocusesonhormonalandrelatedsig- st o
levelsforgivenenvironmentalconditions.Energyhomeostasis nalsthatinformthebrainofenergylevels,therebyinfluencing n
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thusincludestheregulationofnutrientlevelsinkeystorageor- energyintakeandultimatelybodyweight. 9 A
eglasnews h(ee.rge.)faastwinelaldaispoinsethtiessbuleooadnd(e.ggl.ycbologoend ginlutchoesel)i.veTroaancd- encAesfoaogdeinnetraakleraunled,esnigenrgaylseaxrpiseinndgitiunrtehceapnebreipphaerrtyittiohnatedinifnluto- pril 20
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complishthis,thebrainreceivescontinuousinformationabout twobroadcategories(Fig.1)(1–3).Onecomprisesthesignals 9
energy stores and fluxes in critical organs, about food that is generatedduringmealsthatcausesatiation(i.e.feelingsoffull-
0021-972X/08/$15.00/0 Abbreviations:AgRP,Agouti-relatedpeptide;apoA-IV,ApolipoproteinA-IV;ARC,arcuate
nucleus;CCK,cholecystokinin;DPP-IV,dipeptidylpeptidaseIV;GI,gastrointestinal;GLP-1,
PrintedinU.S.A.
glucagon-likepeptide-1;GLP-1r,GLP-1receptor;GRP,gastrin-releasingpeptide;LHA,
Copyright©2008byTheEndocrineSociety lateralhypothalamicarea;MC3R,melanocortin3receptor;MC4R,melanocortin4recep-
doi:10.1210/jc.2008-1630 ReceivedJuly28,2008.AcceptedSeptember8,2008. tor;(cid:1)MSH,(cid:1)-melanocyte-stimulatinghormone;NMB,neuromedinB;NPY,neuropep-
tide-Y; POMC, proopiomelanocortin; PVN, paraventricular nuclei; PYY, peptide
tyrosine-tyrosine.
JClinEndocrinolMetab,November2008,93(11):S37–S50 jcem.endojournals.org S37
S38 WoodsandD’Alessio CentralControlofBodyWeightandAppetite JClinEndocrinolMetab,November2008,93(11):S37–S50
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FIG.1.Modelsummarizingdifferentlevelsofcontroloverenergyhomeostasis.Duringmeals,signalssuchasCCK,GLP-1,anddistensionofthestomachthatarise /jc
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fromthegut(stomachandintestine)triggernerveimpulsesinsensorynervestravelingtothehindbrain.Thesesatiationsignalssynapsewithneuronsinthenucleusof m
thesolitarytract(NTS)wheretheyinfluencemealsize.GhrelinfromthestomachbothactsonthevagusnerveandstimulatesneuronsintheARCdirectly.Signals /a
relatedtobodyfatcontentsuchasleptinandinsulin,collectivelycalledadipositysignals,circulateinthebloodtothebrain.Theypassthroughtheblood-brainbarrier rtic
intheregionoftheARCandinteractwithneuronsthatsynthesizePOMCorNPYandAgRP.ARCneuronsinturnprojecttootherhypothalamicareasincludingthe le-a
PVNandtheLHA.ThenetoutputofthePVNiscatabolicandenhancesthepotencyofsatiationsignalsinthehindbrain.ThenetoutputoftheLHA,ontheotherhand, b
s
isanabolic,suppressingtheactivityofthesatiationsignals.Inthiswaybodyfatcontenttendstoremainrelativelyconstantoverlongintervalsbymeansofchangesof tra
mealsize. c
t/9
3
/1
1
nessthatcontributetothedecisiontostopeating)and/orsatiety hasbeenthecasethroughouthumanevolutionaswell,withthe _s
u
(i.e.prolongationoftheintervaluntilhungeroradrivetoeat initiationoffeedinggovernedbynonhomeostaticfactorssuchas p
p
reappears).Theprototypicalsatiationsignalistheduodenalpep- foodavailabilityorhavingasafehaventoeat.Thus,thehomeo- lem
e
tidecholecystokinin(CCK),whichissecretedinresponsetodi- staticinfluenceoverfoodintakeisoftenlefttothecontrolover n
t_
etarylipidorproteinandwhichactivatesreceptorsonlocalsen- howmanycaloriesareconsumedonceamealbegins;i.e.onmeal 1
/s
sorynervesintheduodenum,sendingamessagetothebrainvia size.Consistentwiththis,manyofthesecretionsofthegastro- 3
7
thevagusnervethatcontributestosatiation.Thesecondcate- intestinal(GI)tractduringameal,suchasCCK,areproportional /26
2
goryincludeshormonessuchasinsulinandleptinthatarese- tothenumberofcaloriesconsumed,andsomeofthesesecretions 7
2
1
creted in proportion to the amount of fat in the body. These functionassatiationsignalstotheCNStohelplimitmealsize(see 4
b
“adiposity”hormonesenterthebrainbytransportthroughthe reviewsinRefs.7–9). y
g
blood-brainbarrierandinteractwithspecificneuronalreceptors In contrast to satiation signals that are phasically secreted u
e
s
primarilyinthehypothalamustoaffectenergybalance.Satiation during meals, adiposity signals are more tonically active, pro- t o
n
andadipositysignalsinteractwithotherfactorsinthehypothal- viding an ongoing message to the brain proportional to total 0
9
amusandelsewhereinthebraintocontrolappetiteandbody body fat. Insulin is tonically secreted in basal amounts, with A
p
weight,andtheyarethetopicofthisreview. phasicincrementsoccurringduringmeals,andbothcomponents ril 2
Bodyweight(adiposity)isahomeostaticallyregulatedvari- oftotalinsulinsecretion(i.e.basalandmeal-stimulated)aredi- 0
1
able,anditslong-termmaintenancecanonlyoccurviaaclose rectlyproportionaltobodyfat(10).Leptinissecretedindirect 9
linkageofenergyintaketoenergyexpenditure.Thismeansthat proportiontobodyadiposity,followingadiurnalpatternwith
overlongintervals,theamountoffoodconsumedmustprovide lessdirectconnectiontomealsthaninsulin(11).Asanindividual
energyequivalenttotheamountofenergyexpended.Humans changesbodyweightthroughcaloricrestrictionorovereating,
andmostmammalsacquireenergyindiscreteepisodesormeals. theamountsofinsulinandleptinsecretedintothebloodchange
Formanymodern-dayhumans,theimpetustobeginamealis inparallel,andthisinturnisreflectedasanalteredsignalofbody
rarelyifeverbasedonabiologicaldeficitorneedsuchasinsuf- fatness, tantamount to body energy stores, reaching the brain
ficient glucose. Rather, “appetite” and “hunger” occur, and (1–3).Theseadipositysignalsinteractwithanabolicandcata-
meals are initiated based on habit, time of day, specific social bolicneuralcircuits,causingachangeinsensitivityofthebrain
situations,convenience,orstress,factorsthatarenotlinkedto to satiation signals. For example, during food deprivation or
energyneedsandsoarenonhomeostatic(4–6).Arguably,this dieting,reducedbraininsulin/leptinsignalingrendersneuralcir-
JClinEndocrinolMetab,November2008,93(11):S37–S50 jcem.endojournals.org S39
cuitscontrollingmealsizelesssensitivetosatiationsignalssuch
TABLE 1. GIhormonesthataffectsatiation
asCCK.Asaconsequence,thehomeostaticsettingisgearedfor
theintakeoflargermealsbecausemorefoodmustbeconsumed Peptide Effectonfoodintake
before a sufficient satiation signal is generated to stop eating. CCK Decrease
This situation of extra-large meals persists until body weight GLP-1 Decrease
(and hence the insulin/leptin signal) returns to normal. Con- PYY Decrease
ApoA-IV Decrease
versely,afterexcessiveweightgain,theincreasedinsulin/leptin
Enterostatin Decrease
brainsignalresultsinincreasedsensitivitytosatiationsignals,
Bombesin/GRP/NMB Decrease
andsmallermealsareconsumeduntiltheexcessweightislost.A Oxyntomodulin Decrease
major dilemma facing clinicians and others involved in public Amylin Decrease D
o
healthistheslippageinthelatterlimbofthishomeostaticsystem Ghrelin Increase wn
lo
thatpermitsexcessiveenergystorage,obesity,andtheassociated a
d
edaisseea,saensdosfonmuterictaionncearlse.xcess;e.g.diabetes,cardiovasculardis- CtilCitKy,ecnotnetrrsatchteiobnlooofdthaendgahlalbslahdodrmero,npaalnicnrfelauteincceenszoynmgeustemcroe-- ed from
tion,gastricemptying,andgastricacidsecretion(16–19).How- h
ttp
ever,CCKalsodiffuseslocallytoprovideaparacrinestimulusto s
Satiation Signals CCK-1 receptors on nearby branches of vagal sensory nerves ://a
c
a
(20–23).Throughthismechanismamessage,generallythatin- d
e
Bydefinition,satiationfactors,whenadministeredtohumansor m
gestedfat/proteinisbeingprocessedandwillsoonbeabsorbed,
animalsatthestartofameal,resultinasmaller-than-normal isconveyedtothehindbrainandrelayedtothehypothalamus ic.o
u
mealbeingconsumed.Exogenouslyadministeredsatiationfac- p
whereitisintegratedintothecompositeinformationonenergy .c
tors,orendogenoussecretionofthesecompounds,activatesspe- o
homeostasis(20,24–28)(Fig.2). m
cificreceptorsthatcauseprematurecessationofeating.Thereare ThedecreaseofmealsizeelicitedbyexogenousCCKisdose- /jce
severalexcellentreviewsofsatiationsignalssuchthatonlythe m
dependent,withhigherdosescausinggreaterreductionsofmeal /a
salientpointsneedtobereviewedhere(7–9,12–14).Itisgen- size. However, CCK does not prevent meals from occurring; rtic
erallyacceptedthatforanendogenouscompoundtobeconsid- le
rather,itdecreasesthesizeofthemealonceithasbegun,reducing -a
eredasatiationsignal,itissecretedinresponsetofoodingestion, b
hungerandincreasingfullnesswithoutconcomitantsensations s
acts within the time frame of a single meal, reduces meal size tra
ofillnessormalaise.WhenaCCK-1receptorantagonistisad- c
without creating malaise or incapacitation, and is effective at ministeredbeforethepresentationoffoodtoanimalsorhumans, t/93
physiologicaldoses,andremovingorantagonizingitsendoge- /1
larger-than-normal meals are consumed (29–31), providing 1
nousactivityincreasesmealsize(7,15). compellingevidencethatendogenousCCKnormallyactstosup- _su
Thebest-establishedsatiationsignalsaresecretedfromspe- p
p
cialized enteroendocrine cells in the wall of the GI tract in re- lem
e
sponsetothedigestionandabsorptionofmeals.Intheclassic n
t_
model of satiation, local sensory nerves express receptors for 1
/s
these gut peptides as they are secreted such that the brain is 3
7
immediatelyinformedaboutthenutritionalcontentofthemeal /26
2
bymonitoringthelevelofhormonessecretedtocopewithit.As 7
2
1
acomplexmealisconsumed,themixofmacronutrients(carbo- 4
b
hydrates,fats,andproteins)stimulatesaproportionalblendof y
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satiationpeptides,andanoverallmessageindicatingmealcon- u
e
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tentisintegratedinthehindbrainwhereitactivatesappropriate t o
n
responses,includingultimatelycessationofthemeal.Inhumans, 0
9
thisisassociatedwithasensationoffullness.Althoughnotall A
p
intestinalhormonesdoubleassatiationsignals,theyallpresum- ril 2
ablycontributetotheassimilationofnutrients;i.e.bystimulat- 0
ingthesecretionofappropriateenzymes,water,andothercom- FIG.2.SatiationsignalsarisingintheGIsystemconvergeonthedorsal 19
hindbrain(D)wheretheyareintegratedwithtasteandotherinputs.Thedorsal
pounds into the lumen of the gut and regulating GI motility. hindbrainmakesdirectconnectionswiththeventralhindbrain(V)whereneural
Table1providesalistofGIandothermeal-relatedhormones/ circuitsdirecttheautonomicnervoussystemtoinfluencebloodglucoseand
wherethemotorcontrolovereatingbehaviorislocated.Thedorsalhindbrain
peptidesthataregenerallyconsideredtobesatiationsignals.
alsoconveysinformationonsatiationandotherfactorsanteriorlytothe
hypothalamusandotherbrainareas.Theseareasinturnintegratesatiationand
Cholecystokinin adipositysignalsaswellasavailablenutrientswithexperience,thesocialsituation
andstressors,andwithtimeofdayandotherfactors.Theintegratedinformation
CCKwasthecompoundfirstidentifiedtofitthecriteriafor
isthenconveyedposteriorlybacktotheventralhindbrainaswellastothe
asatiationfactor,sothatmuchisknownaboutitsactions.Con- pituitarytoinfluenceallaspectsofenergyhomeostasis.Animalslackingneural
sequently, CCK has become the model for the larger class of connectionsbetweenthehindbrainandthehypothalamusreducetheintakeof
individualboutsofeatingwhenthestomachisdistendedortheyare
satiation factors. When food containing fat or protein is con-
administeredCCK.However,thoseanimalscannotregulatetheirbodyweight
sumedandenterstheduodenum,CCKissecretedfromIcells. andarenotsensitivetopastexperience,timeofday,orsocialfactors(243).
S40 WoodsandD’Alessio CentralControlofBodyWeightandAppetite JClinEndocrinolMetab,November2008,93(11):S37–S50
press intake during meals. However, the effect of exogenous importantinthecontrolofenergyhomeostasis(55,56).Cen-
CCKisshort-lived;themeal-reducingsignaldoesnotcarryover trallyadministeredGLP-1reducesfoodintakethroughatleast
to a second meal. Moreover, the effect of repeated or chronic twomechanisms.GLP-1rinthehypothalamusappeartoreduce
administration of CCK (32, 33) has no effect on body weight intake by acting on caloric homeostatic circuits (57–60),
becausetheshort-termregulationofmealsizeisoverriddenby whereasGLP-1rintheamygdalareducefoodintakebyeliciting
overallenergybalance.Thatis,inthecontextofloweradiposity, symptomsofstressormalaise(61,62).
leptinandinsulinsignalstothebrainarereducedandsatiation SystemicallyadministeredGLP-1elicitssatiationinhealthy
factorslikeCCKhaveareducedeffecttorestrictmealsize. (53),obese(63),anddiabetic(64,65)humans.Becausethehalf-
Thereisstrongexperimentalevidencesupportingarolefor lifeofactiveGLP-1islessthan2min,anydirecteffectsarelikely
CCKasasatiationfactorinhumans.CCKlevelsincreaseafter transient,andthereductionoffoodintakemayresultfromin- D
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meals, and infusion of an exogenous CCK-1 receptor agonist, hibitoryeffectsofGLP-1onGItransitandreducedgastricemp- n
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CCK-33,topostprandiallevelssuppressesfoodintake(34,35). tying (66). However, peripherally administered GLP-1 does a
d
Furthermore,infusionofaCCK-1receptorantagonisttohealthy crosstheblood-brainbarrier(67),perhapsenablingcirculating ed
humanscausesanincreaseincaloricintake,stronglyimplicating GLP-1tointeractwiththebrainGLP-1r.Becauseitbothreduces fro
m
endogenousCCKasabrakeonmealsize(29,36).Theeffectsof foodintakeandstimulatesinsulinsecretion,theGLP-1system h
CCK-1agonismandantagonismaresimilarinleanandobese hasbeenadaptedtothetreatmentoftype2diabetes(68,69). ttp
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humansandareassociatedwithappropriatechangesinhunger DPP-IV-resistant, long-acting GLP-1r agonists are effective at ://a
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andfullness.Interestingly,blockadeofCCK-1receptorsaffects reducingbloodglucoseinpersonswithtype2diabetesandalso a
d
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the postprandial responses of other GI hormones, attenuating causeweightloss(70).Inaddition,inhibitorsofDPP-IV,which m
theusualriseinpeptideYY(PYY)andabolishingthesuppres- elevateendogenousGLP-1levels,arealsoeffectiveatimproving ic.o
u
sion of ghrelin (37). This latter finding suggests that beyond glycemiccontrolindiabeticpatients(71,72). p
.c
directlyinhibitingfoodintake,CCKactsasaproximalmediator TheeffectofchronicGLP-1ragoniststocauseweightlossis o
m
of the broader satiation process. Two minor single nucleotide notconsistentwiththegeneralprinciplethatsatiationpeptides /jc
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polymorphismsintheCCK-1receptorgenepromoterhavebeen aresubservienttolong-termregulatorsofenergybalance,such m
/a
associated with increased body fatness, but the mechanism of asleptin(3).OnepotentialexplanationisthatbecauseGLP-1 rtic
thisassociationhasnotbeenexplained(38). canactivatenonhomeostaticpathwaysthatsuppressfoodintake le
-a
andotherwisereducebodyweight,theeffectsofchronicadmin- b
s
Glucagon-likepeptide-1 istrationofGLP-1ragonistsworkaroundthehomeostaticsys- tra
c
Glucagon-like peptide-1 (GLP-1) is derived from progluca- temscontrollingbodyweight.Indeed,nausea,ahallmarkfeature t/9
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goninintestinalLcellsthataremostprevalentintheileumand ofnonhomeostaticanorexia,isverycommonwithGLP-1rag- /1
1
colon(39).GLP-1secretioniselicitedbynutrients,butthemech- onisttreatment(73),althoughthisresponsewaneswithcontin- _s
u
anismwherebythedistalLcellsarestimulatedearlywithinmeals uedtreatmentandisnotpresentinallpersonswholoseweight. p
p
mayrequireneurohumoralsignalsinitiatedintheproximalre- Anotherpossibleexplanationforwhypatientstreatedwithin- lem
e
gions of the small intestine (40). GLP-1 has a broad range of dictableGLP-1ragonistsloseweightisthatrepeatedpharma- n
t_
actionsonglucosemetabolism(41),mostprominentlystimula- cologicaldosesofasatiationsignalcanovercomehomeostatic 1
/s
tionofinsulinsecretion,butalsoinhibitionofglucagonrelease. restraints. Consistent with this hypothesis is the failure of 3
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BecauseGLP-1inhibitsGImotilityandsecretions,ithasbeen DPP-IVinhibitortreatment,whichhasasmallereffecttoraise /26
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implicatedasamajorcomponentofthe“ilealbrake,”aninhib- circulating concentrations of GLP-1r agonist activity than do 7
2
1
itory feedback mechanism that regulates transit of nutrients injectableGLP-1mimeticstocauseweightloss.Althoughitisnot 4
b
throughthecourseoftheGItract(42,43).Ithasgenerallybeen yetclearhowGLP-1ragonistscauseweightloss,thefactthat y
g
assumedthatGLP-1mediatesthesevariousactionsthroughan theydochallengesthecurrentmodeloftheinteractionofsati- u
e
s
endocrinemechanism,bybindingdirectlytokeytargettissues ationfactorswithoverallenergyhomeostasis. t o
n
likepancreaticisletcells.However,thismechanismhasrecently 0
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beencalledintoquestion,inlargepartbecauseGLP-1israpidly Glicentin,GLP-2,oxyntomodulin,andglucagon A
p
metabolizedinthecirculationbytheproteasedipeptidylpepti- Otherpeptidesderivedfromtheprocessingofproglucagon ril 2
daseIV(DPP-IV)(44).Indeed,thehalf-lifeofGLP-1inhuman includeglicentin,GLP-2,andoxyntomodulin,aswellasgluca- 0
1
plasma is only 1–2 min, and the product of DPP-IV action, a gonitself(39).Glicentininhibitsgastricacidsecretion(74),but 9
truncatedGLP-1,isinactivewithregardtoglucosemetabolism at least in rats, does not affect food intake (75). In contrast,
(45).BecausetheGLP-1receptor(GLP-1r)isexpressedbype- oxyntomodulin,aC-terminallyextendedcongenerofglucagon,
ripheralandCNSneuronsaswellasbycellsinthepancreatic doesreducefoodintakeinanimalswhengivencentrallyorpe-
islets and the GI tract, recent attention has focused on neural ripherally(75,76).Althoughauniquereceptorforoxyntomodu-
mechanismsofGLP-1action(46–48). lin has yet to be identified, oxyntomodulin may exert its ano-
GLP-1 administration reduces food intake in animals and recticeffectthroughtheGLP-1rbecausesubthresholddosesof
humans(49–54),andtheseanorecticactionsarethoughttobe theGLP-1rantagonist,exendin(9–39),blockbothGLP-1and
mediated through both peripheral and central mechanisms. A oxyntomodulin-inducedreductionsinfoodintake(75).Oxyn-
population of neurons that synthesize GLP-1 is located in the tomodulinisthoughttocrosstheblood-brainbarrierandstim-
brainstemandprojectstohypothalamicandbrainstemareas ulateneuronsinthearcuatenucleus(ARC)thatexpressGLP-1r
JClinEndocrinolMetab,November2008,93(11):S37–S50 jcem.endojournals.org S41
andcontrolenergyhomeostasis(77,78).Long-termtreatment orifneurohumoralsignalsoriginatingfromthemoreproximal
withoxyntomodulincausesapersistentdecreaseinfoodintake GItractmediatetheresponse.ThereisevidencethatPYYinflu-
andattenuatedweightgaininrats(79).Interestingly,weightloss encesfoodintakethroughitsinteractionwithY2receptorsinthe
inanimalsgivenoxyntomodulinchronicallyisgreaterthanwhat ARCbecauseitfreelycrossestheblood-brainbarrier(102)and
wouldbeanticipatedfromreducedcaloricintake(78),suggest- becausesystemicPYY(3–36)isineffectiveinreducingfoodin-
ingadditionaleffectsonenergyexpenditure. takeintheY2-deficientmouse(103).
Short-termtreatmentwithivoxyntomodulindecreaseshun- StudiesinhumanshavedemonstratedthatPYYsignalingre-
ger, reduces consumption of an ad libitum meal, and has an duces food intake and that abnormalities in this system are
anorecticactionthatpersistsfor12haftercessationoftreatment presentinobesesubjects.PYYsecretionisproportionaltothe
inleanhumans(80).Moreover,inobesesubjectsrandomizedto caloriccontentofmeals,withlargermealselicitingasignificantly D
o
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injectionsofoxyntomodulinorplacebobeforeeachmealfor4 larger response (104, 105). Fasting and postprandial levels of n
lo
wk,therewasasignificantlossofweightassociatedwithactive PYYarelowerinobeseadultscomparedwithleancontrols(105, a
d
treatment.Oxyntomodulincausedanapproximately0.5kg/wk 106).TheattenuatedriseinPYYaftereatinghasalsobeenob- ed
reductioninbodyweightandwasgenerallywelltolerated.These servedinobeseadolescents(107).InfusionofPYY(3–36)into fro
m
findingssuggestthatatleasttwoproglucagonproductsmayhave lean and obese humans reduced food consumption measured h
aroleintheregulationoffoodintake.Distinguishingbetween duringtestmeals(104–106),althoughthereremainssomeques- ttp
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theeffectsofGLP-1andoxyntomodulin,inparticulartherela- tionastowhetherthiseffectofPYY(3–36)ispharmacological ://a
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tiveinvivoactionsontheGLP-1r,isanimportantnextstepin oroccursatcirculatinglevelsseenaftereating.Obesesubjectsdid a
d
e
applyingthesecompoundstoclinicalmedicine. notdifferintheirsensitivitytoPYY,andtherewasnodifference m
GLP-2 acts through a specific GLP-2 receptor to stimulate intherelativePYY(1–36)andPYY(3–36)levelsafterexogenous ic.o
u
intestinalmucosalgrowthandhasbecomethefocusofresearch administration.Takentogether,thesefindingssuggestthatab- p
.c
on short-bowel syndrome (81, 82). GLP-2 and GLP-1 have normalPYYproduction,ratherthananorecticactionofmetab- o
m
nearly50%sequencehomologyandaresecretedinparallelfrom olism,couldcontributetoobesity. /jc
e
perfusedilealpreparations(83).Intracranialadministrationof Interestingly,thereisevidencethatgeneticvariationsinthe m
/a
GLP-2reducesfoodintakeinrats,andtheeffectcanbeblocked PYYandY2sequencesareassociatedwithbodyweight.Acom- rtic
withaspecificGLP-1rantagonist(84).Morerecentstudiesin mongenepolymorphismintheY2receptorhasbeenassociated le
-a
humansfoundnoeffectofivGLP-2onfoodintake(85). withareducedlikelihoodofobesityinacohortstudyofmenwith b
s
Glucagonisthemostwidelystudiedhormonecleavedfrom abroadrangeofBMI(108).Additionally,inasurveyofleanand tra
c
preproglucagon(39).ItissecretedfrombothpancreaticAcells veryobesemen,apolymorphisminthePYYallelewasfoundto t/9
3
andprobablyalsoinsmallamountsfromthedistalintestine.The segregatewithincreasedbodyweight;thisgeneticvariantofPYY /1
1
best known action of glucagon is to increase hepatic glucose wasalsofoundtohavereducedbindingtoitsreceptorandan _s
u
productionbystimulatingglycogenolysisandgluconeogenesis. attenuatedanorecticeffectinmice(109).Intotal,thedatacol- p
p
Glucagonalsoreducesmealsizewhenadministeredsystemically lectedinhumanstudiessupportaroleforPYYintheregulation lem
e
(86,87),butnotcentrally(88),thesignalbeingdetectedinthe offoodintakeandbuildthestrongestcaseforanyofthesatiation n
t_
liver and relayed to the brain (89). A role for glucagon in the factorsinthepathogenesisofobesity. 1
/s
normalcontrolofmealsizewasdemonstratedbytheobservation 3
7
thatblockingendogenousglucagonactioninratsincreasesfood ApolipoproteinA-IV /26
2
intake(90,91).Thereislittleconvincingevidencethatglucagon ApolipoproteinA-IV(apoA-IV)issynthesizedbyintestinal 7
2
1
playsaroleinfoodintakeinhealthyhumans. mucosalcellsduringthepackagingofdigestedlipidsintochy- 4
b
lomicronsthatsubsequentlyenterthebloodviathelymphatic y
g
Peptidetyrosine-tyrosine(PYY) system (110). Apo A-IV is also synthesized in the ARC (111). u
e
s
PYYisamemberofafamilyofhomologouspeptidesthatalso Systemic or central administration of apo A-IV reduces food t o
n
includes pancreatic polypeptide and neuropeptide-Y (NPY). intakeandbodyweightofrats(112),andadministrationofapo 0
9
Likeproglucagon-derivedpeptides,PYYissynthesizedandse- A-IVantibodiesincreasesfoodintake(113).ApoA-IVappears A
p
cretedbyLcellsinthedistalileumandcolon(92).PYYissecreted toworkbyinteractingwiththeCCKsignal(114).Becauseboth ril 2
asPYY(1–36)andismetabolizedtoPYY(3–36)byDPP-IV(93, intestinalandhypothalamicapoA-IVareregulatedbyabsorp- 0
1
94).ReceptorsthatmediatetheeffectsofPYY,includingreduc- tionoflipidbutnotcarbohydrate(115),thispeptidemaybean 9
tionoffoodintake,belongtotheNPYreceptorfamilyandin- importantlinkbetweenshort-andlong-termregulatorsofbody
cludeY1,Y2,Y4,andY5(95).However,PYY(3–36)isahighly fat(seereviewbyTsoandLiuinRef.116).
selectiveagonistactivityfortheY2receptor,anditalsoreduces
foodintakeinhumansandanimals(96,97).LikeGLP-1,PYY Enterostatin
has been implicated in GI motility and is considered a major A second digestion-related peptide, enterostatin, is also
componentoftheilealbrake(98,99).SecretionofPYYisstim- closelytiedtointestinalprocessingoflipid.Theexocrinepan-
ulatedbyfoodintake(100)andalsobythepresenceofnutrients creassecreteslipaseandcolipasetoaidinthedigestionoffat,and
within the ileum itself (101); lipid seems to be a particularly enterostatin,apentapeptide,iscleavedfromcolipaseinthein-
effectivestimulus.SimilartothecasewithGLP-1,itisnotclear testinallumenandentersthecirculation.Administrationofex-
whetherPYYreleaserequiresdirectnutrientcontactwithLcells, ogenousenterostatineithersystemically(117,118)ordirectly
S42 WoodsandD’Alessio CentralControlofBodyWeightandAppetite JClinEndocrinolMetab,November2008,93(11):S37–S50
intothebrain(119)reducesfoodintake,and,whenratsaregiven Amylin has been developed as a therapeutic, with the syn-
achoiceoffoods,thereductionisspecificforfats;thatis,en- theticanalogpramlintidenowavailableforthetreatmentoftype
terostatindoesnotdecreasetheintakeofcarbohydrateorpro- 1andtype2diabetesandclinicaltrialsunderwaytodetermine
tein(120).Therefore,twopeptidesthataresecretedfromthegut theefficacyintreatingobesity.Indiabeticpatientstreatedwith
duringthedigestionandabsorptionoflipids,apoA-IVanden- pramlintidefor1yr,weightlossaveragedapproximately2kg
terostatin,actassignalsthatdecreasefoodintake,andatleast relativetoplacebo-treatedcontrols(143,144).Similartotreat-
oneofthemselectivelyreducestheintakeoffat.Macronutrient mentwiththeGLP-1ragonistexendin-4,pramlintidepresents
specificityhasnotbeenassessedwithapoA-IV.Therearenodata supraphysiologicallevelsofamylin-likeactivitytopatients,and
fromhumanstudiestoconfirmthefindingswithapoA-IVand theprimarysideeffectisnausea.Nonetheless,theclinicalexpe-
enterostatinonfoodintake. riencewithpramlintidesupportstheideathatchronicactivityof D
o
w
asatiatingcompoundcancauseweightloss. n
lo
Bombesin-familypeptides a
d
Membersofthebombesinfamilyofpeptidesincludingbomb- Ghrelin ed
esinitself(anamphibianpeptide)anditsmammaliananalogs, Ghrelin,aproductofspecificendocrinecellsinthestomach fro
m
gastrin-releasingpeptide(GRP)andneuromedinB(NMB),re- andduodenum,actuallystimulatesfoodintakeandisthemost h
ducefoodintakewhenadministeredsystemicallyinhumansand potent known circulating orexigen (145). Ghrelin is secreted ttp
s
animalsorintotheCNSofanimals(121–123).Consistentwith fromthefundicregionofthestomachandhasbeenidentifiedas ://a
c
the possibility that these peptides act endogenously to reduce theendogenousligandfortheGHsecretagoguereceptor.Fasting a
d
e
foodintake,micedeficientfortheGRPreceptoreatsignificantly increasesplasmaghrelin(146),andexogenousghrelinincreases m
largermealsanddeveloplate-onsetobesity(124).Whereasmost foodintakewhenadministeredperipherallyorcentrally(147– ic.o
u
satiationfactorsactbyreducingthesizeofanongoingmeal(4), 149).Ghrelinhasalsobeenlinkedtotheanticipatoryaspectsof p
.c
bombesinpeptidesareaninterestingexceptioninthatwhenthey meal ingestion because levels peak shortly before scheduled o
m
are administered between meals, they increase the amount of mealsinhumansandrats(150)andfallshortlyaftermealsend. /jc
e
timeuntilthesubsequentmealbegins;i.e.theyincreasesatietyas Moreover,elevatedghrelinhasbeenlinkedtothehyperphagia m
/a
wellassatiation(125,126). andobesityofindividualswiththePrader-Willisyndrome(151). rtic
Both bombesin and GRP reduce food intake when infused GhrelinisalsouniqueamongtheGIsignalsinthatitsmessage le
-a
into human subjects (127, 128). Antagonism of endogenous appearstobeconveyeddirectlytoreceptorsinthehypothalamus b
s
bombesinreceptorshasdemonstrableeffectsongastric,intesti- (152–155),although,asisthecaseforCCK,GLP-1,andother tra
c
nal,andgallbladderfunctionbuthasnotbeenstudiedwithre- GIsignals,thereareghrelinreceptorsonvagalsensorynerves t/9
3
gardtofoodintake(129,130).ThereforethecaseforGRPasa (156)buttheydonotappeartosignalsatiation(157). /1
1
physiologicalmediatorofsatiationinhumansisnotasstrongas _s
u
forCCK. Satiationsignals:summaryofgeneralprinciples p
p
Satiationappearstobeacomplexphenomenon,mediatedby lem
Amylin anumberofGIpeptides.Althoughitisclearthatthedifferent en
t_
Amylin (also called islet amyloid polypeptide) is a peptide satiationfactorsrespondtospecificnutrientstimuli(e.g.CCKto 1
/s
hormonesecretedbypancreaticBcellsintandemwithinsulin proteinandfat,GLP-1tocarbohydrateandfat,PYYprimarily 3
7
secretion, which inhibits gastric emptying and gastric acid se- tofat,andsoon),ithasnotbeenproventhatmixedmealsof /26
2
cretion, lowers glucagon concentrations, and reduces food in- differingmacronutrientcontentelicitthereleaseofdistinctcock- 7
2
1
take(131).Amylincausesadose-dependentreductionofmeal tailsofGIhormones.However,giventhewiderangeofspecific 4
b
size when administered systemically or directly into the brain factorsthatseemtomediatesatiation,itislogicaltopresumethat y
g
(132–136),andantagonismofamylinactionintheCNScauses this process is subject to highly refined regulation. Especially u
e
s
increasedfoodintakeandbodyweight(137).Consistentwith importantisthemodulationoftheactionofsatiationbyfactors t o
n
this,targeteddeletionoftheamylingenecausesincreasedbody suchasleptinandinsulinthatareresponsivetobodyadiposity. 0
9
weightinmice. This interaction is the critical site of endocrine regulation of A
p
Amylin signals through the calcitonin receptor when it has eatingandenergyhomeostasis. ril 2
been modified by receptor activity modifying proteins (138, Akeyfeatureofthesystemregulatingfoodintakeisthatmost 0
1
139),andincontrasttomanysatiationpeptidesthatreducefood ifnotallofthepeptidesthataremadeintheGItractandinfluence 9
intakebystimulatingthevisceralafferentnerves,amylinseems satiationarealsosynthesizedinthebrain.ThisincludesCCK,
to act as a hormone, directly stimulating neurons in the area GLP-1, GLP-2, oxyntomodulin, apo A-IV, GRP, NMB, PYY,
postremainthehindbrain(133,140).Infact,theanorecticac- andghrelin.Exceptionsarethepancreatichormonesthatinflu-
tionofamylinsharesfeatureswithbothsatiationsignals(phasic, enceenergyhomeostasis(i.e.insulin,glucagon,andamylin)and
meal-inducedsecretion)andadipositysignals(chronicinterrup- the adipose tissue/stomach hormone leptin; and each of these
tionofactioninrodentscausesincreasedbodyfatness).Amylin latterhormoneshaslong-termeffectsonbodyfataswell.The
seemstointeractwithbothtypesofregulationinthattheability factthatsomanyperipheralsignalsthatinfluencefoodintakeare
ofamylintoreducemealsizeisaugmentedwhenbraininsulin also synthesized locally in the brain raises the question of
actioniselevated(141)andtheeffectsofCCKandbombesinare whetherandhowthesamesignalssecretedfromdifferentplaces
mutedintheabsenceofamylinsignaling(142). inthebodyinteract.Asimplegeneralizationisthat,ifapeptide
JClinEndocrinolMetab,November2008,93(11):S37–S50 jcem.endojournals.org S43
reduces(orincreases)foodintakewhenadministeredsystemi- quentlyloseweight(169).Theadventoflong-actingformula-
cally,itprobablyhasthesameactionwhenadministeredcen- tionsofGLP-1andamylin,peptidesthatseemtohavearolein
trally.Withregardtochangesoffoodintake,thisistrueofCCK, satiation(170,171),hasresultedinweightloss(172,173).How-
GLP-1,apoA-IV,GRP,NMB,PYY,andghrelin.Interestingly, ever,atpresentitisnotclearthatthechroniceffectsofGLP-1and
itisalsogenerallytruethatpeptidesignalsthatarenotsynthe- amylinreceptoragonistsareentirelyduetocontinuedhypopha-
sizedinthebrainnonethelesshavethesameeffectonfoodintake gia as opposed to other, nonbehavioral actions of the com-
whenadministereddirectlyintothebrain.Thisistrueofleptin, pounds.Understandinghowachronicpharmacologicalstimulus
insulin,andamylin,butnotglucagon. tothesatiationsystemlowersbodyweightisimportantforre-
Itisworthcontemplatingwhythereissuchalargeimbalance finingthemodelsfornormalenergyhomeostasis.
amongGIhormonesthatsuppressandstimulatefoodintake;i.e. D
o
w
whereasnumerouspeptidessecretedfromthestomachandin- n
lo
testines decrease food intake, only one known factor, ghrelin, Adiposity Signals ad
increasesit.Onepossibilityrelatestothephenomenonofsati- ed
ationitselfandthebenefitsofmealtermination.Mealsendlong InsulinfromthepancreaticBcellsandleptinfromwhiteadipo- fro
m
beforeanyphysicallimitofthestomachisreached.Thisiseasily cytes(aswellasthestomachandothertissues)areeachsecreted h
demonstrated when food is diluted with noncaloric bulk and indirectproportiontobodyfat.Bothhormonesaretransported ttp
s
animals increase the volume of food consumed to attain their throughtheblood-brainbarrier(174,175)andgainaccessto ://a
c
normalcaloricload(158,159).Ithasthereforebeenarguedthat neuronsinthehypothalamusandelsewhereinthebraintoin- a
d
e
aprimaryfunctionofsatiationsignalsistopreventtheconsump- fluenceenergyhomeostasis.Hence,neuronssensitivetoinsulin m
tionoftoomanycaloriesatonetime,lesttheinfluxofnutrients and/orleptinreceiveasignaldirectlyproportionaltotheamount ic.o
u
andsubstratesoverwhelmthecapacityoftheanimaltomaintain offatinthebody.Consistentwiththis,ifexogenousinsulinor p
.c
homeostasis(5,160).Thatis,animportantroleoftheGItract leptinisaddedlocallyintothebrain,theindividualrespondsas o
m
istoanalyzeandrespondtotheincomingmacronutrientswhile ifexcessfatexistsinthebody;i.e.foodintakeisreducedand /jc
e
amealisbeingeaten,helpingtopreemptexcessivechallengesto bodyweightislost.Analogously,ifeithertheleptinortheinsulin m
/a
biochemicalhomeostasis.Acorollarytothisroleforsatiation signalisreducedlocallyinthebrain,theindividualrespondsas rtic
signalsisthatadequatefoodintakedoesnotrequiremuchspe- ifinsufficientfatispresentinthebody,morefoodiseaten,and le
-a
cificstimulation,onlytheabsenceofinhibitorysignalsforfood the individual gains weight. There are many reviews of these b
s
intakecombinedwiththepresenceoffood.Untilrecentlythere phenomena(1,2,87,176–178). tra
c
wassomequestionastowhethermanipulationofmealsizeby Animportantdistinctionisthatwhereassatiationsignalspri- t/9
3
factors activating the satiation system could have therapeutic marilyinfluencehowmanycaloriesareeatenduringindividual /1
1
efficacyforweightreduction.Onepossibilitywasthatbecause meals,adipositysignalsaremoredirectlyrelatedtohowmuchfat _s
u
theeffectsofsatiationpeptidesaredependentonbodyadiposity, the body carries and maintains. Developing novel compounds p
p
their action would become muted as food intake decreased thatinteractdirectlywiththenormaldetectionofandresponse lem
e
duetohomeostaticregulationofbodyenergystores.Evidence toadipositysignalswouldthereforeseemamorepromisingther- n
t_
for this was demonstrated for the satiating action of CCK in apeuticapproachforobesity.Akeyquestionthereforeiswhether 1
/s
geneticallyobeseZuckerrats(161,162),butnotforratsren- agonistsfortheleptinand/orinsulinreceptorwouldbeviable 3
7
deredobesebylesionsoftheventromedialhypothalamus(163). targetsforthepharmaceuticalindustry.Oneobstacleisthatto /26
2
Furthermore,ratsgeneticallypronetobecomingobesewhenfed be effective, any compound would have to gain access to key 7
2
1
ahigh-fatdiet(diet-inducedobesityrats)areactuallymoresen- receptorsinthebrain,yetanysuchcompoundwouldmostlikely 4
b
sitivetothesatiatingactionofCCKbothbeforeandafterbe- havetobeadministeredsystemically.Administeringinsulinsys- y
g
comingobese(164).Somestrainsofgeneticallyobesemiceare temicallyelicitshypoglycemiaandothersideeffects,andhypo- u
e
s
comparablyassensitiveasleancontrols(165),andCCKworks glycemiaperseincreasesfoodintake(179–181),thusworking t o
n
wellinobesehumanswhenadministerediv(166).Hence,there againstthetherapeuticintent.Systemicallyadministeredinsulin 0
9
is no general principle with regard to sensitivity in obesity, at doesresultinreducedfoodintakewhenplasmaglucoseispre- A
p
least with regard to CCK. There is evidence that the satiating vented from decreasing in animal models (182, 183), but this ril 2
actionofGLP-1isleptin-dependent(167).Alloftheseobserva- wouldbedifficulttoachievetherapeutically.Alternatively,there 0
1
tions were made with animals having relatively free access to arereportsthatsomeformulationsofnasallyadministeredin- 9
their diets so that they could vary their meal patterns in the sulinelicitreducedfoodintakeandbodyweightinhumanswith-
serviceofmaintainingbodyfat;i.e.whenindividualsarecon- outalteringplasmaglucose(184,185).
strainedtoeatingonlysmallmeals,theycompensatebyeating Leptin does not have the same counterproductive systemic
moreoften,therebymaintainingdailycaloricintakeandbody effects as insulin, and in fact improves insulin sensitivity and
weight.ThishasbeenobservedwhenCCKisadministeredbe- circulatinglipoproteinconcentrationsinsubjectswithmetabolic
foreeverymealinexperimentalanimals;animalsreceivingthis abnormalitiesassociatedwithanti-HIVtreatment(186).More-
treatment eat smaller and more frequent meals while keeping over,chronicleptintreatmentofpatientswithgeneralizedlipo-
bodyweightconstant(33,168).Incontrast,ifanimalsarecon- dystrophycausessignificantimprovementsofinsulinresistance,
strainedtoeatingonlythreemealsadayandreceiveasatiating hypertriglyceridemia,hepaticsteatosis,andglucosemetabolism
peptide at each mealtime, they cannot compensate and conse- (187),responsesfoundacrossthespectrumoflipodystrophies.
S44 WoodsandD’Alessio CentralControlofBodyWeightandAppetite JClinEndocrinolMetab,November2008,93(11):S37–S50
However,theresultsofclinicaltrialsusingleptininhealthyobese ulatefoodintake(205–207).WheneitherAgRPorNPYisad-
subjectshavebeenvariable,withsignificantweightloss,butnot ministered chronically into the brain, body weight increases
ofaremarkablemagnitude,andsomebothersomesideeffects (202,208–211).Infact,whenasingledoseofAgRPisadmin-
relatedtopeptideadministration. isteredintothebrainneartheARC,foodintakeisincreasedfor
Insulin and leptin resistance characterize the obese state, 1wkormore(212,213).Insulinandleptineachhaveaneteffect
meaning that more of each hormone is required to achieve a tosuppresstheactivityofNPY/AgRPneuronsintheARC.
particular physiological effect than occurs in lean individuals. ThePOMCandNPY/AgRPneuronsintheARCsharemany
Individuals with diabetes cannot achieve a maximum insulin importantfeatures.Eachistheoriginoftractsprojectingtoother
responsebecauseofdefectsininsulinsecretionandinsulinac- hypothalamicandbrainareas,thetwotractsoftenoccurringin
tion.Theinsulinandleptinresistancethatcharacterizesperiph- parallel. The POMC-originating tract has an overall catabolic D
o
w
eral tissues in obesity is also manifested in the brain. For one effect such that when it is more active food intake is reduced, n
lo
thing,thetransportofbothhormonesfromthebloodtothebrain energyexpenditureisincreased,andifprolonged,bodyfatislost. a
d
iscompromisedinobesitysuchthatlesssignalreachescritical Conversely, the NPY/AgRP-originating tract is anabolic, with ed
neurons(188–190),andtheabilityofthoseneuronstorespond heightenedactivitycausingmorefoodtobeingestedandbodyfat fro
m
isalsocompromised.Wheninsulinisadministeredlocallyinto to increase. Under normal conditions, both circuits are active h
thebrainnearthehypothalamus,bothgeneticallyobese(191) suchthatachangeofinputthatiseitherstimulatoryorinhibitory ttp
s
and dietary obese individuals (192) have a reduced or absent toeithertypeofneuronelicitsrapidchangesofmanyenergetic ://a
c
reductionoffoodintake,andthisisthecaseforleptinaswell parameters.Intheacutesituation,bothfoodintakeandplasma a
d
e
(193).Hence,aninabilityonthepartofthebraintorespondto glucosearealteredbecausetheARCinfluencescircuitsproject- m
signalsindicatingthatthereisexcessfatinthebodymaybea ingtobehavioralsitesaswellasautonomiccircuitsinfluencing ic.o
u
contributing and/or confounding factor in obesity. An insulin hepatic glucose secretion and pancreatic insulin secretion p
.c
mimeticthatinteractswiththeinsulinreceptorandisefficacious (214–216). o
m
whengivenorallyordirectlyintothebrainhasbeenreportedto AnotherimportantaspectoftheareaincludingtheARCand /jc
e
reducefoodintakeandbodyweightinobeserodents(194,195), nearby hypothalamic nuclei is that receptors for many of the m
/a
butitevidentlyhasproblematicsideeffects. satiationsignalsdiscussedaboveareexpressedthere;i.e.circu- rtic
latingghrelinisthoughttointeractdirectlywithARCneurons le
-a
(152),whicharealsodirectlyorindirectlysensitivetochangesof b
s
Central Integrating Circuits CCK,GLP-1,NMB,andapoA-IV.Becausemostofthesepep- trac
tidesaremadewithinthebrain,theoriginofmoleculesaltering t/9
3
Although receptors for insulin and leptin are found in several ARCactivitymaynotbedirectlyfromtheplasmaasoccurswith /1
1
discrete areas throughout the brain, many that are especially insulin, leptin, and ghrelin. Numerous circuits from the hind- _s
u
importantforcontrollingenergyhomeostasisarelocalizedinthe brain satiation area and elsewhere in the brain project to the p
p
ARCofthehypothalamus(Fig.1).TheARCisideallysuitedas regionoftheARC(25,27,217).Finally,ARCneuronsarealso lem
e
a receptor site for body adiposity as well as for integration of sensitivetolocallevelsofenergy-richnutrients,includingglucose n
diverse hormonal and neural signals because there is evidence (218),somelong-chainfattyacids(cid:1)e.g.oleicacid(219,220)(cid:2), t_1
thatblood-bornemoleculeshaverelativelygreateraccesstore- andsomeaminoacids(cid:1)e.g.leucine(221)(cid:2). /s3
7
ceptorstherethantootherbrainareas,andthisisthoughttobe Thus,theARCissituatedtobesensitivetoawidearrayof /26
2
dueinparttoarelativelyleakyblood-brainbarrierintheARC signalsimportantinenergyregulation(216,222–224).Itisdi- 7
2
1
(196,197).TwocategoriesofARCneuronsareparticularlyim- rectlysensitivetohormoneswhosesecretionisproportionalto 4
b
portant.Onesynthesizestheprepropeptide,proopiomelanocor- bodyfat(insulinandleptin);itreceivesinformationonongoing y
g
tin(POMC),andintheARCPOMCiscleavedto(cid:1)-melanocyte- mealseitherdirectlyorindirectly;anditissensitivetolocallevels u
e
stimulatinghormone((cid:1)MSH)asaneurotransmitter.(cid:1)MSHacts ofnutrients.Importantly,numerousneuronalcircuitsintercon- st o
n
at melanocortin 3 and melanocortin 4 receptors (MC3R and necttheARCandnearbyhypothalamicareaswiththenucleusof 0
9
MC4R)onneuronsinotherhypothalamicareasandelsewhere the solitary tract, enabling the hypothalamic homeostatic net- A
p
inthebraintoreducefoodintake,andsyntheticagonistsfor worktobeconstantlyawareofongoingGIactivitywhileatthe ril 2
MC3R/MC4R are available that cause hypophagia and sametimeinfluencingbrainstemautonomicareasprojectingto 0
1
weightlossinexperimentalanimals(seereviewsinRefs.1,2, theGItract,liver,pancreas,andothertissues(25,27,225–227). 9
196,and198–202).Thecatabolicactionofbothleptinand TheARCcanthereforebeconsideredasakeyafferentaswellas
insulinreliesupon(cid:1)MSHsignalingbecauseadministrationof efferentareafortheregulationofenergyhomeostasis.
antagonists to MC3R/MC4R blocks each of their actions in Although ARC neurons project throughout the brain, two
thebrain(203,204). nearbytargetareasarethoughttobeespeciallyimportant.The
ThesecondgroupofARCneuronssynthesizesandsecretes paraventricular nuclei (PVN) express both MC3R/MC4R and
twoneuropeptidesimportantinenergyhomeostasis,andtheir various Y receptors, and PVN neurons in turn synthesize and
axonsprojecttomanyofthesamebrainareasasPOMCneurons. secreteneuropeptidesthathaveanetcatabolicaction,including
Agouti-related peptide (AgRP) is an antagonist at MC3R and CRHandoxytocin.AdministrationofexogenousCRH(228)or
MC4R(199)suchthatoneactionoftheseneuronsistocounter oxytocin(229)intothebrainreducesfoodintake.Hence,acat-
theactivityofPOMCneurons.NPYactsatYreceptorstostim- aboliccircuitexistsinwhichanincreaseofbodyfatisassociated
JClinEndocrinolMetab,November2008,93(11):S37–S50 jcem.endojournals.org S45
with increased insulin and leptin, increased (cid:1)MSH, and de- influencing not only when meals occur but how much food is
creasedNPYandAgRPactivity,andconsequentlyincreasedac- consumedaswell.Onlywhenextraneousfactorsaretightlycon-
tivityofCRH,oxytocin,andothercatabolicsignals;allofthese trolledinlaboratoryanimalexperiments,orelsewheningestion
lead in turn to reduced food intake and increased energy is precisely monitored and quantified over periods of days or
expenditure. weeksinfree-feedinghumans,dotheeffectsofthesehomeostatic
Thelateralhypothalamicarea(LHA)hasacontrastingprofile signalsbecomeapparent.
fromthePVN(230).ItalsoreceivesdirectinputsfromtheARC,
anditcontainsneuronsthatsynthesizeandsecreteanabolicpep-
tides,includingmelanin-concentratinghormoneandtheorex-
Acknowledgments
ins. Administration of melanin-concentrating hormone (231, D
o
w
232) or orexin agonists (233) increases food intake and body Addressallcorrespondenceandrequestsforreprintsto:StephenC. n
weightgain.Thearchitectureandfunctioningoftheseopposing Woods, Department of Psychiatry, University of Cincinnati, 2170 loa
d
hypothalamic circuits therefore enables rapid and fine-tuned EastGalbraithRoad,Cincinnati,Ohio45237.E-mail:steve.woods@ ed
controloverenergyhomeostasisbecausethebraincansimulta- psychiatry.uc.edu. fro
ThisworkwassupportedbyNationalInstitutesofHealthAwards m
neously turn up one system (e.g. catabolic or anabolic) while DK17844andDK57900. h
turningdowntheother. DisclosureSummary:S.C.W.receivedlecturefeesfromSanofi-Aven- ttp
s
tisandfromMerck.D.A.D.receivedlecturefeesfromMerck,Takeda, ://a
andMannKind. ca
d
e
Integration of Satiation and Adiposity Signals m
ic
.o
Totalfoodintakeeachdayisthesumoftheintakeinindividual References up
.c
meals(includingsnacks).Asdiscussedabove,thetimethatmeals o
m
areinitiatedisoftenunderthecontrolofnonhomeostaticinflu- 1. nScehrvwoaurstzsyMstWem,WcoonotrdoslSoCf,foPoodrtientJarkDe.,NSeaetlueyreR4J0,4B:6as6k1i–n6D71G2000Central /jce
ences(4,5,160,234).Hence,whateverregulatorycontrolexists 2. WoodsSC,SeeleyRJ,PorteJrD,SchwartzMW1998Signalsthatregulate m
forbodyweightmustbeexertedonhowmuchiseateninindi- 3. fWooododinstSaCke2a0n0d5eSnigenrgaylshthoamteionsfltuaesinsc.eScfoieondcein2ta8k0e:1a3n7d8b–o1d3y83weight.Physiol /artic
vidual meals, and meal termination is consequently under the le
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1
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