Gastrointestinal-Brain (Gut-Brain) Interactions & The Control of Feeding Behavior

7/6/2016
GastrointestinalBrain(GutBrain)InteractionsandtheControlofFeedingBehavior
GutBrainInterrelationshipsandControlofFeedingBehavior
IntroductiontotheGutBrainConnection
HypothalamicControlofFeedingBehavior
OrexigenicPeptides
Neuropeptidetyrosine,NPY
Agoutirelatedpeptide,AgRP
Melaninconcentratinghormone,MCH
Orexins
Galanin,GAL
AnorexigenicPeptides
POMCDerivedMelanocortins
CocaineandAmphetamineRegulatedTranscript,CART
Galaninlikepeptide,GALP
Corticotropinreleasingfactor(CRForCRH)andrelatedpeptides
HypothalamicLipidMetabolismandEnergyHomeostasis
GastrointestinalHormones
GLP1andGIP
Oxyntomodulin
Cholecystokinin
GhrelinandObestatin
Pancreaticpolypeptide
Proteintyrosinetyrosine,PYY
Enterostatin
FibroblastGrowthFactor19
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IntroductiontoGutBrainInteractions
Thebrain,inparticularthehypothalamus,playshighlycriticalrolesintheregulationofenergymetabolism,
nutrientpartitioning,andthecontroloffeedingbehaviors.Thegastrointestinaltractisintimatelyconnectedtothe
actionsofthehypothalamicpituitaryaxisviathereleaseofpeptidesthatexertresponseswithinthebrainaswell
as through neuroendocrine and sensory inputs from the gut. Although a complete discussion of the
interrelationshipsbetweenthegutandthebraininthecontrolofenergyhomeostasisandregulationoffeedingis
beyond the intended scope of this page, focus will be placed on briefly reviewing the current literature. The
primarycentersinthebraininvolvedinthecontrolofappetitearethehypothalamicpituitaryaxisandthebrain
stem. The role of these brain regions in appetite control are discussed in the section below on Hypothalamic
ControlofFeedingBehavior.
http://themedicalbiochemistrypage.org/gutbrain.php#hypothalamus
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The consumption of food initiates a cascade of neuronal and hormonal responses within and by the
gastrointestinal system that impact responses in the central nervous system. The brain initiates responses to
feeding even before the ingestion of food. The very sight and smell of food stimulates exocrine and endocrine
secretionsinthegutaswellasincreasinggutmotility.Ingestionoffoodstimulatesmechanoreceptorsleadingto
distension and propulsion to accommodate the food. As the food is propelled through the gut regions of the
intestinessecretevarioushormonesthatcirculatetothebrainandimpacthypothalamicresponsesasdiscussed
inthesectionsbelow.Themechanoreceptorresponsesaretransmittedviaafferentnervesignalsalongthevagus
nervetothedorsalvagalcomplexinthemedullaandterminatinginthenucleusofthesolitarytract(NTS,forthe
latintermnucleustractussolitarii).ProjectionsfromtheNTSenterthevisceralsensorycomplexofthethalamus
whichmediatestheperceptionofgastrointestinalfullnessandsatiety.Severalhormonesreleasedfromthegutin
response to food intake exert anorexigenic (appetite suppressing) responses in the brain, particularly in the
hypothalamus.Thesehormonesincludeglucagonlikepeptide1(GLP1),cholecystokinin(CCK),peptidetyrosine
tyrosine (PYY), pancreatic polypeptide (PP), and oxyntomodulin (OXM or OXY). A single orexigenic (appetite
stimulating)hormone,ghrelin,isknowntobereleasedbycellsofthegut.
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HypothalamicControlofFeedingBehavior
Thehypothalamusislocatedbelowthethalamusandjustabovethebrainstemandiscomposedofseveral
domains(nuclei)thatperformavarietyoffunctions.Thehypothalamusformstheventralportionoftheregionof
thebraincalledthediencephalon.Anatomicallythehypothalamusisdividedintothreebroaddomainstermedthe
posterior,tuberal,andanteriorregions.Eachofthesethreeregionsisfurthersubdividedintomedialandlateral
areas. The various nuclei of the hypothalamus constitute the functional domains of the various hypothalamic
areas.Theprimarynucleiofthehypothalamusthatareinvolvedinfeedingbehaviorsandsatiety(thesensationof
being full) include the arcuate nucleus of the hypothalamus (ARC, also abbreviated ARH), the dorsomedial
hypothalamicnucleus(DMHorDMN),andtheventromedialhypothalamicnucleus(VMHorVMN)allofwhichare
located in the tuberal medial area. The ARC is involved in control of feeding behavior as well as secretion of
variouspituitaryreleasinghormones,theDMHisinvolvedinstimulatinggastrointestinalactivity,andtheVMHis
involved in satiety. Early experiments involving lesions in the hypothalamus demonstrated that the lateral
hypothalamicarea(LHA)isresponsiblefortransmittingorexigenicsignals(desireforfoodintake)andlossofthis
region results in starvation. The medial hypothalamic nuclei (VMH and to a lesser extent the DMH) are
responsibleforthesensationsofsatietyandlesionsintheseregionsofthehypothalamusresultinhyperphagia
(excessivehunger)andobesity.
Appetiteisacomplexprocessthatresultsfromtheintegrationofmultiplesignalsatthehypothalamus.The
hypothalamus receives neural signals, hormonal signals such as leptin, cholecystokinin (CCK) and ghrelin and
nutrientsignalssuchasglucose,freefattyacids,aminoacidsandvolatilefattyacids.Thiseffectisprocessedby
aspecificsequenceofneurotransmittersbeginningwithintheARCandorexigeniccellscontainingneuropeptide
Y (NPY) and Agoutirelated peptide (AgRP) responsive neurons and anorexigenic cells containing pro
opiomelanocortin, POMC (yielding the neurotransmitter MSH) and cocaine and amphetamineregulated
transcript (CART) responsive neurons. These so called first order neurons act on second order orexigenic
neurons (containing either melanin concentrating hormone, MCH or orexin) or act on anorexigenic neurons
(expressingcorticotropinreleasinghormone,CRH)toalterfeedintake.Inaddition,satietysignalsfromtheliver
andgastrointestinaltractsignalthroughthevagusnervetothenucleusofthesolitarytract(NTS,forthelatinterm
nucleus tractus solitarii) to cause meal termination, and in combination with the hypothalamus, integrate the
varioussignalstodeterminethefeedingresponse.Theactivitiesoftheseneuronalpathwaysarealsoinfluenced
bynumerousfactorssuchasnutrients,fastinganddiseasetomodifyappetiteandhenceimpactongrowthand
reproduction.
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Hormonalcircuitsfromthegut(stomach,smallintestine,andpancreas)andfat(adiposetissue)thatimpact
thesensationsofhungerandsatietythatareexertedviahypothalamicneuroendocrinepathways.Ghrelinfrom
thestomach,leptinfromadiposetissue,insulinfromthepancreas,andpeptidetyrosinetyrosine(PYY)fromthe
smallintestinebindtoreceptorsonorexigenicand/oranorexigenicneuronsintheARCofthe hypothalamus.
Theeffectsofthesepeptidehormonereceptorinteractionsarereleaseofeithertheorexigenicneuropeptides
NPY and AgRP or the anorexigenic neuropeptides CART and the POMCderived peptide MSH. These
neuropeptidesfromtheARCtravelalongaxonstosecondaryneuronsinotherareasofthehypothalamussuch
as the paraventricular nucleus (PVN). The ultimate effects of these signaling cascades are changes in the
sensation of hunger and satiety in the NTS. LEPRB is the large form of the leptin receptor (see the Adipose
Tissue page for descriptions of leptin and leptin receptors). GHSR is the growth hormone secretagogue
receptor to which ghrelin binds. MC3R and MC4R are melanocortin 3 receptor and melanocortin 4 receptor,
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respectively.Y1RandY2RaretheNPYreceptors1and2,respectively(seethenextsectionbelowformore
informationonNPYreceptors.
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NeuropeptideY,NPY
NPY is a hypothalamic neuroendocrine protein that is a member of a family of structurallyrelatedproteins
identifiedasthepancreaticpolypeptide(PP)familyofhormones.InadditiontoNPYthisfamilyiscomposedof
twoguthormones,pancreaticpolypeptide(PP)andpeptidetyrosinetyrosine(PYY)bothofwhicharediscussed
below.Eachofthesepeptidehormonescontains36aminoacidsconsistingofnumeroustyrosines(hencetheY
peptides nomenclature) and an amidation at the Cterminus. The threedimensional structure of these
hormones includes a hairpinlike motif referred to as the pancreatic polypeptide fold (PPfold). The PPfold is
requiredforinteractionofthehormoneswithspecificGproteincoupledreceptors(GPCRs).
ThePPfamilyofproteinsbindtoafamilyofreceptorsthatwereoriginallycharacterizedasNPYreceptors.
TherearefourNPYreceptorsinhumansandtheyaredesignatedasY1,Y2,Y4,andY5.Anadditionalreceptor
identified as Y6 is found in mice and rabbits. Comparisons of the amino acid sequences of the four human Y
receptors show that receptors Y1, Y4 are more closely related to each other than to the receptors Y2 and Y5.
ReceptorsY1,Y2,andY5preferentiallybindNPYandPYY,whereas,Y4exhibitshighestaffinityforPP.Although
the Y5 receptor is expressed and binds ligand it is a truncated protein. The Y2 receptor is involved in
anorexigenicresponses(suppressionofappetite)whereastheY1andY5receptorshavebeenshowntoinduce
orexigenicresponses(stimulationofappetite).TheY2receptorsarethus,referredtoasinhibitoryreceptorswith
respecttotheactivityofNPYandtheyareabundantlyexpressedonNPYneuronsinthearcuatenucleus(ARC)
ofthehypothalamus.
NPY is expressed throughout the mammalian brain with highest levels found in the ARC of the
hypothalamus.NPYisoneofthemostpotentorexigenicfactorsproducedbythehumanbody.WithintheARC
there are two neuronal populations that exert opposing actions on the desire for food intake. Neuronsthatco
express NPY and another neuropeptide called agoutirelated peptide (AgRP) stimulate food intake, whereas,
neuronsthatcoexpressPOMCandcocaineandamphetamineregulatedtranscript(CART)suppressthedesire
forfoodintake.TheroleofNPYinappetitecontrolcanbedemonstratedbycentraladministrationofNPYwhich
resultsinamarkedlyincreaseddesireforfoodintake.TheY1andY5receptorsmediatethebulkoftheeffectsof
NPY on the hypothalamicpituitarythyroid axis. Within the ventromedial nucleus (VMN) of the hypothalamus,
bindingofNPYtotheY1receptorresultsininhibitionofneuronalfunction(viahyperpolarization)whichresultsin
interference with the satiety role of the VMN. The majority of hypothalamic Y2 receptors are found on NPY
containing neurons. Conversely, Y2 receptor activation in the ARC results in inhibition of the actions of NPY
whichaccountsfortheanorexigenicactionsassociatedwithY2activation.
OfsignificancetodietingandweightlossisthefactthatwhenpeopleloseexcessweightthelevelofNPY
increases which likely is a contributing factor to the inability of most people to keep the weight off. This
phenomenonhasbeendemonstratedinmicefedahighfatdiet.Thesemicewillbecomeobese,haveincreased
fatmass,andincreasedcirculatinglevelsofleptin.Whentheanimalsareplacedonacalorierestricteddietthey
losetheexcessfatandleptinlevelsdecline.However,thelevelofexpressionoftheNPYgeneisobservedtobe
significantly increased. This and other data indicate that NPY is also one of the most important hypothalamic
derived neuropeptides mediating the effects of leptin on overall energy homeostasis. Whereas, losing excess
weight is associated with increased expression of NPY, the levels of the anorexigenic peptides, POMC and
CART,donotchange.
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Agoutirelatedpeptide,AgRP
As the name implies, agoutirelated peptide (AgRP), is a protein with sequence homology to the agouti
protein which controls coat color in rodents. AgRP is a protein of 132 amino acids encoded on chromosome
16q22.AgRPisexpressedprimarilyintheARCandisfoundtocolocalizewithneuronsthatalsoproduceNPY.
AlthoughexpressionofAgRPisrestrictedtotheARC,AgRPfibersprojecttoseveralbrainareasaswellasto
multiple areas within the hypothalamus, including the paraventricular nucleus (PVN or PVH) and perifornical
lateralhypothalamus(PFLH).Inaddition,alloftheseAgRPnerveterminalscontainNPY.ThePVNisaregionof
the hypothalamus that integrates neuropeptide signals from numerous regions of the brain and hypothalamus
(e.g.theARC)aswellasthebrainstem.TheperifornicallateralhypothalamusisasubdomainoftheLHAthatis
involvedinarousalandfoodseekingbehaviors.
AgRPtogetherwithNPYrepresentadistinctsetofARCexpressedorexigenicpeptides.AgRPisclassically
referredtoasamemberofthecentralmelanocortinsystem,whichinadditiontoAgRPcomprisesmelanocyte
stimulating hormone, MSH (see below for description of MSH actions) and two melanocortin receptors
identified as melanocortin receptor3 (MC3R) and melanocortin receptor4 (MC4R). Whereas, MSH is an
agonistofbothMC3RandMC4R,AgRPservestoantagonizetheactionsofMSHatthesesamereceptorswith
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highest antagonist activity on MC4R. In addition to antagonizing the effect of MSH at the MC3R and MC4R,
AgRPsuppressesthebasalactivityoftheMC4R,thusdefiningAgRPasaninverseagonist.
TheclosefunctionalrelationshipbetweenAgRPandNPYisdemonstratedbythefactthattheexpressionof
these two peptides is similarly modulated under identical physiological conditions such as negative energy
balance orincreased energy demandthat occurs during food deprivation. During periods of fasting both AgRP
and NPY levels rise and evidence indicates that this is due primarily to a drop in the level of the peripheral
hormonesleptin and insulin and a rise in ghrelin. Also, AgRP like NPY shows a strong circadian rhythm in its
expression, rising at the onset of natural feeding cycles. As to be expected, the expression of both AgRP and
NPYareconverselysuppressedunderconditionsofpositiveenergybalance.Instudiesinexperimentalanimals
manipulationsindietalsoresultinalterationsinthelevelsofAgRPexpression.AgRPgeneexpressionishigher
inratsonalowenergydietcomparedtoafatrichdietorinconditionswhereglucoseutilizationisreduced.Infact
both AgRP and NPY are suppressed by a single injection of glucose. On the other hand, injections of the
compoundIntralipid(whichincreasescirculatinglipids)doesnotresultinchangesinAgRPlevels.
The strong orexigenic effects of AgRP can be demonstrated by injecting the peptide into the brain of
experimentalanimals.CentralinjectionofAgRPhasapotentstimulatoryeffectonfoodintakewhichcanalsobe
seenusingaMC4Rantagonist.TheseresultsconfirmthefunctionofAgRPasanantagonistofMSH.Thefood
intakestimulationexertedbyinjectionofAgRPissimilartothatseenbycentralinjectionofNPYwithdifferences
beingthatthedurationoftheeffectwithAgRPismuchlongerthanthatexertedbyNPY.However,thelongterm
effect does not involve the MC4R, which indicates that AgRP likely induces longterm changes to the neural
signalingpathwaysdownstreamofthisreceptor.ChronicadministrationofAgRPresultsinincreaseddailyfood
intakewhilesimultaneouslydecreasingoxygenconsumptionandthecapacityofbrownadiposetissuetoexpend
energy.Thesechroniceffectsresultinincreasedfatmassaccumulationallofwhichareeffectssimilartothose
seen with chronic administration of NPY. In complimentary studies using transgenic mice that overexpress the
AgRP gene it has been shown that increased levels of AgRP result in increased feeding behavior and food
intake.Thesemiceexhibithyperphagiaandobesity,inadditiontoincreasedbodylength,hyperinsulinemia,late
onset hyperglycemia, and pancreaticislet hyperplasia. These results are similar to those seen in mice that
ectopicallyexpresstheNPYgeneandarealsoevidentinmicethatharboraMC4Rknockout.
There exists an antagonism between the actions of AgRP (and NPY) and the melanocortins in controlling
eatingandbodyweight.ThisisevidentfromstudiesshowingchangesinendogenousAgRPthatareoppositeto
those seen with the melanocortin peptides. In addition, brain mapping shows that AgRP neurons interact with
POMCneuronsintheARCthroughtheinhibitoryneurotransmitteraminobutyricacid(GABA).BothAgRPand
NPY axons that colocalize GABA project onto POMC expressing cells in the ARC and the AgRPstimulated
release of GABA results in inhibition of the activity of the POMC neurons, an effect also seen with NPY.
PeripheralhormonesthatactontheARCandtherebyaffecttheactionsofAgRPandNPYareleptinandghrelin.
LeptinbindstoitsreceptorpresentonAGRPandNPYneuronsandinhibitstheirfiringresultinginreducedGABA
releaseontoPOMCneurons.ThisleptininducedreductioninGABAactionatPOMCneurons is a disinhibition
and is, in part, the mechanism by which leptin decreases feeding behaviors. Conversely, ghrelin binding its
receptoractivatesAgRPandNPYneurons,resultinginanincreaseinGABAreleasewithresultantinhibitionof
POMCneurons.
Given that AgRP and NPY, which are activated under similar conditions and have comparable effects,
indicates that they very likely evolved to ensure the signaling of hunger during food scarcity and to enable the
bodytoendurelongperiodsofnegativeenergybalance.
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MelaninConcentratingHormone,MCH
Melaninconcentrating hormone (MCH) was originally identified as a 19 amino acid cyclic peptide that
inducedthelighteningoftheskininfish.Subsequentlythepeptidewasidentifiedinrodentstobeoverexpressed
inresponsetofastingandalsoelevatedingeneticallyobesemice(ob/obmice).Inhumansandothermammals
MCH is expressed exclusively in the lateral hypothalamus and zona incerta (region of gray matter cells in the
subthalamusbelowthethalamus).InhumanstherearetwoGproteincoupledreceptors(GPCRs)thatbindMCH
identified as MCH1R and MCH2R. Rodents, however, do not possess the MCH2R gene. MCH1R is a typical
GPCR that couples to the activation of both Gq and Gi type Gproteins. The Gq class of Gprotein activates
phospholipaseC(PLC)resultinginincreasesinintracellularCa2+.TheGiclassrepressesadenylatecyclase
activityresultingindecreasedcAMPproduction.ExpressionofMCH1Risseenthroughoutthebrainwithhighest
levels in the cortex, hippocampus, amygdala, and nucleus accumbens. MCH1R expression is also seen in
peripheral tissues such as adipose tissue, intestines, lymphocytes, and the pituitary. The pattern of central
nervoussystemexpressionofMCHandMCH1Rsuggeststhatthispeptidereceptorsystemisinvolvedinahost
ofphysiologicalfunctionswithinthebrain.
InvolvementofMCHintheregulationoffeedingbehaviorsandenergyhomeostasishasbeenshowninmice
whereeithertheMCHgeneortheMCH1Rgenehavebeenknockedout.Additionalinformationonthefunctionof
MCHinfeedingandenergyconsumptionhasbeenobtainedwiththeuseofselectivepharmacological MCH1R
antagonists. In mice lacking the MCH gene the prominent phenotype is hypophagia (reduced desire for food
intake) and lean body mass. These results indicate that MCH is an important orexigenic (appetite stimulating)
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hormone.Incontrast,centraladministrationofMCHresultsinincreasedfoodintakeinmice.WhentheMCH1R
geneisknockedoutmicearehyperphagic,hyperactive,andlean.When MCH1Rantagonists areadministered
peripherally animals exhibit decreased MCHinduced food intake. In addition, if MCH1R antagonists are
chronically administered there is observed a decrease in body weight in rats that had dietinduced obesity.
MCH1Rantagonistshavebeenshowntomodulateleptinsecretionandinsulinreleasewhichsuggeststhatthe
weightlossassociatedwithsystemicantagonistadministrationisduetobothcentralandperipheraleffects.Many
studiesindicatethatMCH1Rantagonistsmodulateenergyhomeostasisandthus,theantiobesityeffectsaredue
primarilytoincreasedenergyexpenditureandnottosuppressionoffeedingbehaviors.
Inadditiontomodulationoffeedingbehaviorsandenergyexpenditure,theMCHsystemhasbeenshownto
be involved in affective disorders such as anxiety and depression. Mice in which the MCH1R gene has been
knockedoutexhibitlessanxietylikebehaviorsthanwildtypemice.AdministrationofMCH1Rantagonistshave
alsobeenshowntohaveanxiolytic(reducinganxiety)properties.ThesestudiesindicatethattheMCHsystemis
importantinthemodulationofstressresponses.MCH1Rantagonistshavealsobeenshowntobeefficaciousin
animalmodelsofdepressivebehavioralthoughtheprecisemechanismfortheantidepressanteffectsarenotyet
clearlydefined.
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TheOrexins
The orexins constitute two neuroendocrine peptides derived from the same gene. These peptides are
designated orexin A and orexin B. The orexins are also called the hypocretins as the peptides were
independently isolated. One group used a subtractive cDNA screening approach to enrich for cDNAs from the
hypothalamous(identifiedashypocretins)andanothergroupwasscreeningforligandsthatactivatedorphanG
proteincoupledreceptors(GPCRs)thatwouldinducetransientcalciumcurrentsinGPCRexpressingcells.The
lattergroupdemonstratedthattheidentifiedligandsinducedorexigenic(appetitestimulating)responsesandthus
named the peptides orexin A and orexin B. Orexin A corresponds to hypocretin 1 (HCRT1) and orexin B
correspondstohypocretin2(HCRT2).
Isolationofthehumanorexingene,locatedonchromosome17q21,demonstratedthattheencodedprotein
wasapreproproteinthatcontainedtheaminoacidsequencesofbothorexinAandorexinB.Thepreproprotein
containsa32aminoacidleadersequencetypicalofsecretedproteins.Theorexinpreproproteinis131amino
acidsinlengthwiththe33aminoacidorexinApeptideencodedbyaminoacids3365andthe28aminoacid
orexinBpeptideencodedbyaminoacids6996.BothorexinAandorexinBpeptidesareCterminallyamidated.
TheNterminalglutamineresidueoforexinAiscyclizedintoapyroglutamylresidueandthepeptidecontainstwo
intrachaindisulfidebonds.TheaminoacidsequencesofvertebrateorexinApeptidesare100%conservedand
those of vertebrate orexin B peptides are 93% conserved. Overall the fulllength preproproteins are 75%
conservedacrossvariousvertebratespecies.StructurallybothorexinAandorexinBarehighlyconservedand
thisstructuralconservationexplianstheabilityoftheorexinreceptorstobindbothpeptides.Therearetwoorexin
receptorsidentifiedasOX1RandOX2R(alsoidentifiedasHCRTR1andHCRTR2,respectively).OX1Rexhibits
anorderofmagnitudehigheraffinityfororexinAcomparedtoorexinBwhereasOX2Rhasbeenshowntobind
bothpeptideswithequalaffinity.TheorexinreceptorsaretypicalGPCRswithOX1RcouplingtotheGqsubclass
ofGproteinsandOX2RcouplingtoboththeGqandGiclassofGprotein.TheGqclassofGproteinactivates
phospholipaseC(PLC)resultinginincreasesinintracellularCa2+.TheGiclassrepressesadenylatecyclase
activityresultingindecreasedcAMPproduction.
Thecellbodiesoforexinexpressingneuronsarefoundinthelateralandposteriorhypothalamicareaswith
axonalprojectionsthroughoutthebrain.Expressionoftheorexinreceptorsisalsowidelydistributedthroughout
thecentralnervoussystem.Thisdistributionoforexinandorexinreceptorexpressionissuggestiveofimportant
roles in the emotional and motivational aspects of feeding behavior. Indeed, as their name implies, injection of
orexinpeptidesintothebrainwasshowntoincreasefoodconsumptioninrats.However,inadditiontoincreased
feeding behavior central administration of orexins increases wakefulness and suppresses REM sleep. These
latter observations demonstrate that orexins play a causative role in the regulation of sleepwake cycles.
Subsequentresearchdemonstratedthatlossoforexinfunctionresultsinaconditioninanimalsthatmimicsthe
sleep disorder in humans known as narcolepsy. When the orexin gene is knocked out in mice they exhibit
increasedREMsleepduringdarkperiodswhentheyarenormallyawake.Inadditionthesemicehavefrequent
episodes of sudden collapse, during dark cycles, that resembles cataplexy in humans. Cataplexy often
accompaniesnarcolepsyinhumans.Inhumannarcolepsypatientsthereisasignificantreductionintheamount
ofdetectable orexin A and orexin B as well as an 80%100% reduction in the number of neurons that contain
detectable preproorexin mRNA. However, no mutation has been found in either the preproorexin or orexin
receptorgenesexceptforonerareearlyonsetseverecasewheretherewasamutationinthesignalpeptideof
preproorexin that impaired protein trafficking and processing. There is an association between certain HLA
allelesandnarcolepsythatsuggeststhereducedorexinlevelsmayresultfromselectiveautoimmunedestruction
of orexin neurons. Dogs that harbor a null mutation in the OX2R gene exhibit a narcolepsy phenotype that is
highlysimilartohumannarcolepsy.
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Galanin,GAL
Galanin(GAL)isa29aminoacidpeptidewhosenameisderivedfromthefactthatitcontainsanNterminal
glycine residue and a Cterminal alanine. GAL is expressed in the gut and the brain with wide distribution
throughout the hypothalamus including the PVN, the PFLH, and ARC. The expression of GAL in the
hypothalamus is directly correlated to its role in energy homeostasis and the control of feeding behaviors. In
additiontoregulatingfeeding,GALservesasagrowthandprolactinreleasingfactortothelactotroph,especially
instatesofhighestrogenexposure,isinvolvedinlearningandmemorythrougheffectsinthehippocampus,and
is involved in pain and seizures. Additionally, GAL exerts affective responses such as mood disorders and
anxiety. GAL exerts these myriad effects via binding to three distinct G proteincoupled receptors (GPCRs)
identifiedasGALR1,GALR2,andGALR3.ThehighestlevelsofexpressionofGALR1areseeninhypothalamic
nucleithatincludesthePVNandsupraopticnucleiGALR2intheARC,DMH,andPVNandGALR3inthePVN,
VMH, and DMH. When GAL is injected into the third ventricle of the brain or into the PVN it elicits a strong
orexigenic(increasedfeeding) response with a preference for fat over protein and carbohydrates. The feeding
behaviorresponsestoGALexposureareprimarilyduetobindingGALR1inthehypothalamus.
Although GAL is an orexigenic peptide it has marked differences in its responses to food deprivation and
intake and the signals it induces compared to those of NPY and AgRP in terms of their responsiveness to
endocrineandphysiologicalsignals.InjectionofGALresultsinastimulatoryeffectonfeeding behavior yet the
responseissmallerandofshorterdurationthanthatinducedbyNPY.ThefeedingresponseelicitedbyGALhas
little impact on food preference, whether for carbohydrate or fat, whereas the responses to NPY result in a
preference for carbohydrates. In addition, GALinduced feeding is greatly attenuated when fat is removed from
the diet. The primary function of GAL when an animal is consuming a highfat diet is to restore carbohydrate
balance,throughbehavioralandmetabolicactions,underconditionswherecarbohydrateintakeandmetabolism
are suppressed. The adrenal steroid, corticosterone, only transiently inhibits GAL gene expression in PVN
neuronsandhasnoeffectonfeedingresponsesofGAL.Incontrastthissteroidhormonehasapotentstimulatory
effect on NPY and AgRP and on NPYinduced feeding. Although insulin suppresses both GAL and NPY
expression, leptin strongly inhibits NPY gene expression and release, yet produces little or no change in basal
GAL expression in the ARC and only a small suppression of GAL expression in the PVN. The differential
responsiveness of GAL neurons to leptin is likely due to the low concentration of leptin receptors on GAL
neurons. The low leptin receptor level on GAL neurons compared to NPY neurons also explains their different
responses to food restriction, which reduces leptin levels. Food restriction does little to the level of GAL
expression while markedly enhancing NPY gene expression. Difference in GAL and NPY expression are also
foundunderconditionsofalterednutrientmetabolism.Administrationofinhibitorsoffattyacidoxidationsuppress
GALexpressionbuthavenoeffectonNPY.Conversely,administrationofinhibitorsofglucoseoxidationdonot
alterGALexpressionbutresultinelevatedexpressionofNPY.Thesenutrientdifferencesarealsoobservedin
experimental animals fed different diets. GAL expression in the PVN is stimulated by a highfat diet whereas,
NPYexpressionintheARCisunaffectedorreducedbyfatconsumption.Thesedifferencesinresponsetofat
richdietsarealsoseenwithfataccumulationandarelikelytheresultofdifferencesinresponsestoleptin.The
ability of GAL to exert its stimulation of feeding responses may be due to its interactions with other peptide
systems.TheopioidsarebelievedtohavesomeroleinmediatingGALinducedfeeding,sincetheopioidreceptor
agonist naloxone attenuates the GAL feeding response. GAL may also induce feeding via an inhibition of the
anorexigenicmelanocortinsystyem (POMC see below). This is suggested by evidence that POMC neurons in
theARCareinnervatedbyGALexpressingneuronsaswellasexpressingtheGALR1gene.Evidenceindicates
thatGALhasadirectinhibitoryactiononARCneuronsexpressingGALR1,aswellasmodulatingthesecretory
activityofPOMCneurons.
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POMCDerivedMelanocortins
The POMCderived melanocortin peptides include MSH, MSH, MSH, ACTH124, and ACTH113NH2
(desacetylMSH). The POMCderived melanocortins belong to a family of peptides referred to as the
melanocortinsystem.ThissystemincludesthePOMCderivedmelanocotinswhichexhibitagonistactivities,the
antagonistpeptideAgRP,the melanocortin receptors (MCR), and the melanocortin receptor accessory proteins
(MRAPs).TheMCRfamilyofreceptorsconsistsoffiveidentifiedmemberstermedMC1RthroughMC5R.
The melanocortin system has been shown to be critical in the regulation of food intake and energy
expenditureviaanumberofdifferentassaysystemsinvolvingbothhumansandanimals.Itisimportanttonote
thatalthoughMSHandMSHarefoundtobeproducedinhumanbraintheyarenotfoundinrodentbrainor
pituitary.However,whenadministeredintothebrainofanimalsthemelanocortinsMSH,MSH,andACTH124
inhibittheintakeoffood.TheactionsofMSHpeptidesinfeedingbehaviorisexertedprimarilyviapeptidebinding
totheMC4RandtoalesserextenttotheMC3R.Geneticmutationsinhumansaswellasinanimalsthatdisrupt
theexpressionandprocessing(thisincludestheproteasesthatprocessthePOMCprecursor)ofPOMCpeptides
and MCRs are associated with changes in energy balance and can lead to obesity and type 2 diabetes. In
humans there have been mutations identified in prohormone convertase 1/3 (PC1/3) and carboxypeptidase E
(CPE), as well as in the MSH degrading enzyme prolylcarboxypeptidase (PRCP) that are associated with
energy imbalance and a propensity for obesity. In mice a mutation in the CPE gene also results in the
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development of lateonset obesity. In genomewide screens for gene polymorphisms associated with an
increasedriskofdevelopingtype2diabetestheMC4Rgenewasidentified.MutationsintheMC4Rgenearethe
mostfrequentcausesofsevereobesityinhumans.
In mice ablation of the POMC gene (POMCnull) results in viable animals, even though they have minimal
adrenaltissueandundetectableglucocorticoidsduetothelackofACTH.Theseanimalsdevelopobesitybutdo
not become diabetic. Although not diabetic these mice do have a disruption in the regulation of glucagon
secretioninresponsetoexperimentalhypoglycemia.ThisindicatesthatPOMCderivedpeptidesareinvolvedin
theregulationofglucagon.InhumansararePOMCnullmutationhasbeendescribed.Unlikethesituationinthe
POMCnull mice, humans with a lack of POMC expression are unable to survive without glucocorticoid
supplementationfrombirth.Individualsthatsurvivehaveredhair,dramaticallyincreaseddesireforfoodintake,
andhighpropensityforobesity.TheseconditionsarethesameasthoseseeninPOMCnullmice.AnotherPOMC
mutationthathasbeenidentifiedinhumansresultinginobesityisapointmutationinthecleavagesitebetween
MSH and endorphin. The consequences of this mutation suggests that MSH may be a significant
endogenousanorecticagonistthatactivatestheMC4R.
backtothetop
CocaineandAmphetamineRegulatedTranscript,CART
Thecocaineandamphetamineregulatedtranscript(CART)peptidesareneuroendocrinepeptidesinvolved
infeedingbehavior,drugrewardsystems,stress,cardiovascularfunctions,andboneremodeling.Expressionof
the CART gene is essentially confined to hypothalamic neuroendocrine neurons and limbic system circuits
involved in reward processes. CART peptides are found areas of the brain involved in the control of feeding
behaviorsincludingregionsofthehypothalamussuchastheVMN,lateralhypothalamus(LH),PVN,NTS,ARC,
andthenucleusaccumbens.
ThehumanCARTgene(symbol=CARTPTforCARTprepropeptide)islocatedonchromosome5q12q14
and is composed of three exons. The gene is transcribed into two alternatively spliced mRNAs that encode
proCART peptides of different lengths identified as proCART189 and proCART1102. However, only the
proCART189peptideisfoundinhumans.TheproCARTproteincontainsasignalsequencetypicalofsecreted
proteinsandisrequiredforinsertionoftheproteinintovesiclesandsubsequentprocessing.Theactiveportions
oftheCARTpeptidesarelocateddownstreamofthealternativelysplicedregionandthusbothproCART189and
proCART1102 encode the same biologically active hormones. The proCART proteins contain several sites for
posttranslational processing by prohormone convertases. In humans, where only the short form proCART189
peptideispresent,theprocessingyieldsCARTpeptidesidentifiedasCART4289andCART4989.Inrodents
wherebothCARTmRNAtranscriptsyieldproCARTproteinsthenomenclatureoftheprocessedpeptidereflects
theaminoacidnumberingofthelonger102aminoacidproproteinandareidentifiedasCART55102andCART
62102. There is a high degree of interspecies conservation of the active CART peptide sequences with the
humanrathomologybeing91%.AdefinitiveCARTreceptorhasasyetnotbeenisolated.However,severallines
of evidence indicate that CART peptides bind with high affinity and specificity to a cell surface protein(s) that
triggers signaling events typical of a GPCR class receptor. In cell culture assays addition of CART peptides
resultsinphosphorylationofextracellularsignalregulatedkinase(ERK)aswellasthetranscriptionfactorcyclic
AMPresponseelementbindingprotein(CREB).TheseresultsindicatethattheCARTreceptorisaGPCRthat
activatestheGi/oclassofGproteins.
AroleforCARTpeptidesintheregulationoffeedingbehaviorswasdemonstratedinanimalmodelswhere
intracerebrovascular (icv) injection results in decreased food intake. These types of results indicate that CART
peptides are anorexigenic (decrease appetite). Within the ARC of the hypothalamus CARTpeptide containing
neurons are surrounded by NPY expressing nerve terminals. The distribution of CART and NPY in the ARC
suggests that these two neuropeptides may exhibit crosstalk in the regulation of feeding since NPY is an
orexigenic (appetite stimulating) hormone and CART is an anorexigenic hormone. When animals are food
deprivedthelevelofCARTmRNAintheARCdecreases.Conversely,whenleptinisadministeredtoanimalsthe
level of CART mRNA in the ARC increases. In addition, in animals with disrupted leptin signaling the level of
CARTmRNAisnearlyundetectableintheARC.ThefunctionsofCARTpeptidesininhibitingthedesireforfood
intake may involve circuits that include the serotonin4 receptor and MDMA receptors. MDMA is 3,4
methylenedioxyNmethylamphetamine more commonly known as "ecstasy". When CART mRNA levels are
experimentallyreducedtheanorecticeffectsofMDMAaswellasserotonin4receptoractivationareabolished.In
addition, mice in which the CARTPT gene has been knocked out exhibit increased desire for feeding and gain
weight.
Several human studies have also indicated that CART peptides function in appetite control. In an Italian
familywhereseveralmembersareobeseitwasfoundthatamissensemutationwaspresentintheirCARTgene.
ThismutationchangedaLeuatposition34toaPheandresultedindeficiencyofCARTpeptideintheblood.If
this mutant human gene is expressed in a mouse pituitary tumor cell line the expressed protein is poorly
processed and secreted. In another study of morbidly obese individuals in France, a single nucleotide
polymorphism(SNP)wasidentifiedintheCARTgeneatposition3608whereaTwasreplacedwithaC.Ina
study examining the promoter region of the CART gene from several hundred individuals it was found that a
polymorphismresidesapproximately156kbupstreamthatmaybeassociatedwithobesity.
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backtothetop
Galaninlikepeptide,GALP
Galaninlike peptide (GALP) is a 60 amino acid peptide that is structurally related to galanin, hence the
derivationofitsname.Aminoacids921ofGALPareidenticaltothefirst13aminoacidsofGAL.Thestructural
and sequence similarities between GALP and GAL explain the fact that GALP functions by binding with high
affinity to GAL receptors. However, there are differences in affinities of the two peptides for the different GAL
receptors.GALbindsallthreereceptorsubtypes(GALR1, GALR2, and GALR3) with similar affinities whereas,
GALPbindswithhighestaffinitytoGALR3followedbyGALR2withGALR1bindingwithleastaffinity.Expression
ofGALPisalmostexclusivelyfoundinthehypothalamicARC,andGALPneuronsprojecttothePVNbutnotthe
lateralhypothalamus.
Central injection studies revealed the anorexigenic effects of GALP as well as its responsiveness to the
effectsofleptin.However,itshouldbenotedthattherearedifferencesintheresponsestoGALPinjectionwhen
comparingratsandmice.InjectionofGALPintomiceresultsintheinhibitionoffeedingresponsesandalsoleads
toanincreaseinenergyexpenditureandfatoxidationinbrownadiposetissueresultinginahyperthermiceffect.
Incontrast,injectionofGALPintoratbrainsresultsinanorexigenicresponse.
TheleptinreceptorisexpressedonmostGALPneuronsandexpressionofGALPintheARCisinducedby
leptin. In contrast, GALP expression in the ARC is significantly reduced in leptindeficient (ob/ob) and leptin
receptordeficient (db/db) mice. Food deprivation results in reduced circulating levels of leptin and this in turn
reducestherapidentryofcirculatingGALPintothebrain.FastingresultsinadecreaseinboththelevelofGALP
mRNAaswellasthenumberofGALPexpressingneurons.LeptinadministrationwillrestoreGALPexpressionin
fastedanimalsaswellasinleptindeficient(ob/ob)mice.
backtothetop
Corticotropinreleasingfactor(CRF)andrelatedpeptides
Corticotropinreleasing factor (CRF, also known as corticotropinreleasing hormone, CRH) belongs to an
interactingfamilyofproteinsthatincludesCRF,atleasttwodifferentCRFreceptorsubtypes(CRF1andCRF2),a
CRFbindingprotein(CRFBP)andtheurocortinswhichareendogenousCRFreceptorligands.Therearethree
known urocortins identified as urocortin 1, 2, and 3 (Ucn1, Ucn2, Ucn3). The urocortins are also identified by
Roman numeral designations urocortin I, II, and III. CRF is a 41 amino acid peptide that is found widely
expressedinthebrain.CRFexpressingneuronsareabundantinthehypothalamicPVNwheretheycontrolthe
pituitaryadrenalaxisregulatingthereleaseofACTHandglucocorticoids.
Ucn1 is a 40 amino acid peptide that is expressed primarily in the lateral hypothalamus and supraoptic
nucleus, with urocortincontaining neurons projecting to the VMH. Ucn2 is a 43 amino acid peptide and is
expressedinthemousehypothalamusinthePVNandARC.Inhumans,increasedUcn2expressionisalsoseen
incardiacmyocytesduringheartfailure.Ucn3isa38aminoacidpeptidewhoseexpressionisfoundintherostral
perifornical area lateral to the PVN with Ucn3 neurons projecting throughout the hypothalamus and the limbic
system. Ucn3 expression is also high in pancreatic cells where it stimulates insulin as well as glucagon
secretion.
CRFandtheurocortinsfunctionthroughtwoGproteincoupledreceptors,CRF1andCRF2.CRFandUcn1
bindwithhighaffinitytotheCRF1.Incontrast,Ucn2andUcn3bindwithmuchhigheraffinitythanCRFtoCRF2
andaretherefore,arelikelytobetheendogenousligandsofthisreceptor.Inadditiontobindingtotworeceptors,
CRF and urocortins also bind to CRFBP, which is expressed in association with CRFexpressing neurons in
many brain areas including the hypothalamus. CRFBP acts as an inhibitor of both CRF and the urocortins,
thereby,modulatingthebiologicalactionsofthesepeptides.
Hypothalamic expression of CRF is negatively regulated bythecirculatinglevelofcortisosteronesuchthat
CRFmRNAandproteinlevelsarehighestwhencorticosteronelevelsaredeclining.Inrodents,whofeedduring
thedarkcycle,corticosteronelevelsriseattheonsetoffeedingandCRFlevelsdecrease.Glucocorticoidsalso
negativelyregulateCRFexpression.ThiseffectofglucocorticoidsonCRFexpressionsupportsapermissiverole
fortheadreanlsteroidsinpromotingbodyfataccrual.DiabetesleadstoincreasedCRF expressionin thePVN
andthiseffectiscanbefurtherenhancedbytheadministrationofinsulin.ExpressionofCRFisalsostimulatedin
statesofpositiveenergybalanceandisreducedinstatesofnegativeenergybalance,suchasfooddeprivation.
CirculatingnutrientsalsoaffectthelevelofCRFexpression.Whenglucoselevelsrise,CRFlevelsdeclinewith
theoppositeoccurringwhenglucoselevelsfall.IncontrasttothechangesinCRFlevelsinresponsetoserum
glucosechanges,excessfatconsumptiondoesnotappeartoalterCRFexpression.
Central administration of CRF results in suppression of spontaneous feeding responses demonstrating its
anorexigenicproperties.TheCRFmediatedsuppressionoffeedingoccursalongwithastimulationsympathetic
nervoussystemactivityandrestingoxygenconsumptionwhichresultsinincreasedfatmobilizationandoxidation
and raises blood glucose while inhibiting insulin secretion. Central administration of Ucn1 also suppresses
feeding, and its effect is strongest in the PVN and more potent and longerlasting than that of CRF. Ucn2
administrationalsosuppressesfoodintakeaswellasresultingindelayedgastricemptying,anddecreasedheat
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inducededema.ChronicadministrationofCRF,butnotUcn1,increasesbrownadiposetissuemassandraises
circulating levels of corticosterone and lipids while reducing the levels of glucose. Experimental evidence
indicatesthatCRF2mediatestheanorecticeffectsoftheseligands,whileCRF1mediatestheirmetaboliceffects.
Mice lacking the CRF2 receptor exhibit a blunted response to the feedinginhibitory effects of urocortin and
selectiveCRF2receptorantagonistsblockthesuppressiveeffectsofurocortinsandCRFonfoodintakeandbody
weight.
TheroleofCRFasananorexigenichormonemayinvolvetheNPY,melanocortinandCARTsystems,acting
inadownstreamfashion.TheCRFneuronsinthehypothalamuscolocalizewithboththeNPYY5receptorand
the MC4R. In addition, CRF expression in the PVN is stimulated by central administration of a melanocortin
agonist but is inhibited by an MC4R antagonist. There is an antagonistic relationship between CRF and NPY
demonstraetdbythefactthatadministrationofCRFandUcn1resultinareductioninbothNPYexpressionand
NPYmediated feeding. Also, administration of CRF antagonists result in increased NPYinduced feeding
responses.IncontrasttotheCRFNPYantagonism,centraladministrationofCARTactivatesCRFneuronsinthe
PVN,indicatingthatCRFmaymediatetheanorecticeffectofCART.LeptinisalsoinvolvedintheeffectsofCRF
and the urocortins as demonstrated by the fact that the anorexigenic actions of leptin are attenuated in the
presence of CRF antagonists. Leptin also facilitates the uptake of Ucn1 into the brain, thereby potentiating its
anorexigenicactions.
backtothetop
HypothalamicLipidMetabolismandEnergyHomeostasis
HypothalamicFattyAcidMetabolism
Within the central nervous system the metabolism of fatty acids is primarily for the purposes of membrane
functionandthecentralregulationofenergymetabolism.Fatsdonotserveasamajorsourceofenergywithin
the brain, this need is obtained from the oxidation of glucose and ketone bodies. Although ketone bodies are
essentiallyderivedfromfattyacids(viatheacetylCoAderivedfromoxidation),thesecompoundsarriveinthe
brainfromthebloodbeingproducedwithintheliver.Mostofthefattyacidswithinthebrainaresynthesizedde
novowithinthevariouscellsoftheCNS.Whilemanysaturatedandunsaturatedfattyacidsdonotgenerallycross
thebloodbrainbarrier(BBB),polyunsaturatedfattyacids,suchaslinolenicacid,aretransportedacrosstheBBB.
Mostofthefattyacidsdeliveredtothebrainarereleasedfromlipoproteinassociatedtriglyceridesviatheaction
ofendothelialcelllipoproteinlipaseorthelipoproteinsareendocytosedbytheendothelialcellsandthefattyacids
releasedbylysosomalhydrolases.Albuminboundfattyacidsgainaccessintothebrainbybothpassivediffusion
andproteincarriermediatedtransportviaFAT/CD36andFATP1.Forinformationonfattyacidtransportintocells
visittheFattyAcidOxidationpage.
Oncefattyacidsaretakenupbycellsinthebraintheyareactivatedthroughtheactionthevariousfattyacyl
CoAsynthetases.AlthoughfattyacylCoAsaresubstratesforoxidation,theratesofmitochondrialfatoxidation
are extremely low in the brain. The fates of fatty acylCoAs, in the brain, are conversion into various structural
entities including phospholipids, triacylglycerides, diacylglycerides, and fatty acylcarnitine species as well as
lipidderivedsignalingmolecules.Studiesusingpalmiticacidhavedemonstratedthatthemajorityofpalmitateis
incorporated into the neutral lipid fraction, principally consisting of triacylglycerides and nonesterified free fatty
acids.Inaddition,incontrasttononneuraltissues,thedesaturationandelongationofpalmitatewithinthebrain
represents a very minor fate of the fat. Instead, palmitate is converted into fatty acids of less than 16 carbon
atoms. The largest pool of lipid derived from palmitate is phospholipid of which the primary species is
phosphatidylcholine.
Although oxidation of fatty acids represents a minor, if at all, source of the ATP pool in neurons, it is an
importantmetabolicpathwaydeterminingtheultimatefateoffattyacidsthatenterthebrain.Asaresultoffatty
acid oxidation, a number of aqueous byproducts are detected in the brain such as fatty acylCoAs, fatty acyl
carnitines,ketonebodiesandvariousaminoacids.Whenusinginvitroassayswithpalmitateitisfoundthatthe
majorityofthecarbonsfromthisfattyacidendupintheaminoacidsglutamate,glutamine,aspartate,asparagine,
and GABA. In addition, numerous organic acids including citrate, malate, hydroxybutyrate, and acetyl CoA
resultfrompalmitateoxidation.Byfar,citraterepresentsthelargestbyproductoffattyacidoxidationinthebrain.
These fates of fatty acids that enter the brain have been worked out with the use of a selective carnitine
palmitoyltransferase1(CPT1)inhibitor.AsdiscussedintheFattyAcidOxidationpage,regulationoftherateof
fatty acid entry into the mitochondria for oxidation is exerted by malonylCoAmediated inhibition of CPT1.
Indeed, inhibition of mitochondrial CPT1 is emerging as a viable target for the central regulation of feeding
behaviorsandenergyhomeostasis.InhibitionofbrainCPT1decreasestheentryoffattyacidcarbonsintothe
aqueous metabolic pools but does not alter the distribution into various longchain acylCoA compounds and
triacylglycerides.
Fatty acids, specifically longchain fatty acids via the formation of longchain fatty acylCoAs, have very
recentlybeenshowntoexertanorexigeniceffectsviathehypothalamus.Forexample,whenoleicacidisinjected
intocerebralventriclesthereisaresultantdecreaseinfeedingbehaviorinlaboratoryanimals.Thedecreasesin
feeding behavior are associated with declines in the expression and release of NPY and AgRP in the
hypothalamus. In addition to reducing feeding behaviors, central administration of oleic acid is associated with
increasedperipheralglucosehomeostasis.OleicacidmustbeconvertedtoitsCoAderivativefortheseeffectsto
beexertedsinceithasbeenshownthatblockadeoffattyacylCoAsynthetaseactivityabolishestheoleicacid
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regulated glucose homeostasis. Mitochondrial CPT1 activity has also been shown to play a role in the central
effectsoffattyacids.Forexamplethe8carbonfattyacid,octanoicacid,doesnotexertanyanorexigeniceffects
andmitochondrialuptakeofoctanoylCoAdoesnotrequireCPT1.Additionally,inhibitionofhypothalamicCPT1
leadstoanincreaseincytosoliclongchainacylCoAcontentandresultsinanorexigeniceffects.
HumansexpressthreedifferentCPT1genesidentifiedasCPT1A,CPT1B,andCPT1C.TheCPT1Bgene
isnotexpressedinthehypothalamusandthelevelofhypothalamicCPT1Aexpressionisminimal.In addition,
thebindingaffinityofCPT1AformalonylCoAisrelativelylow.TheCPT1Cgeneisbrainspecificandbindingof
malonylCoAtotheCPT1CproteinisofsimilaraffinitytothatoftheCPT1Bisoform.Inexperimentsinmiceit
hasbeenshownthatdeletionofCPT1Cresultsinreducedfeedingbehaviorandloweredbodyweightsimilarto
studiesinwhichhypothalamicmalonylCoAlevelsareelevated.Theseresultspointtothefactthathypothalamic
malonylCoAlevelslikelyplayamajorroleinthecontroloffeedingbehaviors.However,theprecisemechanisms
bywhichmalonylCoAandcytosoliclongchainfattyacylCoAinteractionsresultinreducedappetitearenotfully
characterized. In the CPT1C knockout mice experiments, although the animals exhibited reduced feeding
behaviortheybecameobesemorequicklyonahighfatdietthancontrolanimalseventhoughtheyateless.Also,
the brain specific CPT1C isoform does not catalyze carnitine transferase activity. Therefore, precisely how the
inhibitionofhypothalamicCPT1CleadstolongchainacylCoAaccumulationremainsunclear.
HypothalamicMalonylCoARegulation
Asindicatedabovethebraindoesnotreadilyoxidizefattyacidsforenergyproduction.However,themajor
enzymesofthefattyacidbiosyntheticpathway,suchasacetylCoAcarboxylase(ACC)andfattyacidsynthase
(FAS),areexpressedinneuronalregionsofthehypothalamusthatareinvolvedinenergyhomeostasis.Various
hormones and metabolic fuels affect hypothalamic malonylCoA levels and malonylCoA is considered a key
satiety inducing signal in the brain. During periods of fasting, hypothalamic levels of malonylCoA rapidly
decreaseandactasasignalofhunger.Conversely,duringfeeding,hypothalamiclevelsofmalonylCoArapidly
riseand act as a signal to stop eating. Therefore, an understanding of the regulation of hypothalamic malonyl
CoAlevelsisofsignificanceespeciallywithrespecttoeffortstocontrolfeedingbehaviorsinhumans.
AsdescribedintheLipidSynthesispage,theproductionofmalonylCoAiscatalyzedbyACC.Therearetwo
isoforms of ACC, ACC1 and ACC2 (sometimes referred to as the ACC and ACC isoforms, respectively).
ExpressionofACC1predominatesintheliver,whereas,expressionofACC2predominatesintissueswithahigh
oxidativecapacity.ThesedifferencesinexpressionhaveledtothesuggestionthatthemalonylCoAproducedby
ACC2ispreferentiallyinvolvedintheregulationoffattyacidoxidation,whereas,malonylCoAproducedbyACC1
ispreferentiallyinvolvedintheregulationoffattyacidsynthesis.
Both isoforms of ACC are allosterically activated by citrate and inhibited by palmitoylCoA and other short
andlongchainfattyacylCoAs.CitratetriggersthepolymerizationofACC1whichleadstosignificantincreasesin
its activity. Although ACC2 does not undergo significant polymerization (presumably due to its mitochondrial
association)itisallostericallyactivatedbycitrate.Glutamateandotherdicarboxylicacidscanalsoallosterically
activatebothACCisoforms.ACCactivityisalsoregulatedbyphosphorylation.BothACC1andACC2containat
least eight sites that undergo phosphorylation. The sites of phosphorylation in ACC2 have not been as
extensively studied as those in ACC1. Phosphorylation of ACC1 at three serine residues (S79, S1200, and
S1215)byAMPKleadstoinhibitionoftheenzyme.GlucagonstimulatedincreasesincAMPandsubsequentlyto
increased PKA activity also lead to phosphorylation of ACC where ACC2 is a better substrate for PKA than is
ACC1.
TheroleofACCinregulatingmalonylCoAsynthesisinthehypothalamusleadingtoanorexigeniceffectshas
beendemonstratedinstudiesonleptin.TheanorexigeniceffectsofleptininvolvetheactivationofACCleadingto
increasedmalonylCoAlevelsintheARC.WhentheactivityofACC2isinhibitedintheARC,leptinisunableto
reducefoodintakeandsubsequentbodyweight,becauseitisnolongerabletoaltermalonylCoAcontentwithin
theARC.ThislattereffectoccurseventhoughleptinstillinducesaninhibitionofAMPKindicatingthatmalonyl
CoAmediated effects on appetite and feeding behaviors are downstream of any effects of AMPK. These
experimentalresultsinanimalsdemonstratethatACCactivityisanimportantregulatoroffeedingbehaviorsvia
the ability of ACC2 to regulate hypothalamic malonylCoA levels. Potential differences in ability of ACC1 and
ACC2toelicitdecreasesinappetitearedifficulttoassesssincedeletionofACC1inmiceresultsinembryonic
lethality.
HypothalamicMalonylCoADecarboxylase(MCD)
TheintracellularlevelsofmalonylCoArepresentabalancebetweenitssynthesisfromacetylCoAbyACC
and its utilization in fatty acid synthesis by FAS as well as by its degradation to acetylCoA via the action of
malonylCoAdecarboxylase(MCD).Indeed,MCDisinvolvedinregulatingmalonylCoAlevelsinmultipletissues.
InhibitionofMCDresultsinreducedratesoffattyacidoxidationinhighlyoxidativetissuessuchastheheart.As
well,MCDinhibitionleadstoreducedtriacylglyceridecontentinlipidsynthesizingtissuessuchastheliver.When
hypothalamicMCDlevelsareexperimentallyincreasedinlaboratoryanimalsthereisadramaticincreaseinfood
intake,weightgain,andultimatelyresultsinobesity.
TranscriptionalregulationoftheMCDgeneisexertedbyPPAR,amajortranscriptionfactorinvolvedinthe
regulation of fatty acid oxidation. Hypothalamic PPAR has been shown to play a role in the regulation of
appetite,presumablyviaenhancedexpressionofMCD,withtheuseofpirinixicacidwhichisaPPARagonist.
As discussed below, inhibition of fatty acid synthase (FAS), the ratelimiting enzyme in de novo lipogenesis,
decreasesappetiteandpromotesweightloss.Administrationofpirinixicacidresultsinnormalizationofmalonyl
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CoA levels in mice that have hypothalamicspecific knockout of FAS. The PPARmediated increase in MCD
resultsinreducedlevelsofmalonylCoAinthehypothalamus.Thisisassociatedwithincreasedfoodintakeinthe
FAS knockout mice demonstrating that malonylCoA levels are indeed responsible for the hypophagic effects
observedintheFASknockoutmice.
HypothalamicFattyAcidSynthase(FAS)
As indicated above, the intracellular levels of malonylCoA will decline as it is incorporatred into de novo
synthesizedfattyacidsviatheactionofFAS.TheroleofFASintheregulationoffeedingbehaviorandappetite
hasbeendemonstratedwiththeuseoftheFASinhibitorsC75andceruleninaswellasinFASknockoutmice
(asindicatedabove).InhibitionofFAScausespotentanorexigeniceffectsthatareassociatedwithareductionin
hypothalamic NPY expression and increases in intracellular malonylCoA content. Mice with FAS deleted
specifically in the ARC and PVN regions of the hypothalamus exhibit reduced appetite and weigh significantly
lessthancontrolanimals.
The anorexigenic effects of FAS inhibition with the use of C75 may not be due entirely to alterations in
malonylCoA content. The anorexigenic effects of C75 have also been associated with increases in glucose
metabolismwhichresultsinincreasedlevelsofATP.IncreasesinATPleadtoinhibitionofAMPKactivitywhichin
turn,resultsinreducedAMPKmediatedphosphorylationandinhibitionofACC.Therefore,therewillbeincreased
levelsofmalonylCoAdemonstratingthatmalonylCoAislikelytobetheprimarysignalingmoleculeresponsible
forthehypophagiceffectsofC75.FASinhibitors,suchasC75,alsoactivatethemammaliantargetofrapamycin
(mTOR),andsincemTORandAMPKactivitiesareinverselyrelatedtheyarelikelytobereciprocallyinvolvedin
theregulationofappetite.
backtothetop
GastrointestinalHormonesandPeptides
Therearemorethan30peptidescurrentlyidentifiedasbeingexpressedwithinthedigestivetract,makingthe
gutthelargestendocrineorganinthebody.Theregulatorypeptidessynthesizedbythegutincludehormones,
peptideneurotransmittersandgrowthfactors.Indeed,severalhormonesandneurotransmittersfirstidentifiedin
thecentralnervoussystemandotherendocrineorganshavesubsequentlybeenfoundinendocrinecellsand/or
neuronsofthegut.VisitthePeptideHormonespagetoseeamorecompletelistofgastrointestinalpeptidesand
hormones and their modes of action. The following discussion will focus on the gut peptides with the best
demonstratedrolesinthecontrolofappetiteandfeedingbehaviorviatheirinteractionswithsignalsproducedin
thehypothalamicpituitaryaxis.
Hormone
Location
MajorAction
Cholecystokinin
(CCK)
enteroendocrineI
cellspredominantly
intheduodenum,
jejunum
stimulatesgallbladdercontractionandbileflow,increasessecretion
ofdigestiveenzymesfrompancreas,vagalnervesinthegutexpress
CCK1receptors
Enterostain
derivedfromN
terminalendof
pancreatic
colipase
pentapeptide
existinginthree
formsinmammals:
APGPR(human),
VPDPR,and
VPGPR
regulatesfatintake,peripheralorcentraladministrationinhibits
consumptionofahighfatdietbutnotalowfatdiet
gallbladder,
duodenum,ileum
memberofthelargeFGFfamilyofgrowthfactorsexpressionof
FGF19geneactivatedbytranscriptionfactorFXR,FXRisactivated
whenilealenterocytesabsorbbileacids,whenreleasedtotheportal
circulationFGF19stimulateshepaticglycogenandproteinsynthesis
whileinhibitingglucoseproductionreducestheexpressionand
activityofCYP7A1whichistheratelimitingenzymeinbileacid
synthesisactsinthegallbladdertoinducerelaxationandrefilling
withbileacids
FGF19
primarysiteisX/A
like
enteroendocrine
cellsofthe
regulationofappetite(increasesdesireforfoodintake),energy
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Ghrelin
stomachoxyntic
(acidsecreting)
glands,minor
synthesisin
intestine,pancreas
andhypothalamus
homeostasis,glucosemetabolism,gastricsecretionandemptying,
insulinsecretion
Glucagonlike
peptide1
(GLP1)
enteroendocrineL
cellspredominantly
intheileumand
colon
potentiatesglucosedependentinsulinsecretion,inhibitsglucagon
secretion,inhibitsgastricemptying
Glucose
dependent
insulinotropic
polypeptide
(GIP),originally
calledgastric
inhibitory
polypeptide
enteroendocrineK
cellsofthe
duodenumand
proximaljejunum
inhibitssecretionofgastricacid,enhancesinsulinsecretion
Obestatin
primarysiteis
stomach,minor
synthesisin
intestine
derivedfromproghrelinprotein,actsinoppositiontoghrelinaction
onappetite
Oxyntomodulin
enteroendocrineL
cellspredominantly
intheileumand
colon
containsalloftheaminoacidsofglucagon(seeFigurebelow)
inhibitsmealstimulatedgastricacidsecretionsimilartoGLP1and
GLP2actioninducessatiety,decreasesweightgain,andincreases
energyconsumptionhasweakaffinityforGLP1receptoraswellas
glucagonreceptor,maymimicglucagonactionsinliverand
pancreas
Pancreatic
polypeptide:PP
pancreas
inhibitspancreaticbicarbonateandproteinsecretion
Peptide
tyrosine
tyrosine:PYY
enteroendocrineL
cellspredominantly
intheileumand
colon
reducedgutmotility,delaysgastricemptying,inhibitionofgallbladder
contraction,inducessatietyviaactionsinthearcuatenucleus(ARC)
ofthehypothalamus
Vasoactive
intestinal
peptide(VIP)
pancreas
smoothmusclerelaxationstimulatespancreaticbicarbonate
secretion
backtothetop
GLP1andGIP
The glucagon gene encodes a precursor protein identified as preproglucagon. Depending on the tissue of
expression,coupledwiththepresenceofspecificproteasescalledprohormoneconvertases,preproglucagoncan
be processed into several different biological peptides in addition to glucagon. The glucagonlike peptides
(principally glucagonlike peptide1, GLP1) and glucosedependent insulinotropic peptide (GIP) are gut
hormonesthatconstitutetheclassofmoleculesreferredtoastheincretins.Incretinsaremoleculesassociated
withfoodintakestimulationofinsulinsecretionfromthepancreas.
GlucagonlikePeptide1
GLP1 is derived from the product of the glucagon gene. This gene encodes a preproprotein that is
differentially cleaved dependent upon the tissue in which it is synthesized. For example, in pancreatic cells
prohormoneconvertase2actionleadstothereleaseofglucagon.Inthegutprohormoneconvertase1/3action
leadstoreleaseof several peptides including GLP1. Upon nutrientingestionGLP1issecretedfromintestinal
enteroendocrineLcellsthatarefoundpredominantlyinthedistalileumandproximalcolonwithsomeproduction
from these cell types in the duodenum and jejunum. Processing of preproglucagon in enteroendocrine Lcells
resultsintheproductionoffourformsofGLP1[GLP1(136)NH2,GLP1(736)NH2,GLP1(137),andGLP1(7
37)], GLP2, glicentin, and oxyntomodulin. Bioactive GLP1 consists of two forms GLP1(737) and GLP1(7
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36)amide,wherethelatterformconstitutesthemajority(80%)ofthecirculatinghormone.
Structure of the mammalian preproglucagon product shown in the middle. On the top half are the
processing results that occur when the GCG gene is expressed in the gastrointestinal system and the brain.
ShownonthebottomhalfaretheprocessingresultsthatoccurwhenGCGgeneisexpressedinthepancreas.
GRPP=glicentinrelated pancreatic peptide. IP=intervening peptide. GLP2=glucagonlike peptide2. Glicentin
(composed of amino acids 169) is found in the small intestine but the majority is processed to GRPP and
oxyntomodulin. MPGF=major proglucagon fragment comprises amino acids 72158 and is found in the
pancreas.
AlloftheeffectsofGLP1aremediatedfollowingactivationoftheGLP1receptor(GLP1R).TheGLP1Ris
a GPCR of the class B1 family. GLP1 binding to GLP1R is coupled to Gprotein activation, increased cAMP
production and activation of PKA. However, there are also PKAindependent responses initiated through the
GLP1R.TheGLP1Risexpressedon,,andcellsofpancreaticislets,heart,lung,kidney,stomach,small
intestine,skinandnervesintheperipheralandcentralnervoussystems.ResponsestoGLP1arealsoexertedin
theliver,adiposetissue,andmusclebuttheseareindirectresponsesnotduetodirectreceptorbinding.
The primary physiological responses to GLP1 are glucosedependent insulin secretion, inhibition of
glucagon secretion and inhibition of gastric acid secretion and gastric emptying. The latter effect will lead to
increasedsatietywithreducedfoodintakealongwithareduceddesiretoingestfood.Withinthepancreas,GLP
1R activation also results in cell proliferation and expansion concomitant with a reduction of cell apoptosis
(death). Inaddition, GLP1 activityin the pancreas results inincreasedexpression of theglucosetransporter2
(GLUT2)andglucokinasegenes.WithintheCNS,GLP1exertspotentappetitesuppressionviaeffectsexerted
directly via GLP1R activation within the hypothalamus. Indirectly, GLP1 activity results in reduced hepatic
gluconeogenesiswhileatthesametimeleadingtoincreasedglucoseuptakeandstorageinskeletalmuscleand
adiposetissue.
TheactionofGLP1atthelevelofinsulinandglucagonsecretionresultsinsignificantreductionincirculating
levelsofglucosefollowingnutrientintake.Thisactivityhassignificanceinthecontextofdiabetes.The glucose
lowering activity of GLP1 is highly transient as the halflife of this hormone in the circulation is less than 2
minutes. Removal of bioactive GLP1 is a consequence of Nterminal proteolysis catalyzed by dipeptidyl
peptidaseIV(DPPIVorDPP4).DPP4isalsoknownasthelymphocytesurfaceantigenCD26andhasnumerous
activitiesunrelatedtoincretininactivation(seeDPP4pageformoreinformationonDPP4).
GlucoseDependentInsulinotropicPeptide
Glucosedependentinsulinotropicpeptide(GIP)isderivedfroma153aminoacidproproteinencodedbythe
GIPgeneandcirculatesasabiologicallyactive42aminoacidpeptide.GIPissynthesizedbyenteroendocrineK
cellswhoselocationsareprimarilyintheduodenumandproximaljejunum.Theoriginalactivityassociatedwith
GIPwastheinhibitionofgastricacidsecretionandwasthus,originallycalledgastricinhibitorypeptide.However,
subsequent research demonstrated that this gut hormone possessed potent stimulation of glucosedependent
insulin secretion. In addition, GIP has significant effects on fat metabolism exerted at the level of adipocytes.
These actions include stimulation of lipoprotein lipase activity leading to increased uptake and incorporation of
fatty acids by adipocytes. Whereas GIP exerts positive effects on pancreatic cell proliferation and survival
similartothatshownforGLP1,thehormonedoesnotaffectglucagonsecretionnorgastricemptying.LikeGLP
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1,GIPisinactivatedthroughtheactionofDPP4.
TheGIPreceptor(GIPR)isaseventransmembraneGproteincoupledreceptorfoundonpancreaticcells.
ResponsestoGIPhavebeenshowntobedefectiveintype2diabeticpatients.Interestingly,ingeneknockout
miceithasbeenshownthatlossoftheGIPRiscorrelatedtoresistancetoobesityeveniftheanimalsarefeda
highfatdiet.
backtothetop
Oxyntomodulin
Oxyntomodulin(OXM)issocalledgiventhatiswasoriginallydiscoveredfromworkexaminingtheinhibition
oftheactivityofoxynticglands(gastricacidsecreting)ofthestomach.OXMisa37aminoacidpeptidederived
from the preproglucagon gene and contains the entire 29 amino acids of the pancreasderived glucose
regulatinghormoneglucagon.TheOXMproteincontainsanadditional8aminoacidsatitsCterminusrelativeto
glucagon.SynthesisandreleaseofOXMoccursintheenteroendocrineLcellsofthedistalgut.Thesearethe
samecellpopulationsthatsecreteGLP1andPYY.ThesecretionofOXMoccurswithin510minutesfollowing
ingestion of food and peaks within 30 minutes. The amount of OXM that is released is directly proportional to
caloricintake. In addition to stimulated release in response to food intake, OXM exhibits diurnal variation in its
concentrationinthebloodwithhighestlevelsdetectedintheeveningandlowestlevelsinthemorning.
ThusfartherehasbeennospecificOXMreceptoridentified.Evidencesuggeststhattheanorexigeniceffects
of OXM are in fact exerted via the GLP1 receptor (GLP1R). In mice in which the GLP1R gene has been
knockedouttheanorecticresponsestoinjectedOXMareabolished.LikeGLP1,OXMhasdemonstratedincretin
activity(incretinsstimulateinsulinreleaseinresponsetofoodintake)andthisactivityisabolishedintheGLP1R
knockoutmouse.Inaddition,OXMexertsaprotectiveeffectonpancreaticcellssimilartothatexertedbyGLP
1.AlthoughtheaffinityofOXMfortheGLP1Risatleast50foldlessthanthatofGLP1itself,theabilityofOXM
toexertinhibitionoffoodintakeisequaltothatofGLP1.Withrespecttoeffectsonfoodintakeexertedviathe
hypothalamuswheneitherOXMorGLP1areadministeredperipherallytheyexertdifferentialneuronalactivation
within the hypothalamus. This suggests that these two hormones act via different hypothalamic pathways
involvedinappetitecontrol.WhenOXMisadministeredintothebraintheresponseissuppressionoftheeffects
ofcirculatingghrelin.TheseresultssuggestthatpartoftheappetitesuppressingeffectsofOXMaremediatedby
reducedghrelinaswellasincreasedhypothalamicreleaseofanorexigenicpeptides.
Of potential significance to the treatment of obesity, when OXM is administered intravenously to human
subjectsthereisanobservedreduction(19.3%)infoodintakeatmealtime.Additionallysignificantisthefactthat
this reduction in desire for food intake persisted over the course of 12 hours. When OXM is administered
subcutaneously to overweight and obese subjects over a period of 4 weeks there is a significant reduction in
body weight. The average weight loss in the volunteers was 2.3kg (1 lb) compared to only 0.5kg in untreated
controlsubjects.Theweightlossobservedinthesestudieswaslikelyduetoacombinationofreduceddesirefor
foodintakeaswellasanincreasedmetabolicexpenditure.WhenOXMwasadministeredovera4dayperiodto
humansubjectstherewasanobserved10%increaseintotalenergyexpenditure.Althoughtheseresultsprove
promising for the potential for OXM in the treatment of obesity it is important to note that OXM is a target for
inactivationbyDPP4justasisGLP1.Therefore,anyOXMagonistmustberesistanttoinactivationbyDPP4.
backtothetop
Cholecystokinin,CCK
Cholecystokinin(CCK)isderivedviaposttranslationalmodificationoftheprocholecystokiningeneproduct.
CCKwasthefirstguthormonetobeidentifiedashavinganeffectonappetite.Thereareseveralbioactiveforms
ofCCKthataredesignatedbaseduponthenumberofaminoacidsinthepeptide.ThefourmajorformsareCCK
8,CCK22,CCK33,andCCK58.ThepredominantformthatisfoundinhumanplasmaistheCCK33form.The
CCK isoforms are also found as sulfated and nonsulfated variants. CCK is secreted from intestinal
enteroendocrineIcellspredominantlyintheduodenumandjejunum.ThelevelofCCKinthebloodriseswithin
15minutesoffoodingestionandreachesapeakby25minutes.TheelevationinplasmaCCKlevelsremainsfor
approximately3hoursfollowingameal.ThemostpotentsubstancesinitiatingareleaseofCCKfromtheIcells
arefatsandproteins.ConverselyduodenalbileacidsarepotentsuppressorsofthesecretionofCCK.
CCKexertsitsbiologicalactionsbybindingtospecificGproteincoupledreceptors(GPCRs).Therearetwo
CCKreceptortypesidentifiedasCCK1andCCK2.TheCCKreceptorsarealsoidentifiedasCCKAandCCKB
whosedesignationsreferredtotheirlocationofprominentexpressionwithCCKAreferringtothealimentarytract
(thegut)andCCKBreferringtothebrain.However,bothreceptorsarefoundwidelyexpressedintheCNSaswell
astheperiphery.TheCCKBreceptorexhibitsequalaffinityforCCKandanothergutpeptide,gastrin.Gastrinis
involvedintheproductionandreleaseofH+,therebygeneratinggastricacid.
UponbindingitsreceptorsinthegutCCKinducescontractionsofthegallbladderandreleaseofpancreatic
enzymesandalsoinhibitsgastricemptying.Withinthebrain(specificallythemedianeminenceandventromedial
nucleusofthehypothalamus,VMH)CCKactionselicitbehavioralresponsesandsatiation.TheCCK1receptoris
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believedtobethereceptorprimarilyresponsibleforalterationsinfeedingbehavior.Evidenceforthiscomesfrom
the Otsuka Long Evans Tokushima Fatty rat which has a null mutation in the CCK1 receptor. These rats are
hyperphagicanddevelopobesityevenonafatrestricteddiet.Thesituationisnotentirelyconclusivesinceknock
outoftheCCK1receptorinmicedoesnotresultinasimilarphenotype.However,theabilityofCCKtoregulate
food intake has been clearly demonstrated in numerous studies. For example central administration of CCK
resultsinreducedfoodintake.Ofsignificancetoappetitecontrol,thiseffectisenhancedwithcoadministrationof
leptin.ThesynergisticeffectsofCCKandleptinmaybeduetothefactthattheirreceptorsarecolocalizedtothe
samesensoryvagalafferentneurons.
InhumansthecorrelationsbetweenCCKandobesityaregrowing.Studieshaveshownthatthefastinglevels
ofCCKarelowerinmorbidlyobeseindividualsthaninleanindividuals.Inaddition,thepostfeedingresponsesto
CCKinmorbidlyobeseindividualsinattenuatedcomparedtoleanindividuals.Theprimaryappetitesuppressing
effects of CCK are exerted via its inhibitory actions on NPY neurons (orexigenic neurons) in the DMH and the
NTS.
Usinggenome wide screens for polymorphisms in genes associated with obesity and/or increased feeding
behaviorshaveshownacorrelationtotheCCK_H3haplotype.PolymorphismsintheCCK1receptorgenemay
alsopredisposeanindividualtoobesity. Although CCK is known to be involved in satiation it may have limited
use as a therapeutic for the treatment of obesity at least when used alone. This is due to the fact that when
studiedinlaboratoryanimalsadministrationofCCKresultedinreducedmealsizebuttheanimalsincreasedtheir
frequencyoffoodintake such that the overall outcome was no net change in body weight. However, given the
synergisticactionsofCCKandleptincombinationtherapiesofthesetwohormonesmayproveuseful.
backtothetop
GhrelinandObestatin
Growth hormone secretagogues (GHSs) were originally characterized by small synthetic molecules that
acted upon the pituitary and hypothalamus leading to amplification of the pulsatile release of growth hormone.
Ghrelin was first discovered based upon its ability to interact with the GHS receptor (GHSR) and stimulate the
releaseof growth hormone. Indeed, ghrelin was found to be the endogenous ligand for the GHSR. The name
ghrelin is derived from growthhormone release. The specific receptor to which ghrelin binds and activates is
identifiedasGHSRtype1a(GHSR1a).
Theghrelingene(symbol=GHRL)islocatedonchromosome3p26p25andiscomposedof5exonsand
encodes the ghrelin preproprotein that can undergo differential processing to yield mature ghrelin peptide or
obestatin.Obestatinexertsitseffectinexactoppositiontothatofghrelin.Thenameobestatinisderivedfroma
contraction of obese and statin (to suppress). Whereas, treatment of animals with ghrelin results in increased
appetiteandfoodintake,obestatintreatmentsuppressesfoodintake.
Ghrelin is produced and secreted by the X/Alike enteroendocrine cells of the stomach oxyntic (acid
secreting)glands.BecausetheX/Alikecellsexpressghrelintheyarealsosometimesreferredtoasghrelincells
orGrcells.X/Alikecellsexpressthereceptorforgastrin(guthormonethatstimulatesgastricacidsecretionby
thestomach)and,therefore,itisbelievedthatgastrinmaydirectlystimulateghrelinrelease.Smalleramountsof
ghrelinarereleasedfromthesmallintestineandevenlessfromthecolon.
The ghrelin gene primary transcription product can undergo alternative splicing. As a result of alternative
splicingandposttranslationalcleavage,the117aminoacidpreproghrelinproteincanbeprocessedintoghrelin
(28 amino acids corresponding to amino acids 2451 of the preproprotein), obestatin (23 amino acids
correspondingtoaminoacids7698ofthepreproprotein)anddesacylghrelin(27aminoacids).Bioactiveghrelin
isacylatedontheserineatposition3withnoctanicacid.Theprocessingofghrelinfrompreproghrelininvolves
cleavage by prohormone convertase 1/3 (PC1/3). The attachment of ocatnoic acid to Ser3 of ghrelin is
accomplished by the acyltransferase identified as ghrelin Oacyltransferase (GOAT also referred to as
membranebound Oacyltransferase domaincontaining 4, MBOAT4). Recent data implicates the nonacylated
formofghrelinmayactasanantagonistoftheacylatedhormone.Thedesacylghrelinproteinisalsoacylatedon
Ser3 and that acylation is required for its activity as for fulllength ghrelin. The formation of desghrelin is the
consequenceofalternativesplicingduetoanintronthatresidebetweentheglutaminesatpositions13and14
(Q13andQ14)ofthepreproghrelinsequence.
The major effect of ghrelin is exerted within the central nervous system at thelevel ofthe arcuatenucleus
whereitstimulatesthereleaseofneuropeptideY(NPY)andagoutirelatedprotein(AgRP).TheactionsofNPY
andAgRPenhanceappetiteandthus,foodintake.Withinthehypothalamusghrelinactionresultsinactivationof
AMPKleadingtoreducedintracellularlevelsoflongchainfattyacids.Thereductioninfattyacidlevelsappearsto
bethemolecularsignalleadingtoincreasedexpressionofNPYandAgRP.However,itisimportanttonotethat
the signaling events triggered by ghrelin binding to GHSR1a are complex. There is activation of a Gprotein
coupledtoPLCactivationwithresultantactivationofPKCandanadditionallycoupledGproteinactivatesPKA.
The secretion of ghrelin is the inverse of that of insulin. The primary mechanisms that are coupled to
productionofghrelinarefasting,hypoglycemia,andleptin.Conversely,inhibitionofghrelinproductionisexerted
byfoodintake,hyperglycemia,andobesity.TheactionofghrelinatthelevelofincreasingthereleaseofNPYis
theexactoppositetothatofleptinwhichinhibitsNPYrelease.Additionaleffectsofghrelinincludeinhibitionofthe
expressionofproinflammatorycytokines,influencesexocrineandendocrinefunctionsofthepancreas,controls
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gastric acid secretion and gastric motility, influences sleep patterns, memory and anxietylike behavioral
responses.
Obestatinexertsitseffectinexactoppositiontothatofghrelin.Releaseofobestatinsuppressesfoodintake
andgastricemptyingactivity.Likeghrelin,whichisposttranslationallymodified,obestatinisalsomodifiedbutits
modificationisanamidation.OnereportindicatedthatobestatinboundtoanorphanGproteincoupledreceptor
(GPCR) identified as GPR39. Evidence indicates that GPR39 is also the zincsensing receptor (ZnR) that
respondstoZn2+ in the processes of tissue repair. GPR39 is expressed in liver, gastrointestinal tract, adipose
tissue, and pancreas. Activation of the receptor results in increased cAMP and consequent activation of PKA
mediatedsignalingpathways.WithinthepancreasGPR39hasbeenshowntoregulatetheexpressionofinsulin
receptor substrate2 (IRS2) and pancreatic and duodenal homeobox1 (PDX1) and that activation of the
receptor is required for increased insulin secretion. It is now clear that GPR39 is not the receptor for obestatin
andtheoriginalobservationwaslikelytheresultofzincinthepreparationsofobestatin.Althoughobestatinhas
cleardemonstratedactivityasananorectichormone,inducingdecreasedfoodintake,reducedbodyweightgain,
aswellasbeinginvolvedintheregulationofsleeppatternsandcellproliferation,nodefinitivereceptorfor this
hormonehasbeenidentified.
backtothetop
PancreaticPolypeptide,PP
Pancreatic polypeptide was the first member of the PPfold family to be isolated and characterized. It was
originallyfoundasanimpurityinpreparationsofinsulinfromchickenpancreas.Subsequentlyitwasshowntobe
producedandsecretedbytypeFcellswithintheperipheryofpancreaticislets.ThestimulusforthereleaseofPP
istheingestionoffoodandthelevelofreleaseisproportionaltothecaloricintake.Increasedcirculatinglevelsof
PPcanbedetectedinthebloodforupto6hoursfollowingingestionoffood.Humoralsignalsthatareinvolvedin
food intakemediated secretion of PP include ghrelin, cholecystokinin (CCK), motilin, and secretin. Additionally,
adrenergic stimulation secondary to either hypoglycemia or exercise results in increased release of PP. The
actions of PP include delaying gastric emptying, inhibition of gallbladder contraction, and attenuation of
pancreaticexocrine secretions. These gut actions of PP are associated with the mechanism referred to as the
"ilealbrake"whichismanifestwiththeslowingofthepassageofnutrientsthroughthegut.
PP induces an anorexigenic response within the brainstem (area postremus, AP) and vagus. These
responses are mediated via activation of the Y4 receptor which binds PP with highest affinity. In addition to its
expression in the AP, the Y4 receptor is also expressed in regions of the hypothalamus including the ARC.
Therefore,additionalanorexigenicresponsestoPPcanbeinducedwithinthehypothalamus.Thus,PPplaysan
importantroleintheregulationofsatiety(thesensationofbeingfull).Inobeseindividualsthereisareducedlevel
ofPPsecretioninresponsetofoodintake,whereas,inanorexianervosathereisincreasedPPreleasefollowing
consumptionoffood.PPmayalsoplayaroleinthepathogenesisofPraderWillisyndrome(PWS).Thisdisorder
ischaracterizedbyshortstature,reducedintellect,andhyperphagia(excessivehungerandabnormallylargefood
intake).InpatientswithPWSthereisareducedsecretionofPPinresponsetofoodintakeaswellasareduced
basallevelofcirculatingPP.
backtothetop
ProteinTyrosineTyrosine,PYY
PYYisproducedby,andsecretedfrom,intestinalenteroendocrineLcellsoftheileumandcolon.Additional
guthormonesthataresecretedalongwithPYYincludeGLP1andoxyntomodulin(OXM).Bothoftheselattergut
hormones are discussed above. Secreted forms of PYY include PYY136 and PYY336. PYY136 is fulllength
proteinandismorecommonlyreferredtoasjustPYY.PYY336isgeneratedviatheactionsofdipetidylpeptidase
4(DPP4orDPPIV)onPYY.DPP4isthesameenzymethatinactivatesGLP1.Withinthegastrointestinaltract
thehighestdetectablelevelsPYYarefoundintherectumwithlowlevelsfoundintheduodenumandjejunum.
Withinthecentralnervoussystem(CNS)PYYisdetectableinthehypothalamus,medulla,pons,andspinalcord.
As indicated above in the discussion of NPY, PYY binds to members of the Y receptor family. PYY is a potent
agonistofbothY1andY2receptors,whereasPYY336isaY2specificagonist.TheaffinityofPYY336fortheY2
receptorisapproximately1,000foldhigherthanfortheY1receptor.
ThereleaseofPYYresultsinreducedgutmotility,adelayingastricemptying,andaninhibitionofgallbladder
contraction.Alloftheseactionsare,likethatofPP,associatedwiththeilealbrake.GiventhatPYYissecreted
fromcellsofthedistalguttheremustbesignalsassociatedwiththeresponseoftheproximalguttofoodintake
that lead to PYY release. Indeed humoral factors such as CCK and gastrin are thought to mediate the rapid
release of PYY in response to eating. The amount of PYY released in response to the ingestion of food is
proportional to the caloric intake. Animal and human studies of anorectic conditions indicate that PYY has a
critical role in satiety. Within the CNS, PYY exerts its effects on satiety via actions in the hypothalamus,
specificallytheARCofthehypothalamus.TheARCisincloseproximitytothedeficientbloodbrainbarrierofthe
median eminence of the hypothalamus, thus allowing this region to respond rapidly to the release of a gut
hormoneintothecirculation.EvidenceconfirmingtheroleofPYY336ininducinganorexiahasbeenobtainedin
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micebydirectinjectionofthepeptideintotheARC.PYY336hasbeenshowntoexerttheinhibitiononfoodintake
in a Y2dependent manner. Although it was proposed that PYY336 might exert its anorexigenic effects by
activating Y2 receptors on POMC neurons in the ARC, the PYY336induced inhibition of food intake has been
shown to still occur in POMC knockout mice. Given the role of PYY in appetite suppression it is thought that
disturbancesinPYYreleaseinresponsetofoodintakemayplayaroleinthedevelopmentofobesity.Indeed,in
obese humans there is a blunted PYY response following food intake compared to lean humans. Current
therapeutic interventions designed to combat obesity involve studies of the efficacy of PYY at suppressing
appetite.
backtothetop
Enterostatin
Dietarytriglyceridesarehydrolyzedbypancreaticlipaseinconjunctionwiththecoactivatorprotein,colipase.
The importance of the role colipase in pancreatic lipase mediated triglyceride digestion was demonstrated in
colipaseknockoutmice,whodisplayedseverelyreducedfatdigestionandfatabsorptionwhenfedahighfatdiet.
Studiesonthefunctionofcolipasedemonstratedthattheproteinissecretedasaprocolipasewhichisactivated
bytrypsincleavage.Notonlyisactivecolipasereleasedfromprocolipaseupontrypsindigestionbutanadditional
peptide of five amino acids (pentpeptide) is also released. This pentapeptide was termed enterostatin andwas
showntohavenoroleinfatdigestionandabsorption.However,andquitestrikingly,itwassubsequentlyshown
that enterostatin exhibited appetite regulating properties. The appetite regulating effects of enterostatin are
specific to highfat or fat diets but not towards diets rich in protein or carbohydrate. These effects were
demonstrated after intraperitoneal, intraduodenal, and intracerebrovascular injection of enterostatin. From the
intestine,theanorexigeniceffectsofenterostatinrequireintactvagalafferentconnectionstothebrain.Basedon
these experimental observations it has been proposed that enterostatin functions in a negative feedback
mechanismtocontrolfatintake.Inadditiontothenegativeregulationoffatintake,enterostatinincreasesenergy
expenditurethroughbothcentralandperipheralpathways.Thefunctionsofenterostatininvolveeffectsexerted
throughtheopioidsystemsoftheintestinesandthebrain.
There are three forms of enterostatin found in vertebrates with the AlaProGlyProArg (APGPR)
pentapeptidepresentinhumans.TheValProAspProArg(VPDPR)formisfoundinrodentsandcanines,and
ValProGlyProArg(VPGPR)isalsofoundinrodents.Commontoallthreeformsofenterostatinisthebridged
prolinestructure,PXP.ThesignificanceofthePXPmotifinthevariousformsofenterostatinisdemonstrated
bythebindingtargetsofthispeptide.
Studiesaimedatidentifyingpotentialreceptors/bindingsitesforenterostatindemonstratedthat membranes
fromneuraltissuespossessedbothhighaffinityandalowaffinitybindingsites.Thepresenceoftwobindingsites
with different affinities explains the variable doseresponse characteristics observed with enterostatin. At low
dosesthepeptidesuppresses fat intake while at high doses it exhibits either no effect or in some experiments
high doses stimulate fat intake. The significance of the opioid system to enterostatin function was discovered
during competitive binding studies. The specific highaffinity binding of enterostatin to membranes can be
displaced by casomorphin15 and metenkephalin. Both of these peptides are known to have high affinity
bindingtotheopioidreceptors,MORs.Theenkephalinsrepresenttwodistinctpentapeptides,metenkephalin
(YGGFM)andleuenkephalin(YGGFL),whicharederivedfromtheproenkephalingene.Thecasomorphinsare
smallpeptidesderivedfromtheproteolyticdigestionofthemilkproteincasein.Bovinecasomorphin15(derived
from casein) has the sequence YPFPG which contains the same bridged proline structure, PXP, found in
enterostatin.Thecasomorphinsarereferredtoasnutripoidsduetotheirnutritionaloriginandtothefactthatthey
activatetheopioidreceptorsystemintheintestines,specificallytheopioidreceptors.
Experimentalevidenceindicatesthattheabilityofenterostatintoregulatefatintakeinvolvestheprocessof
thermogenesis(regulatedenergyconsumptionforheatgeneration)andtherewardcircuitryofthecentralnervous
system. The reward pathways in the brain are complex and involve multiple pathways such as the mesolimbic
dopaminergic system and the opioid system. Given that enterostatin binding to neural cell membranes can be
competed by a peptide such as casomorphin which has high affinity for the opioid receptors, it is not
surprising that enterostatin may indeed effect regulation of opioid reward pathways. The and the opioid
receptorsareknowntobeinvolvedintheregulationofrewardspathwaysrelatedtofeedingbehavior.Agonistsof
these receptors stimulate feeding whereas, antigonists suppress feeding. Muopioidspecific agonists stimulate
highfatfeedingandhavebeenshowntoblocktheinhibitoryeffectsofenterostatin.
Theroleofenterostatinintheregulationofthermogenesisissuggestedbytheobservationthatthepeptide
binds to the subunit of F1F0ATP synthase and this binding is also inhibited by casomorphin. However,
bindingofenterostatintotheATPsynthasesubunitisnotblockedorcompetedbyadditionofopioidreceptor
specific agonists. The binding of enterostatin to this protein was unexpected since F1F0ATP synthase is the
mitochondrialcomplexpresentintheinnermitochondrialmembranenecessaryforthegenerationofATPduring
oxidativephosphorylation.Incellcultureexperimentsithasbeenshownthethebindingofenterostatintothe
subunit of F1F0ATP synthase results in decreased ATP production, increased thermogenesis, and increased
oxygenconsumption.Ofpotentialsignificancetodiabetesisthattheseeffectsinpancreaticbetacellsleadsto
decreased insulin secretion. Subsequent studies demonstrated that the subunit of the F1F0ATP synthase
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complexcanactuallybefoundintheplasmamembranesofhepatocytesassociatedwithATPhydrolaseactivity
atthecellsurface.Thepresenceofthiscomplexinthehepatocytecellmembranehasbeenshowntobeinvolved
in modulating lipoprotein uptake and given that enterostatin can bind to, and inhibit, the plasma membrane
activity,thecomplexislikelyalsoinvolvedinmodulatingfatintake.
Enterostatinalsoregulatesthermogenesisatthelevelofthefamilyofuncouplingproteins(UCP).Thereare
several UCP family members in humans and several of the encoding genes are induced under highfat diet
conditions.UCP1isexpressedinbrownadiposetissue(BAT),UCP2isexpressedinanumberoftissuessuchas
theintestinesandadiposetissue,whileUCP3isexpressedinskeletalandheartmuscle.OnlyUCP1isinvolved
intheprocessofadaptivethermogenesis.WhenanimalsarefedahighfatdietthelevelsofUCP2declineinthe
intestines but increase in adipose tissue. However, if enterostatin is added to the diet there is an observed
increase in intestinal UCP2 expression. Although the role of UCP1 in the regulation of thermogenesis s well
defined,theexactfunctionofUCP2isnot.EvidenceindicatesthatUCP2islikelyinvolvedintheprotectionfrom
reactive oxygen species (ROS) generated in conjunction with highfat diets. Therefore, within the intestines,
enterostatinmaybeplayingaprotectiverolebyinducingincreasedlevelsofUCP2.
A current model for enterostatin function suggests that a highfat diet leads to increased release of
enterostatinintotheintestinallumen.Followingitsrelease,enterostatincanbindandactivateopioidreceptors
inthegutand/orapathwayinvolvingF1F0ATP synthase. Activationof theopioidreceptor signaling pathway
likelyinfluencestherewardcircuitrythroughvagalafferentconnectionsthatinfluencethecentralopioidsignaling
pathways. Simultaneously, or alternatively, the regulation of the F1F0ATP synthase pathway could influences
ATP production and overall energy utilization during highfat feeding. Regardless of the pathway(s) affected by
enterostatin,theevidenceisclearthatthispentapeptideinfluencesfatintakebyrestrictinganoverconsumptionof
fatintake.
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FibroblastGrowthFactor19,FGF19
The fibroblast growth factor family of growth factors and hormones currently consists of 18 members in
humans.Theseproteinsaredividedintosixsubfamilieswithsubfamily6containingFGF19,FGF21andFGF23
(commonlyreferredtoastheFGF19subfamily).AllthreemembersoftheFGF19subfamilyfunctionasendocrine
hormones. FGF19 subfamily members have weak affinity for heparan sulfate proteoglycans (HSPGs) which
allowsthemtoescapefromtheextracellularcompartmentintocirculationenablingthemtofunctionasendocrine
hormones.OthermembersoftheFGFfamilyutilizetheirinteractionswithHSPGstoformhighaffinityinteractions
with FGF receptors (FGFRs). However, since the FGF19 subfamily members have low affinity for HSPGs they
interact with the singletransmembrane containing Klotho proteins to facilitate their interactions with FGFRs.
There are two related Klotho proteins, Klotho and Klotho. FGF19 can interact with both Klotho coreceptor
proteins.FGF19showspreferenceforactivationofFGFreceptor4(FGFR4)butviaitsKlothointeractionscan
alsoactivateFGFR1.FGF21selectivelyuseKlothoasitscoreceptor,whereas,FGF23usesKlotho.
FGF19RegulationofandbyBileAcids
FGF19playsacriticalroleintheoverallprocessesoftheentrohepaticcirculation.Itcarriesoutthisroleby
regulation of bile acid synthesis in the liver, bile acid delivery to the gallbladder, and regulation of gallbladder
function. The ability of intestinal FGF19 to regulate overall bile acid homeostasis is controlled by bile acids
themselves. This process represents an intricate mechanism for feedback regulation of bile acid synthesis
involvingcommunicationfromthesmallintestinetotheliverthroughtheactionsofFGF19.Whenbileacidsare
secretedbythegallbladder,thesecompoundscanbeabsorbedbyilealenterocytes.Withintheenterocytesthe
bile acids bind to, and activate, the nuclear receptor FXR. Bile acid activation of FXR leads to the enhanced
expressionofnumerousgenesintheenterocytes,withtheFGF19genebeingoneoftheseFXRtargets.There
are at least four FXRbinding sites in the promoter region of the FGF19 gene allowing it to be induced on the
orderof300foldviaFXRactivation.ActivationoftheFGF19generesultsintheproteinbeingsecretedintothe
enterohepaticcirculation.Whenthehormonereachestheliver,itinteractswiththeKlotho/FGFR4complexand
triggersactivationofasignaltransductioncascade.Thenetresult,intheliver,istranscriptionalrepressionofthe
CYP7A1gene,whichencodestheratelimitingenzymeinthe"classicpathway"ofbileacidsynthesis.Inaddition
totheregulationofhepaticbileacidsynthesis,FGF19enhanceshepaticglycogensynthesisandreduceshepatic
glucoseoutput.BothoftheselatterconsequencesofFGF19havesignificantclinicalimplicationsinthecontrolof
glucosehomeostasisandinsulinsensitivityinobeseandtype2diabetes.
FGF19FunctionsintheHypothalamus
Emerging evidence has implicated FGF19 as a major hormone in the control of normal metabolic
homeostasis,bothviasystemicactionsandviaactionswithintheCNS.Inmousemodelsofobesity(dietindiced
obesity:DIO),levelsofFGF15(themouseorthologofhumanFGF19)arereducedandinhumans,serumlevels
ofFGF19arefoundtobesignificantlyreducedinpatientswithtype2diabetes.SystemicadministrationofFGF19
toDIOmiceresultsinweightlossandreversestheassociateddiabetes.
The FGF receptors are known to be expressed in the brain. FGFR1 expression is abundant within the
medianeminenceofthehypothalamus.Withinthehypothalamus,expressionofFGFR1andFGFR4isevident,
particularlyonNPYandAgRPexpressingneurons.ExperimentsinvolvingcentraladministrationofFGF19result
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in improved glucose homeostasis primarily via suppression of NPY and AgRP release from hypothalamic
neurons.Thus,althoughFGF19clearlyexertsaglucoseloweringeffectviaitsactionsintheliver,functionsofthe
hormone in the hypothalamus contribute to the overall glucose homeostatic functions of FGF19. The primary
central effects of FGF19 result in the normalization of glucose metabolism in obese subjects, enhancement in
glucose tolerance and insulin sensitivity in the liver and skeletal muscle, and increased insulin secretion. The
ability of FGF19 to suppress NPY and AgRP neuronal activity relies on the FGFRmediated activation of the
ERK1/2signaltransduction cascade. Of potential clinical significance is that the leptinlike effects of FGF19 on
glucosehomeostasisandinsulinsensitivityareeffectiveevenintheDIOmousewhereleptineffectsarelost.
In addition to the metabolic regulation exerted by FGF19 within the brain, central administration of the
hormone has been shown to result reductions in food intake. The reduced desire for food intake is what
contributestotheweightlossobservedinDIOmicefollowingacutesystemicadministrationofFGF19.However,
the effects of FGF19 are not so clearcut with respect to the control of feeding behavior and management of
weight. This is likely due to the fact that normal functions of FGF19 include enhanced energy expenditure via
actions within anorexigenic (aMSH) neurons in the hypothalamus. Chronic systemic administration of FGF19
mayresultinincreased food intake secondary to the resultantincreasedenergyexpenditureresultingfromthe
actionsofFGF19.
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MichaelWKing,PhD|19962016themedicalbiochemistrypage.org,LLC|info@themedicalbiochemistrypage.org
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Gastrointestinal-Brain (Gut-Brain) Interactions & The Control of Feeding Behavior

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