Review Article The Use of Functional MRI to Study Appetite Control in the CNS

14 Pages·2014·2.51 MB·English

HindawiPublishingCorporation
ExperimentalDiabetesResearch
Volume2012,ArticleID764017,13pages
doi:10.1155/2012/764017
Review Article
The Use of Functional MRI to Study Appetite Control in the CNS
AkilaDeSilva,1VictoriaSalem,1PaulM.Matthews,2,3andWaljitS.Dhillo1
1SectionofInvestigativeMedicine,DivisionofDiabetes,EndocrinologyandMetabolism,ImperialCollegeLondon,
HammersmithHospitalCampus,DuCaneRoad,LondonW120NN,UK
2GlaxoSmithKlineGlobalImagingUnit,ImperialCollegeLondon,HammersmithHospitalCampus,DuCaneRoad,
LondonW120NN,UK
3CentreforNeuroscience,DepartmentofMedicine,ImperialCollegeLondon,HammersmithHospitalCampus,DuCaneRoad,
LondonW120NN,UK
CorrespondenceshouldbeaddressedtoWaljitS.Dhillo,[email protected]
Received1February2012;Accepted28April2012
AcademicEditor:AlainKtorza
Copyright©2012AkilaDeSilvaetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Functionalmagneticresonanceimaging(fMRI)hasprovidedtheopportunitytosafelyinvestigatetheworkingsofthehuman
brain.Thispaperfocusesonitsuseinthefieldofhumanappetitivebehaviouranditsimpactinobesityresearch.Inthepresent
absenceofanysafeoreffectivecentrallyactingappetitesuppressants,abetterunderstandingofhowappetiteiscontrolledisvital
forthedevelopmentofnewantiobesitypharmacotherapies.Earlyfunctionalimagingtechniquesrevealedanattenuationofbrain
rewardareaactivityinresponsetovisualfoodstimuliwhenhumansarefed—inotherwords,thephysiologicalstateofhunger
somehowincreasestheappealvalueoffood.Laterstudieshaveinvestigatedtheactionofappetitemodulatinghormonesonthe
fMRIsignal,showinghowtheattenuationofbrainrewardregionactivitythatfollowsfeedingcanberecreatedinthefastedstateby
theadministrationofanorecticguthormones.Furthermore,differencesinbrainactivitybetweenobeseandleanindividualshave
providedcluesaboutthepossibleaetiologyofovereating.Thehypothalamusactsasacentralgatewaymodulatinghomeostaticand
nonhomeostaticdrivestoeat.AsfMRItechniquesconstantlyimprove,functionaldataregardingtheroleofthissmallbuthugely
importantstructureinappetitecontrolisemerging.
1.Introduction market.Foracomprehensiveoverviewofthepositionofgut
hormonesinthetreatmentofobesity,wedirectthereaderto
Whenenergyintakeexceedsenergyexpenditureinthelong areviewbyValentinoetal.,2010[2].
term, the excess accumulates as body fat. It is predicted
The control of appetite and food intake can be divided
that, by 2015, as many as 30% of adults in Europe will be
into “homeostatic” and “nonhomeostatic” control. The
obese, as defined by a body mass index (BMI) ≥30kg/m2
alteration in consumption of food that follows sensing of
[1].Itiswellknownthatobesityconfersincreasedrisktoa
energybalanceformsthebasisofthehomeostaticcontrolof
range of diseases, including type 2 diabetes, cardiovascular
appetite: following a meal, appetite is suppressed, whereas,
disease, and cancer. An enhanced understanding of the
following significant energy expenditure, we feel hungry.
physiological mechanisms that regulate appetite is essential
Postprandial satiety signals include changes in circulating
forthedevelopmentofpharmacologicalstrategiestocombat
concentrationsofnutrientsandguthormones.Theseinclude
obesity.Inparticular,withinthefieldofneuroendocrinology,
theanorectichormonesPYYandGLP-1andtheorexigenic
identification of hormone-brain interactions that modulate
appetite (and subsequent food intake) will aid the manip- hormoneghrelin[3],aswellasactivationofsomatosensory
ulation of naturally occurring hormones to develop safe vagalafferentsconveyinginformationsuchasgastricdisten-
and effective antiobesity therapies. This strategy, exploiting sion [4]. Adipokines (hormones secreted by adipose tissue,
physiologicalpathwaysofappetitecontrol,holdspromisefor suchasleptin)conveyinformationtotheCNSaboutlonger-
thefuturetreatmentofobesity,especiallygiventheshortage term energy stores [5]. Furthermore, it is well established
of effective pharmacotherapies for obesity in the existing thatinsulinissecretedacutelyfromthepancreasinresponse
2 ExperimentalDiabetesResearch
to a glucose load but is also basally elevated in states of
overnutrition and obesity, thereby implying a role in con-
veying both short- and longer-term information regarding
energybalance.Innormalphysiology,theintegrationofthe
above inputs within central neural appetite circuits results
in appropriately matching food intake to metabolic need. A C C
PFC
The hypothalamus is widely recognised as the gatekeeper
vs
for this processing task, in line with other important DLPFC
homeostaticfunctionscontrollingbodytemperature,energy NAc VTA
expenditure, and glucose metabolism. In keeping with this, Am
OFC
thereismountingevidencethathypothalamicdysfunctionis H
implicatedinthepathogenesisofobesity[6].
Withregardto“nonhomeostatic”control,foodintakeis
driven by factors including food palatability (incorporating
the key senses of sight, smell, and taste), habitual, socio-
cultural, emotional, and economic influences. From an
emotionalperspective,theevaluationofafoodstimulusfor
Figure 1: Brain reward centres: the hypothalamus (H), as a
itsmotivationalsignificanceoccursinmultiplebrainregions,
homeostatic gatekeeper, has numerous connections with higher
particularly the dopaminergic limbic and prefrontal reward braincentreswhichprocesssalienceandreward.Thehypothalamus
areas [7]. Key areas include the amygdala, hippocampus, transmits to these higher centres information received from the
insula, striatum, and orbitofrontal cortex (OFC), although periphery,suchasnutritionalstatussignalledviathepostprandial
this list is by no means exhaustive. It is now widely releaseofguthormones,andinturnmodulatesmetabolicratevia
accepted that, with regard to appetite control, homeostatic thesympatheticnervoussystem.Thissagittalsectionofthebrain
andnonhomeostaticsystemsdonotfunctionindependently; revealstheimportantareasinvolvedinthehedoniccontrolofeating
instead, there is extensive cross-modulation between them, behaviour; amygdale (Am): emotional and aversive processing;
nucleusaccumbens(Nac):anticipatoryrewardprocessing;ventral
along with a complex integration of inputs before a final
tegmental area (VTA): numerous dopaminergic projections to
decisionismaderegardingfoodconsumption(Figure1).
other limbic areas; ventral striatum (VS): motivation reward;
Over the past decade, functional magnetic resonance expectancyandnoveltyprocessing;anteriorcingulatecortex(ACC):
imaging(fMRI)hasbecomeapopularandrapidlyadvancing decision making; orbitofrontal cortex (OFC): reward encoding;
tool for investigating CNS appetite pathways in humans, prefrontal cortex (PFC): translation of external and internal cues
offering the key advantage of avoiding exposure to ionising intobehaviouralresponses;dorsolateralprefrontalcortex(DLPFC):
radiation. Following on from previous similar articles [8– self-control. Not shown is the insular cortex (a more lateral
10],hereweprovideanupdatedreviewofrecentadvancesin structure),whichisalsoimportantingustatoryprocessing.
ourunderstandingofhumanappetitivebehaviourbasedon
theresultsoffMRIstudies.Westartwithabriefoverviewof
areinalow-energystate.GenerationofMRIimagesrequires
thetechniqueandthensummarisefindingsfromtheearliest
fMRI appetite studies, which first explored differences in application of a radiofrequency (RF) pulse at 90 degrees to
B .Theprotonswillthen“tip”toalignwiththeRFpulse.In
brainactivationpatternsbetweenthenormalfedandfasted 0
doingso,theygainenergy.AftertheRFpulseisswitchedoff,
state and in response to glucose ingestion. This is followed
the protons realign with B . Spins return to the low-energy
by a discussion of a further cluster of studies, exploring 0
differencesbetween obese and lean populations. Finally, we state by emitting the absorbed energy, also in the form of
a radio wave. The emitted energy can be measured by the
review the results of fMRI studies investigating hormonal
receivercoilandconvertedtoimages.Byslightlyalteringthe
influences on appetitive brain processes and in relation to
strength of the magnetic field (and therefore the frequency
this and explore recent functional neuroimaging outcomes
of the emitted radiation) using gradient coils across the
followinginterventioninobesesubjects.
volume to be imaged, spatial information can be inferred.
The T relaxation time is a time constant referring to the
1
2.PrinciplesoffMRIinAppetiteStudies realignmentofspinswithB inthelongitudinalplaneafter
0
theRFpulseisswitchedoff.TheT relaxationtime,onthe
2
A full description of fMRI methodology is clearly outside otherhand,isatimeconstantreferringtothedephasingof
theremitofthispaper.Itisneverthelessusefulforthenon- spins in the transverse plane after the RF pulse is switched
imagingspecialisttounderstandsomeofthetechnicalitiesof off(Figure2).T andT varydependingonthetissuebeing
1 2
fMRI,inordertogainabetterappreciationofhowthefield imaged.Thestrengthofmagneticresonancesignalobtained
hasprogressed,aswellassomeofitslimitations. for a particular tissue depends primarily on the proton
MRI utilises the behaviour of hydrogen nuclei, which density.However,byalteringthetimebetweensuccessiveRF
consist of single protons that possess angular momentum pulsesandthereforethedegreeofT andT relaxation,the
1 2
(spin).Assoonasanexternalmagneticfield(B )isapplied, image can be weighted towards one or the other of these
0
the protons in tissue tend to align with this, causing their tissue-specificproperties.Itshouldbenotedthat,inpractice,
spinstoprecessaboutacircularpatharoundB .Here,they due to localised inhomogeneities in the externally applied
0
ExperimentalDiabetesResearch 3
Z(M0)
x
y

RF pulse
(a) (b) (c)
(d) (e) (f)
Figure2:SchematicofT andT relaxation.MRIutilisesthebehaviourofprotonswithinvaryingmagneticfieldstoproducesignalswhich
1 2
canbeconvertedintoimages.Eachhydrogennucleusinthebraincanbethoughtofasavector(inthezandx-yplanes)representingthe
strengthanddirectionofitsmagneticfieldasitspinsonitsaxis(itsmagneticdipolemoment,MDM).TheMDMsoftheimagedprotons
trytoalignwiththemainexternalmagneticfieldofthescanner(referredtohereasB andconventionallyshownalongthezaxisin3D
0
coordinates).Asecondmagneticfield(intheformofashortradiofrequencyRFpulse)isapplied,whichflipsalloftheMDMsfromalignment
inthezdirectionintothex-yplane(a).BeforeapplicationoftheRFpulsethe,amplitudeinthez-axisismaximalwhiletheamplitudein
thex-yplaneiszero.JustafterapplicationoftheRFpulsethe,amplitudeinthez-axisiszero(a)whiletheamplitudeinthex-yplaneis
maximal(d).Duringrelaxation,theamplitudeinthez-axiswillslowlyincrease((b)and(d))whiletheamplitudeinthex-yplaneslowly
decreases((e)and(f)).T relaxationisthetimetakenforthezvectortoregaininstrength,whereasT relaxationisthetimetakenforthe
1 2
x-yvectortodecay.ThesechangingmagneticvectorsinvoketheirownRFsignals,whicharepickedupbythereceivercoilsandinterpreted
intoinformationabouttheprotondensityofthesubjectbeingscanned.
magneticfield,T isshorterthanexpectedforanyparticular large numbers of images in short spaces of time. Echo-
2
tissue.ThisapparentT isreferredtoasT ∗. planar imaging (EPI), for example, is a technique whereby
2 2
fMRIutilisesadaptationsofthisclassicalMRItechnique, anentire2-dimensionalimagecanbeattainedbytherapid
such that function of tissues can be analysed rather than alterationofspatialgradientsfollowingasingleRFpulse.In
structurealone.Virtually,allfMRIstudiesrelyonameasure this way, the entire brain can now be functionally imaged
calledblood-oxygenation-level-dependent(BOLD)contrast, within the same timeframe as the physiological changes of
based on the fact that oxygenated and deoxygenated blood interest.FunctionalMRIhasthusprovidedhugelyimportant
possess different magnetic properties. Increased neuronal insightsinnumerousdisciplines.However,itsuseinthefield
activity in the brain elicits a local haemodynamic response, ofneuroendocrinologyhasbeenlimitedduetotheinherent
whichcausesanincreaseinbloodflowgreaterthannecessary weaknessofthetechniqueatimagingthehypothalamus.This
for tissue demands. This results in a locally reduced ratio small (approximately 5–8mm in diameter) brain structure
of deoxyhaemoglobin to oxyhaemoglobin concentrations, liesclosetotheair-tissueboundariesofsurroundingsinuses
andtheensuingdifferencesinlocalmagneticfieldinhomo- and is susceptible to signal loss due to resultant distortions
geneitiescanbedetectedonaT ∗-weightedimagingproto- oftheexternalmagneticfield,whichisaparticularissuefor
2
col[11,12];thelocallyreducedratioofdeoxyhaemoglobin T2∗-weightedimagesasalreadydescribed[13].
to oxyhaemoglobin leads to a longer T ∗, producing an fMRI image reconstruction results in the selected brain
2
increased image intensity. Such protocols typically use areadividedintothousandsofvoxels,eachassignedasignal
magneticgradientstogeneratetheMRsignal(gradient-echo intensity.Statisticalanalysisofeachvoxelorclusterofvoxels
imaging)and,asscannerandcomputationalhardwareshave ascertains whether the signal intensity there is greater than
advanced, faster sequences have been developed to acquire comparedwithallothers.Whilstthisapproachmaybeuseful
4 ExperimentalDiabetesResearch
for exploratory studies, most fMRI experiments perform that oral glucose ingestion produced a profound transient
ROI (region of interest) analyses whereby the functional reduction in hypothalamic BOLD fMRI signal in lean
properties of a predetermined set of voxels (corresponding subjects [18]. They alluded to the hypothalamic effects
to a priori anatomical areas of the brain) are analysed. being mediated by neurohumoral factors following glucose
ROI analysis, with very many fewer degrees of freedom ingestion,sincethehypothalamicsignalchangeprecededany
than whole-brain voxelwise analysis, has a greater chance significantriseinbloodglucose.
of finding statistically significant results but entails the
In2000,Liuetal.describedanewtechniquecalledtime
inherent risk of missing activated areas of the brain that
clustering analysis (TCA), whereby the number of voxels
were not included in the original hypothesis. Resting state
reachingmaximumsignalintensityasafunctionoftimewas
functional connectivity analyses investigate the activational
examined [19]. In this way, TCA records the time windows
interrelationships between different brain regions, allowing
in which maximal brain responses occur and from which
for the formation of distinct neuronal networks implicated
ROI analysis can be appropriately extracted. By scanning a
in a coordinated brain response [14]. Resting state scans
1cmmidsagittalslice,theywereabletofurtherconcentrate
are performed when the subject is not performing any
resolution on the hypothalamus and found that significant
purposeful task and have recently reported on blood flow
hypothalamic deactivation occurred 10 minutes following
tothehypothalamusasanROIwithorwithoutinfusionof
glucose ingestion. They also showed that the degree to
anorecticguthormones[15].
whichthehypothalamicsignalreducedpostglucoseingestion
Another commonly used approach in the area of func-
negativelycorrelatedwithfastingplasmainsulinlevels.
tional imaging of appetite is to present the subject with
Using functional MRI in a 1cm midsagittal slice,
images of food (with further subdivision into appetising,
Smeetsandcolleaguesreportedonrestingstateintrasubject
bland, high calorie, or low calorie food) or nonfood items.
hypothalamicresponsebeforeandafteringestionofglucose.
A subtraction analysis is performed to see whether the dif-
In their original experiment, they also found a dose-
ferenceinregionalbrainactivationbetweenviewingimages
of food or nonfood is altered in different physiological dependent decrease in hypothalamic BOLD fMRI signal in
lean,healthysubjectsshortlyafteringestingglucosesolution,
conditions (e.g., the fasted state, the fed state, or in the
whichlastedfor30minutes[20].Usingthesameexperimen-
presenceofexogenouslyadministeredanorectichormones).
talparadigm,theywentontoshowthathypothalamicBOLD
Several studies have utilised this approach; these will be
signal did not decrease following ingestion of an equally
discussedindepthsubsequently.Hypothalamicdataremain
sweet(butcaloriedeficient)solutionofaspartame,oringes-
anelusivegoalwithsuchwholebraintask-basedanalyses;in
additiontotheaforementioneddifficultiesinhypothalamic tionofanequallycalorific(butnotsweet)solutionofmal-
todextrose.Theytherebyinferredthathypothalamicactivity
imaging,activationofsomenucleiwithinthehypothalamus
was specifically glucose-sensitive and that a hypothalamic
promotes food intake, whereas other nuclei are appetite-
responserequiredbothsweettasteandenergycontent[21].
inhibiting[16].Therefore,usingthehungry,fastedstateasan
Interestingly, from a clinical perspective, they subsequently
example,theoverallhypothalamicsignalresultingfromthe
demonstrated that the reduction in hypothalamic BOLD
activationoforexigenicnucleiandinhibitionofanorexigenic
signalfollowingglucoseingestionwasabsentinpatientswith
nuclei may in fact be negligible, due to the above opposing
type2diabetes,theorisingthatinappropriatehypothalamic
signals cancelling each other out. In addition to developing
processing of nutrient availability may be involved in the
strongermagneticfieldstoenhancespatialresolution,newer
perfusion imaging techniques, which are T weighted, may aetiology of the disease [22]. Using the same hypothalamic
1
provide better hypothalamic data which is not so affected BOLD imaging technique as these previous studies, this
group has also alluded to the effects of gut hormones on
by signal loss due to magnetic susceptibility artefacts [17].
hypothalamicactivityfollowingglucoseingestion.Inhealthy
Arterialspinlabelling(ASL)usesRFpulsestomagnetically
men,despitecausingathreefoldlowerriseinbloodglucose
labelprotonsinbloodwatermoleculesbeforetheyreachthe
concentrationthanintravenousglucoseadministration,oral
tissueofinterestwhichliesintheimagingplanefromwhere
glucose ingestion led to a much more robust reduction
dataisacquired.
hypothalamic BOLD signal [23]. As well as the effect of
taste, it was postulated that hormones such as GLP-1,
3.ImagingtheHypothalamicResponseto releasedinresponsetonutrientsenteringthegut,accounted
GlucoseUsingMidsagittalSliceSelection for this greater hypothalamic response to oral rather than
intravenousglucose.
Earlystudiesthathaveconcentratedonhypothalamicsignal
However,incontrasttotheabovefindings,arecentstudy
change involved conventional T ∗-weighted gradient-echo
2 by Purnell et al. in 2011 did not detect any signal change
MRI pulse sequences to functionally scan a sagittal plane in the hypothalamus in response to either glucose or fruc-
through the hypothalamus continuously, acquiring images tose infusion in 9 healthy, normal-weight subjects, despite
before- and after- a given stimulus. By concentrating all focussing their image acquisition parameters to optimise
image processing ability on this thin, central slice, greater hypothalamic signal capture by mid-sagittal T weighting
1
attention can be devoted to a ROI corresponding to the [24]. The authors postulated that differential activation of
hypothalamus,althoughclearlyattheexpenseofimagingthe excitatory and inhibitory nuclei within the hypothalamus
restofthebrain.Inthismanner,Matsudaetal.demonstrated may have cancelled out any overall signal change. This
ExperimentalDiabetesResearch 5
illustrates the ongoing limitations when attempting to of calorific content, food images caused greater activation
visualisethehumanhypothalamusinfMRIstudies. than nonfood images in the amygdala, hippocampus, and
ventromedial prefrontal cortex [30]. The authors point
out the importance of these areas in the expectation and
4.fMRIStudiesinNormal-Weight evaluation of reward. High-calorie foods caused particular
SubjectsComparingtheResponsetoFood activation of the medial and dorsolateral prefrontal cortex,
CuesintheFastedandFedStates understood to be involved in evaluating stimulus relevance
within the current affective state of the individual. In
Before moving into the arena of functional brain imaging contrast, low calorie foods resulted in lesser activation
studies to specificallydetermine the neuroendocrinology of of these reward areas per se and greater activation in
appetite control, it is useful to look at earlier studies which somatosensory areas, with a suggestion from the authors
examineddifferencesinbrainactivityinhungerandsatiety. that this was due to a lesser cephalic phase response by
Such differences may be attributed to a number of physi- classical conditioning to images of less appealing foods. In
ological differences between the fed and fasted state, such 2005,Killgorepublishedareanalysisofthisstudydata,using
as changes in concentrations of gut-derived neuropeptides an ROI approach (specifically, a subanalysis of the OFC)
(PYY, GLP-1, ghrelin, CCK, and insulin to name but a and correlated BOLD activity with BMI. It was reported
few) and vagal afferents conveying information about gut that,forthehighcalorieminusnonfoodcontrast,therewas
distension. These early studies into appetitive behaviour a significant negative correlation between BMI and BOLD
have led to our understanding of how images of food can signal in the OFC [31]. In other words, as BMI increases,
trigger the brain’s reward system and how the motivational activity in the OFC becomes less food responsive. This
potency of this trigger is greater in the fasted state. On highlights the more subtle role of parts of the OFC not
the whole, these studies complemented earlier work which justinsimplyassigningrewardvaluetocertainstimuli,but
utilised PET scanning to assess the effects of hunger and in modifying stimulus-reward associations and accordingly
satietyonregionalcerebralbloodflowdifferencesandwhich redirecting feeding-related behaviour in response to new
particularly implicated the OFC as a critical convergence learning [32]. Of course,in this particular study, it wasnot
zone for sensory information related to rewarding stimuli possible to extend these findings to the obese population,
[25–28]. sincethesubjectsstudiedwereallwithinthenormalweight
Most of these fMRI studies have been task-based sub- range.
traction analyses, looking at differences in regional brain In2005,St-Ongeetal.publishedtheonlyfMRIstudyto
activationbetweenwhenviewingimagesoffoodornonfood datewherefastedindividualswereexposedtofourdifferent
items. It is well understood that, whilst taste provides an stimuli:visualfood,visualnonfood,tactilefood,andtactile
immediatereward(orpunishment)forconsumedfoods,the nonfood. In an uncorrected whole brain analysis, they
visualcharacteristicsoffoodarequicklylearnedandbecome reportedthattheanteriorcingulate,superiortemporalgyrus,
powerful secondary reinforcers, capable of influencing sub- hippocampus, and insula were significantly activated to a
sequentfood-seekingbehaviour.Thus,showingfoodimages greaterextentduringthepresentationoffoods(whetherseen
isausefulwayofexaminingtheappetitiverewardcircuitry. orfelt)overnonfooditems[33].
Inthefirststudyofitskindin2001,LaBaretal.reported In 2006, Porubska´ et al. published the results of an
on9healthysubjects,whounderwentaninitialwhole-brain fMRIstudyof12normal-weightfastedsubjects.Visualfood
fMRI after an 8 hour fast, followed by another postmeal stimuli(incontrasttononfoodimages)activatedtheinsular
scan one hour later. A follow-up study was performed on and orbitofrontal cortices, with a positive modulation of
8 subjects who were fed a meal before the first of the two insular activity induced by subjective ratings of appetite
scans to rule out the potential of habituation effects in [34]. These findings are consistent with the recognition
the first group. The subjects were presented with food and of the insula as being an important region in establishing
nonfood images during each scan and subtraction analysis salience [35]. Following on from this, Fu¨hrer et al. in 2008
was performed [29]. The authors’ hypothesis that variation studied12healthymalevolunteersundergoingtwoseparate
in the state of hunger would modulate the response of the scanningsessions—onewhenfastedovernightandtheother
amygdala and anatomically related corticolimbic structures immediately after a large meal. They performed a whole
was borne out in a ROI analysis, which revealed satiety- brain, uncorrected analysis of the data and particularly
induced reduction in activity in the amygdala, parahip- noted significantly enhanced activity within the OFC when
pocampal gyrus, and fusiform gyrus. They suggested that hungry, again with reference to our understanding of this
theamygdala,withitsextensiveneuralconnectionswiththe areaassubjectifyingtheperceivedpleasantnessoffood[36].
hypothalamus and higher brain centres, was in a pivotal We have also recently demonstrated that feeding reduces
positionforintegratingresponsetovisualfoodstimuliinthe the difference in BOLD signal between viewing images of
contextofnutritionalstatus.However,itwasnotedthatthis food and nonfood in several brain regions (Figure 3), but
study was underpowered to detect similar satiety-induced significantly so in the insula [37]. Furthermore, in 2009,
changesinmanyotherROIsstudied. Goldstone et al. reported the findings from a fMRI study
In 2003, Killgore et al. used a different approach by of twenty individuals in both the fed and fasted state;
scanningsatiatedrecruitswhowerepresentedwithpictures subjects viewed pictures of high calorie, low calorie, and
ofhighcalorie,lowcalorie,andnonfooditems.Irrespective nonfooditemswhilstratingtheappealvalueoftheseimages.
6 ExperimentalDiabetesResearch
Putamen 5.DifferingfMRIResponsesinObesity
Bearing in mind the results of the above studies in normal
weight individuals, it is now interesting to turn to the
Insula resultsofsimilarstudiescomparingobeseandnormalweight
subjects.
As discussed above, in 1999, Matsuda et al. studied
the hypothalamic response before and after oral glucose
ingestion.Althoughtheyshowedthatoralglucoseingestion
produced a profound transient reduction in hypothalamic
signalin10leansubjects,thisresponsewasbothsignificantly
delayed and attenuated in 10 obese individuals. More
tellingly,itwasshownthat,followingglucoseingestion,the
time taken to reach the maximum hypothalamic inhibitory
Orbitofrontal responsewascloselycorrelatedtofastingplasmaglucoseand
cortex insulin levels (which, as expected, were significantly higher
in the obese group) rather than BMI per se, suggesting
hypothalamicdysfunctionaseitherthecauseorconsequence
ofinsulinresistance[18].
To extend the above findings to the study of reward
regions,alaterstudyincorporatingvisualfoodandnonfood
cuemethodologyrevealedthatBOLDfMRIactivationinthe
righthippocampus(withrespecttohighcaloriefoodimages
Figure3:Modulationofneuronalactivityinthefedversusfasted
versusotherimages)correlatedpositivelywithfastinginsulin
state. Representative whole-brain fMRI sections showing regions
levels and waist circumference (but not BMI) in 12 normal
wherethedifferenceinBOLDsignalbetweenviewingfoodimages
weight and 12 obese adolescents who had all been fed a
andnonfoodimagesisbluntedinthefedstatecomparedwiththe
standard breakfast a few hours prior to scanning [42]. On
fastedstate.Unpublishedimagefrom[37].
the other hand, in that study, there wassignificant negative
correlation between activation of the medial right superior
Theyfoundthatwhenfasted,therewassignificantlygreater frontal gyrus and the left thalamus (again, with respect to
activation to high calorie over low calorie food items in the contrast between high calorie food images versus other
theventralstriatum(importantinmediatinghedonicdrive images) with fasting insulin levels. The authors postulated
andaction[38]),amygdala,anteriorinsula,andOFC.They thattheirresultsreflectedapermissiveroleofinsulininthe
foundthathighcaloriefoodswereconsistentlyratedasmore controlofeatingbehaviourbythehippocampus.Wefurther
appealing, that this was augmented with fasting and that speculatethat,inthosewithalargerwaistcircumferenceand
the increase in appeal rating bias for high calorie over low high circulating levels of insulin (i.e., peripherally insulin
calorie foods in the fasted state was positively correlated resistantindividuals),adegreeofcentralinsulinresistancein
withactivityintheOFC[39].Inthesameyear,Schuretal. the hippocampus may explain the greater activation in this
performed a study of ten normal weight, fed subjects region,despitehigherinsulinlevels.
viewing images of fattening food, nonfattening food, and Studiesinvestigatingthedifferentialrewardsystemacti-
nonfood items. These food images were specifically chosen vationpatternswhenlookingathighcaloriefoodsbetween
based on whether the food was perceived to be compatible obese and normal weight subjects have shown significantly
with an effort to lose weight. In a ROI analysis, this was greateractivationintheobesegroupinseveralbrainregions
the first study to report increased hypothalamic activation implicated in food reward. In a study by Rothemund et al.
when viewing pictures of fattening food compared with in 2007 of 13 obese and 13 normal weight women who
nonfooditems,althoughthisfindingdidnotextendtoother had been fasted for at least 90 minutes, increasing BMI
comparisons (i.e., fattening versus nonfattening or all food positivelypredictedBOLDactivationofthedorsalstriatum
versus nonfood). In concordance with other studies, they (caudate/putamen), anterior insula, claustrum, posterior
also found increased activation in the amygdala,insula and cingulate, postcentral cortex, and lateral OFC. This specifi-
OFCwhenviewingfatteningfoodscomparedwithnonfood callypertainedtothecontrastbetweenviewinghighcalorie
items[40].Alsoinagreementwithpreviousfindingswerethe food images versus nonfood images [43]. A further ROI-
resultsofSiepetal.,whoin2009reportedincreasedactivity based study by Stoeckel et al. in 12 obese and 12 normal
intheamygdalaandOFCinresponsetoviewinghighcalorie weight women demonstrated that pictures of high calorie
versuslowcaloriefoodimages,butonlywhentheirsubjects foods (versus nonfood) produced greater activation in
were fasted [41]. Their experimental protocol allowed for the obese group compared with controls in several brain
the further observation that this increased activity in the regions, including the ventral and dorsal striatum, insula,
amygdala and OFC was only evident when participants anterior cingulate cortex, amygdala, OFC, hippocampus,
explicitlyevaluatedfoodsbutnotwhentheirconcentration ventral pallidum, and medial prefrontal cortex [44]. A
wasdivertedelsewhere. furtherfunctionalconnectivityanalysisindicatedthatobese
ExperimentalDiabetesResearch 7
women displayed a relative deficiency in the amygdala’s characterisation, 8 women who showed >2.5% increase in
modulation of the OFC and ventral striatum, along with BMIovera6-monthperiodshowedreducedstriatalBOLD
excessive modulation of the ventral striatum by the OFC fMRIresponsetochocolatemilkshakeconsumption(versus
[45].Collectively,resultsfromtheabovestudiessuggestthat a tasteless control solution) compared with 12 women who
a hyperreactive reward system to high calorie food cues is demonstrated stable weight [49]. These results reinforced
involvedinthepathophysiologyofobesity. the authors’ hypothesis that weight gain may be associated
Fascinatingly, several studies have shown that obese withreducedsensitivityofstriatalrewardcircuitry(probably
individuals respond differently to satiation compared with due to the downregulation of dopamine D2 receptors),
normal weight individuals, which allows us to hypothesize which may be a fundamental mechanism responsible for
that, in obesity, there is a degree of dysregulation in CNS overeating.
appetite regions, which may contribute to overeating and Differences between normal weight and obese indi-
henceweightgain. viduals have been replicated in studies of children; in
A ROI-based study by Martin et al. measured fMRI one such investigation of 10 obese and 10 normal weight
BOLD activation pre- and postprandially (following a 500 children,inthefastedstate,theobesegroupshowedgreater
kCalmeal)inresponsetopicturesoffood(acombinationof BOLDactivation(whenviewingfoodimagesversusnonfood
highcalorieandlowcalorieimages)andnonfoodin10obese images)intheprefrontalcortexcomparedwiththenormal
and10healthyweightadults.Duringthepremealcondition, weightgroup.Followingameal,thereductioninactivation
obese subjects showed increased activation in the anterior oftheprefrontalcortexandnucleusaccumbenswasblunted
cingulateandmedialprefrontalcortex,comparedtohealthy intheobesegroup.Furthermore,thepostmealactivationof
weightcontrols[46],thusconcurringwiththeobservations theOFC(tofoodversusnonfoodimages)wasgreaterinthe
of Stoeckel et al. During the postmeal condition, obese obesegroupcomparedwiththenormalweightgroup[50].
participants also showed greater BOLD activation in the
medial prefrontal cortex compared with healthy weight
6.fMRIStudiesofHormonesImplicatedin
controls.AfurtherrecentstudybyDimitropoulosetal.of22
AppetiteControl
overweight/obesemalesand16normalweightmalesshowed
thatbeforeeating,obesesubjectsshowedgreaterresponseto
Having discussed the first generation of fMRI studies
foodimages(versusnonfoodimages)comparedwithnormal
exploringthephysiologicalresponsestofeeding,followedby
weight subjects in the anterior prefrontal regions [47].
studies investigating alteration of such responses in obese
Postprandially, the obese group demonstrated increased
individuals, we will now direct our focus to research that
response to all food images (versus nonfood) compared
hasinvestigatedtheeffectsofappetitemodulatinghormones
with normal weight individuals in frontal, temporal, and
derivedfromthegastrointestinaltractandadiposetissueon
limbic regions. Specific greater activation to high calorie
thefMRIneuronalresponse.Asalludedtoearlier,suchhor-
foods was seen in the obese group compared with normal
mones are thought to be key mediators of both short-term
weightindividualsinthelateralOFC,caudate,andanterior
and longer-term energy balance; in the postprandial state,
cingulatecortex[47].
anorectic hormones (including PYY, GLP-1, and insulin)
Aninterestinghypothesistoexplainabnormaleatingin
predominate,andinthelonger-term,high-circulatinglevels
obesity was postulated by Stice et al., following an fMRI
of leptin and insulin correlate with nutritional status. In
studyin2008.Here,acomparisonwasmadebetweenbrain
contrast,inthefasted,hungrystate,theorexigenichormone
activity in 7 obese and 11 lean adolescent girls during the
ghrelin is dominant amongst gut hormones. It is therefore
anticipated receipt of chocolate milkshake, during actual
interestingtoobservetheeffectsofexogenousadministration
receipt of the milkshake, during anticipated receipt of a
ofsuchhormonesonthefMRIresponseandcomparethese
tasteless control solution, and during actual receipt of the
results with outcomes from earlier studies comparing the
tasteless control solution. In response to anticipated receipt
physiological fasted and fed states. It is worth noting that,
and actual receipt of the chocolate milkshake (versus the
thusfar,themajorityoffMRIstudiescouplingtheexogenous
tasteless solution), obese adolescent girls showed greater
administration of appetite modulating hormones (with the
BOLD activation bilaterally in the anterior and mid insula,
exception of studies of leptin) have been conducted in
frontal operculum, parietal operculum, and rolandic oper-
healthy, normal weight subjects, in order to investigate the
culum compared with lean adolescent girls. However, the
actionofsuchhormonesinnormalphysiology.
obesegirlsdisplayedlowerBOLDactivationinthecaudatein
responsetoactualconsumptionofthemilkshake(versusthe
tastelesssolution)comparedwiththeleangirls.Fromthese 6.1. PYY and GLP-1. PYY and GLP-1 are anorectic hor-
results, the authors suggested that obese individuals show mones, released by the enteroendocrine L cells of the gut
greater salience-associated responses from anticipated food following a meal; they lead to marked inhibition of food
consumption in gustatory and somatosensory regions, but intakewhenadministeredtofastedhumansubjects[51–53].
weakeractivationinthecaudateduringactualconsumption In healthy human subjects, following intravenous infusion
compared to lean individuals [48]. They further postulated of PYY3−36, there was not only reduced food intake, but
that this reflects increased anticipatory food reward (but increasedactivityinthehypothalamusandOFC,asassessed
reducedconsummatoryfoodreward)inobesity,whichmay byBOLDfMRI[15].Thisstudywasconductedwithsubjects
contribute to overeating. In a further study, after baseline at rest, without engagement in a visual food-cue-based
8 ExperimentalDiabetesResearch
task. Furthermore, during saline infusion visits, subjects’ 6.3.Insulin. Insulinhasacentralanorecticeffectinnormal
caloricintakecorrelatedpositivelywithBOLDsignalchange physiology [56]. This must be distinguished from the
in the hypothalamus, whereas this switched to a negative secondary effect of hunger resulting from hypoglycaemia
correlationbetweencaloricintakeandOFCsignalonstudy that may follow the exogenous administration of insulin
visits when PYY3−36 was infused. It was postulated that the (theassociatedovercompensatoryeatingmayprovidesome
presenceofPYY3−36switchedregulationoffoodintakefrom explanation as to why patients with diabetes treated with
a homeostatic brain region (hypothalamus) to a hedonic insulin tend to gain weight). Therefore, human studies
region(OFC). investigatingthedirectphysiologicalactionofinsulininthe
Using a visual food-cue-activated BOLD fMRI method, CNS have had to overcome the hurdle of maintaining eug-
we recently investigated the effects of PYY3−36 and GLP- lycaemia during insulin administration, for otherwise, it is
17−36amide onneuronalactivityinbrainregionscontributing theeffectofhypoglycaemia(ratherthantheeffectofinsulin
to appetitive processing and behaviour [37]. We scanned per se) that would manifest. Furthermore, to effectively
15 healthy, lean subjects on five separate occasions, during studytheactionofinsulinintheCNS,peripheraleffectsof
which they each received the following interventions in
the hormone should ideally be eliminated, hence even the
randomised order after an overnight fast: a saline infusion;
use of a euglycaemic hyperinsulinaemic clamp technique is
a saline infusion following a large breakfast; an infusion
unsatisfactoryinthisregard.Onegrouphasusedintranasal
of PYY3−36; an infusion of GLP-1; a combined infusion of insulin administration as a method of overcoming this
PreYdYu3c−e3d6 +adGlLibPi-t1u.mCoemnebrignyedinintafkuesioant oafstuhbesgeuqtuehnotrmbuonffeest technical difficulty, demonstrating that insulin resulted in
reducedBOLDfMRIactivation(withrespecttofoodimages
meal to a similar degree as on the day when subjects
versus nonfood images) in 9 healthy, normal-weight adults
received breakfast without either gut hormone. Notably,
comparedwithplacebointherightandleftfusiformgyrus,
the BOLD fMRI signal change (comparing exposure to
food images versus nonfood images) in several a priori therighthippocampus,righttemporalsuperiorcortex,and
brainROIswasreducedfollowingconsumptionofbreakfast the right frontal middle cortex [57]. Notably, peripheral
(Figure 3) and also when the gut hormones were infused plasma glucose did not change following the intranasal
in the fasted state. The largest reduction in BOLD signal insulin administration, thus validating their technique of
occurred in the insula with combined administration of observingthecentraleffectsofinsulin.
PYY3−36andGLP-1,althoughwedetectedsmallerreductions
following feeding and gut hormone administration (either
6.4. Leptin. Leptin-deficient individuals are obese and
singly or in combination) in the striatum and OFC. Of
hyperphagic; replacement of leptin in these individuals
note,ourimageacquisitionparameterswerenotdesignedto
reduces food intake [58]. However, the well-recognised
optimisehypothalamiccaptureinfavourofrewardregions.
phenomenon of leptin resistance in obesity has precluded
Furthermore,whencomparingourresultsfortheOFCwith
itsdevelopmentfromatherapeuticviewpoint.fMRIstudies
thoseofBatterhametal.,itmustberememberedthatadirect
comparison between studies is difficult due to the method- ofleptinadministrationareneverthelessinterestingtoshed
ological differences between them. Nevertheless, our study furtherlightonthephysiologicalregulationofappetite.
In 2 congenitally leptin deficient human subjects, daily
concluded that combined administration of the anorectic
subcutaneousleptinreplacementreducedBOLDfMRIacti-
gwuats ahsosromcioatneedswPiYthY3b−r3a6inanacdtivGaLtiPo-n1antodfsausbtesdequinednitveidautianlgs vation(intermsofthedifferenceinactivationbetweenview-
behaviour changes similar to those after eating a full meal, ing food and nonfood images) in the nucleus accumbens-
thereby reinforcing the view that PYY and GLP-1 are key caudate and putamen-globus pallidus regions compared
mediatorsofpostprandialsatiety. withthecontrol,leptin-deficientstate.Furthermore,before
leptin treatment, activation in the nucleus accumbens-
caudate correlated positively with liking of food images in
6.2. Ghrelin. Ghrelin is a potent orexigenic gut hormone
boththefedandfastedstates,whereas,afterleptintreatment,
released from the stomach in response to fasting; adminis-
activationinthenucleusaccumbens-caudatecorrelatedpos-
tration of ghrelin to humans increases food intake [54]. A
itivelywithlikingoffoodimagesonlyinthefastedstate[59].
study by Malik et al. demonstrated that in normal-weight
Anotherstudythatyeardemonstratedthat,in3congenitally
human subjects, intravenous ghrelin infusion increased
leptin deficient human subjects, daily subcutaneous leptin
hunger ratings and also increased the BOLD fMRI signal replacementreducedthedifferenceinBOLDfMRIactivation
change (between food and nonfood visual cues) compared
(betweenviewinghigh-calorieandlow-caloriefoodimages)
with saline infusion in the amygdala, OFC, insula, visual
in regions implicated in the insula, temporal and parietal
areas, and striatum [55]. The fMRI methodology used in cortex compared with when subjects were not receiving
this study was similar to that used in our PYY and GLP-1 leptin.Ontheotherhand,leptinreplacementincreasedthe
investigation, so it is interesting to compare the results; differenceinBOLDfMRIactivation(betweenviewinghigh-
whereas the anorectic hormones PYY and GLP-1 reduced calorieandlow-caloriefoodimages)intheprefrontalcortex
BOLDsignalinrewardregions,theactionoftheorexigenic comparedwithwhensubjectswerenotreceivingleptin[60].
hormoneghrelindidthereverse,presumablyinkeepingwith Theauthorspostulatedthattheinsula,temporalcortex,and
theopposingphysiologicalrolesofthesepeptides. parietalcortexarehungerregionsandthereforeareinhibited
ExperimentalDiabetesResearch 9
Decreased activity: fed
state, low-calorie food
cues, anorectic gut
hormones
Increased activity: high-
calorie food
cues, obesity
OFC
VC
H
Adiposity signals
Gut hormones Leptin
Ghrelin
Adiponectin
PYY Insulin
GLP-1
Figure4:Modulationoftherewardingaspectsoffood.Inthishighlysimplifiedschematic,theorbitofrontalcortex(OFC)ishighlighted
asthemostimportanthubintherewardencodingnetwork.Externalfoodcues,viathevisualcortex(VC),modulatetheOFCresponse,
withincreasedactivityseeninfastedandobesepatientsandinresponsetohigh-versuslow-caloriefoods.OFCactivityisalsothoughtto
bemodulatedbyinputsfromthehypothalamus,whichsensesinternalinformationaboutnutritionalstatusintheformofadipositysignals
(such as leptin, which gives information about longer-term energy stores) and gut hormones (which are meal dependent and therefore
giveinformationaboutshorter-termnutrientavailability).Anorectic(postprandial)guthormones,suchasPYYandGLP-1,attenuateOFC
activityand,infastedindividualsinduce,anOFCresponsetovisualfoodcuesmoresimilartothatmeasuredwhenfed.Conversely,the
orexigenichormoneghrelinupregulatesrewardcentreactivity.
byleptin,whereastheprefrontalcortexisasatietyregionand 7.ImagingbeforeandafterGastric
isthusinhibitedbyweightlossandactivatedbyleptin. BypassSurgery
Following this, a study by Rosenbaum et al. in 2008
showed that in 6 leptin replete obese human subjects who Themosteffectivetreatmentforobesityavailableatpresent
achieved an initial 10% weight loss (between 36 and 62 is Roux-en-Y gastric bypass surgery, leading to sustained
days) through dietary means, there was increased BOLD weight loss of approximately 30% and often a very prompt
fMRIsignaldifference(betweencomparingfoodimagesand resolutionoftype2diabetes[62].
nonfoodimages)inseveralregionsincludingthebrainstem
Although the mechanisms behind the weight loss seen
and parahippocampal gyrus compared with the baseline
following Roux-en-Y bypass surgery remain to be fully
state before weight loss. These changes were reversed by 5
elucidated, they are unlikely to be solely due to restrictive
weeks of subcutaneous leptin administration. Interestingly,
ormalabsorptivemeansalone.Roux-en-Yresultsingreater
other regions, including the hypothalamus and cingulate
weight loss than adjustable gastric banding, and this is
gyrus responded in the opposite direction following weight
thoughttobeduetoanumberofadditionalneurohormonal
loss, but these changes remained sensitive to reversal by 5
causes [63]. These include elevated postoperative levels of
weeksofsubcutaneousleptinadministration[61].Thisstudy
endogenousanorecticguthormonessuchasPYYandGLP-1
reinforcedtheideathatweightlossleadstoastateofrelative
leptindeficiency,whichmayberesponsiblefortherebound [64–66],increasesinenergyexpenditureandmetabolicrate
hyperphagiaandsubsequentweightgaininmanydieters. [67], changes in taste preference away from calorie dense
Figure4showsasimplifiedschematicofthemodulation foods[68,69],increasedbileaciddeliverytotheileum[70],
of appetite centres by peripheral signals via the hypothala- andchangesingutmicrobiota[71].Recentstudiesimaging
musandinobesity. appetiteinpatientsbeforeandafterweightlossareimportant
10 ExperimentalDiabetesResearch
in helping us to understand some of the CNS-mediated regions implicated in reward processing when food cues
effects. (and in particular high calorie food cues) are presented to
In 2011, Van De Sande-Lee performed fMRI studies on subjects. Obese subjects seem to show heightened response
8 lean control subjects and 13 obese patients before- and to such food cues, which may fundamentally contribute to
after- Roux-en-Y gastric bypass, by which an average 30% increased wanting of food (and thus increased subsequent
reduction in body weight had been achieved [72]. They foodintake)inobeseindividuals.ThefMRIdataalsoseems
replicated the TCA experiment described earlier [19]. In to be in agreement that the consumption of a meal (or
addition,theyalsoperformedafunctionalconnectivityanal- othersurrogatemarkersoffeeding,suchasariseinglucose)
ysis. Their TCA findings mirrored that found previously— tends to deactivate key appetite regions in normal weight
namely that the reduction in hypothalamic signal seen 5– individualsand,furthermore,thatthissatietyresponsemay
10 minutes following glucose ingestion in normal controls also be abnormal in those with obesity. Further studies
wasdiminishedintheobese(preoperative)group.However, shouldleadtoconsolidationofexistingconceptsontherole
a recovery of this impaired hypothalamic response was of individual brain regions and their interconnections in
seen postoperatively when the obese group had lost weight physiologicalandpathologicalsatietyresponses.
following gastric bypass surgery. Interestingly, they also Building on this fundamental understanding of the
reported,inleansubjects,ahighleveloffunctionalconnec- change in BOLD signal between the fasted and fed states,
tivity between the hypothalamus and the orbitofrontal and recentstudieshavesuggestedthat,ingeneral,orexigenicsig-
somatosensorycortices.Thiswasnotseeninobesesubjects, nals,whichareinabundanceinthefastedstate,increasethe
but postoperative weight loss was reported to re-establish BOLD response in brain reward regions, whereas anorectic
theseconnectivitypatterns[72]. signals,whichpredominateinthefedstate,correspondingly
In the same year, a further ROI-based study of 10 deactivate the same regions. Subtle differences in brain
obese female patients 1 month before- and after- Roux- responses between these studies may reflect the slightly
en-Y gastric bypass, there was attenuation of fMRI BOLD different roles of the different hormonal signals in short-
signal (when viewing high-calorie versus low-calorie food term versus longer-tem energy homeostasis and also may
images) in the ventral tegmental area, ventral striatum, reflect differential action on various appetite pathways.
putamen, lentiform nucleus, posterior cingulated, and dor- Nevertheless, studies in obese patients, assessing the effect
somedial prefrontal cortex following the bypass procedure ofgastricbypasssurgeryonthefMRIBOLDresponse,have
[73]. In this study, hunger was also reduced after surgery. furtherconcurredwiththeresultsofstudiesinvestigatingthe
Althoughcirculatingguthormonelevelswerenotmeasured, BOLD response following the exogenous administration of
the authors speculated that postsurgical reductions in the orexigenic and anorectic hormones, thus consolidating the
orexigenic hormone ghrelin could have explained their overallbodyofworkinthearea.
imaging observations. This would certainly be consistent AlthoughfMRIisatpresentusedonlyasaresearchtool
withthepreviousfMRIfindingsbyMaliketal.[55]following to study appetite, the overall goal in the future will be to
exogenous ghrelin administration. Equally, it is possible translate this research into the clinical arena. An obvious
that elevated levels of PYY and GLP-1 after-bypass would role would be to help develop pharmacological treatments
explain the imaging findings, consistent with our recent for obesity, by means of assessing the fMRI response to
fMRI findings [37] following exogenous administration of administration of novel agents in obese individuals. Alter-
theseanorectichormones.Indeed,theelevationinPYYand natively, we may envisage the use of fMRI as a tool to help
GLP-1 levels achieved in our study following exogenous predict response to gastric bypass surgery. To aid effective
administration of the hormones wassimilar to the elevated comparison of results, it would be enormously useful to
endogenous levels of PYY and GLP-1 observed in previous strive towards greater consistency between studies, particu-
studiesfollowinggastricbypasssurgery[65].Thesefindings larly with regard to experimental design, image acquisition
arestriking,giventheneedtodevelopnonsurgicalsolutions and image analysis. The studies outlined in this paper have
forthetreatmentofobesity.Todate,allcentrallyactingdrugs establishedkeyconcepts,anditisexpectedthatthecoming
developed to treat obesity have failed due to cardiovascular decade should see consolidation of these findings. We are
and mood altering side effects, as a result of actions fortunatethatfunctionalMRIstudieshaveallowedscientists
outside pathways solely governing appetite. Therefore, it is to investigate for the first time in humans, the intricacies
foreseeablethat,inthefuture,elevatingcirculatinglevelsof of appetitive processing. As this technology continues to
PYY and GLP-1 (by means of exogenous administration) evolve,itwillremainanimportanttoolforinvestigatingbasic
to similar levels as found naturally after a gastric bypass physiologyaswellasevaluatingnewtherapies.
proceduremayrepresentanovelpharmacologicalmethodof
treatingobesity.
ConflictofInterests
8.Conclusion Theauthorsdeclarethatthereisnoconflictofinterests.
The use of fMRI to study appetite control in humans is
a rapidly evolving field. There appears to be a degree of Authors’Contribution
consistency between studies, suggesting that, in the fasted
state, greater BOLD activation is seen in several brain A.DeSilvaandV.Salemcontributedequallytothiswork.