Brain regulation of food intake and appetite: molecules and networks

27 Pages·2005·1.05 MB·English

JournalofInternalMedicine2005;258:301–327 doi:10.1111/j.1365-2796.2005.01553.x
REVIEW
Brain regulation of food intake and appetite: molecules and
networks
C. BROBERGER
FromtheDepartmentofNeuroscience,KarolinskaInstitute,Stockholm,Sweden
Abstract. Broberger C (Karolinska Institute, to the brain such as leptin, insulin, peptide YY,
Stockholm, Sweden). Brain regulation of food ghrelin and lipid mediators as well as the vagus
intake and appetite: molecules and networks nerve; signalling of the metabolic sensors in the
(Review). J Intern Med 2005; 258: 301–327. brainstem and hypothalamus via, e.g. neuropeptide
Y and melanocortin peptides; integration and
In the clinic, obesity and anorexia constitute
coordination of brain-mediated responses to
prevalent problems whose manifestations are
nutritional challenges; the organization of food
encountered in virtually every field of medicine.
intake in simple model organisms; the mechanisms
However,asthecommandcentreforregulatingfood
underlying food reward and processing of the
intake and energy metabolism is located in the
sensory and metabolic properties of food in the
brain, the basic neuroscientist sees in the same
cerebral cortex; and the development of the central
disorders malfunctions of a model network for how
metabolic system, as well as its pathological
integration of diverse sensory inputs leads to a
regulation in cancer and infections. Finally,
coordinated behavioural, endocrine and autonomic
recent findings on the genetics of human obesity
response. The two approaches are not mutually
are summarized, as well as the potential for novel
exclusive;rather,muchcanbegainedbycombining
treatments of body weight disorders.
bothperspectivestounderstandthepathophysiology
of over- and underweight. The present review Keywords: brainstem, cerebral cortex, feeding,
summarizes recent advances in this field including hypothalamus, metabolic, reward.
the characterization of peripheral metabolic signals
central nervous system has developed a meticu-
Introduction
lously interconnected circuitry to meet this chal-
Few tasks executed by the brain hold greater lenge. A consequence ofthis organization isthat an
survival value than keeping us fed and in adequate energy-dense environment favours the development
nutritional state. It is not surprising then that the ofobesity, whilstovercompensationmayshutdown
the drive to feed. In today’s society where evolving
disease demographics and lifestyle allow for a
This paper builds partly on presentations made at a
greater diversity of metabolic phenotypes than
NobelConferenceon‘BrainControlofFeedingBehaviour’
organizedattheKarolinskaInstitute,Stockholm,Sweden, perhaps ever before [1] disorders of both extremes
inSeptember 9–11, 2004. of energy intake are common in health care.
(cid:1)2005BlackwellPublishingLtd 301
302 C. BROBERGER
Obesity is increasing at an alarming rate in But what systems should such treatments target?
industrialized and developing countries alike [2] Early clinical observations that patients with pituit-
and is associated with a wealth of conditions arytumoursandaccompanyinginjurytothebaseof
afflicting virtually all organ systems [3, 4]. Exam- the brain develop obesity [25–28], inspired experi-
ples diverge widely to include cholelithiasis [5], mental lesion studies [29–33], which demonstrated
osteoarthritis [6], infertility [7], stroke [8], cutane- that damage to particular regions of the hypotha-
ous infections [9], wound healing deficiencies [10], lamus and brainstem lead to profound, often fatal,
as well as a general increase in mortality [11] alterations of feeding behaviour. It also became
and social and professional stigmatization [12]. apparent that signals from the peripheral energy
The urgency of the problem is illustrated dramat- stores [34] and gastrointestinal canal [35] provide
ically by the previous rarity of paediatric obesity- essential cues for appetite and satiety. Based on
associated type 2 diabetes, which is increasing to these and other findings, Stellar [36] half a century
the point of taking over as the leading cause of ago proposed a dual centre hypothesis for the
childhood diabetes [13]. The opposite extreme of initiation of motivated behaviour. The hypothesis
anorexia and hypophagia includes not only anor- included both mechanisms for sensing peripheral
exia nervosa [14] but is also a common and cues, separate nuclei (i.e. the ‘dual centres’) for
potentially fatal complication of infections [15], stimulating and inhibiting behaviour, and connec-
malignancies [16] and ageing [17]. tions between the hypothalamus and higher brain
Unlike many other common diseases, these disor- regions to allow for internal states to determine the
dershaveanobvioussolution:adjustingfoodintake threshold for initiating behaviour. Of all motivated
and exercise until normal body weight has been behaviours,themodelisperhapsmostapplicablefor
restored. However, it is no great revelation that this food intake. Yet, for all its heuristic value, the dual
solution is as simple as it has repeatedly proved centre hypothesis was as low on specifics as it was
elusive [18]. Experimental studies confirm the com- laden with theory. Research dating in particular
mon knowledge that weight loss almost always is from the last decade has changed this. Today, we
followed by a rapid return to initial weight once the have an understanding of the circuitry and neuro-
anorexigenic regimen is terminated [19]. Notably, pharmacology of feeding behaviour that can be
the same applies to humans subjected to voluntary probed for therapeutic targets. The present article is
overfeeding[20],supportingtheconceptofatightly not an exhaustive review of the central control of
regulated set-point for body weight. Treatment of energy metabolism [37, 38], but summarizes recent
eatingdisordershasbeenremarkablyunsuccessful– advances, which have brought new insight into the
a consequence possibly of that we are battling peripheral signals describing the metabolic state to
ancient systems maintained by ‘thrifty genes’ that the brain; the input stations in the hypothalamus
favourthepreservationofenergystores[21].Avail- and brainstem sensitive to these signals, the organ-
ableoptionsforpharmacologicaltherapyleavemuch ization of feeding behaviour in simple and complex
to be desired, and compounds that have been organisms; the link between food intake and energy
introduced for obesity management have subse- expenditure; the neural framework for integrating
quently often been withdrawn due to intolerable metabolic cues and reward properties; the mecha-
side-effects[22].Themosteffectiveobesitytreatment nisms of infection- and cancer-associated anorexia;
at present is bariatric surgery, but this is a developmental and genetic causes of obesity and
complicated procedure not without adverse effects novel therapeutic strategies.
[23]. Preventive measures have frustratingly lim-
ited effect. It has proved even more difficult to
A central framework for sensing and
devise strategies for increasing food intake in cases
orchestrating energy metabolism
of anorexia. Although some success has been
reported with behavioural approaches for anorexia The regulation of energy metabolism presents a
nervosa [24], the more common forms of cancer- prototypical homeostatic system, with the brain
and inflammation-associated anorexia remain a acting as the central coordinator and rectifier
major therapeutic challenge. Novel treatments are (Fig. 1). It is one of the great wonders of the brain
greatly needed. that body weight stays remarkably fixed (as a
(cid:1)2005BlackwellPublishingLtdJournalofInternalMedicine258:301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE 303
the individual, which it does through two main
channels. First, hormonal signals reflecting the
availabilityanddemandformetabolicfuelisrelayed
vianeuronesinthehypothalamus.Thereceptorsfor
NPY these signals are primarily expressed on two neuro-
POMC
chemically distinct sets of neurones located in the
ARC
arcuate nucleus (Arc) in the mediobasal hypothala-
GHRELIN
mus,alongsidethethirdventricle[40].Oneneurone
OEA INSULINPYY VAG UMSX nTS gNvraPorYuieptryeelxeopafrseeaspsoeprsroanacectuihvreaostpioernpetsioudfeltstYheins(NePinnYec)ur;eroiannsceerdseabfsoyinodag
D
intake and decreased energy expenditure. The other
IML group expresses the neuropeptide precursor pro-
N
PTI opiomelanocortin (POMC), which is processed to
E
L
melanocortin peptides; activation of these neurones
hastheoppositeeffectoftriggeringtheNPYcells,i.e.
decreased food intake and increased energy expen-
diture. The yin–yang relationship between the two
Arc groups is further underscored by their opposite
regulation by leptin and insulin, hormones signal-
ling metabolic affluence, which decrease the expres-
sion of NPY, whilst they increase the expression of
POMC. The second main input for information
pertaining to energy balance is the brainstem,
classically viewed as a channel for visceroceptive
information as cranial nerves, in particular the
Fig.1 Thecentralmetaboliccircuitryisregulatedbynumerous vagusnerve,carryinginformationfromthealiment-
endocrineandneuralinputs.Schematicillustrationofhowbrain
ary organs enter the brain here. Vagal afferents
networksregulatingingestivebehaviourcommunicatewithper-
synapse onto [41, 42] and excite [43] neurones in
ipheralorgans.Hormonessupplyinginformationabouttheper-
ipheralmetabolicstatetothebrainincludethegastrointestinal the brainstem nucleus tractus solitarii (nTS). From
peptidesghrelinandPYY(3-36),insulinfromthepancreasand both the hypothalamus and the brainstem, projec-
leptinfromadiposetissue.Ghrelinandleptinactbothonthe
tionsfanfurtherintothebraintoengageotherbrain
hypothalamus(Arc)andthebrainstem(nTS).Theafferentpor-
regions in the initiation and organization of food
tionofthevagusnerveinnervatesmostofthegastrointestinal
tractwhereitcollectsinformationabouttheimmediatealiment- intake. As in all homeostatic systems, the brain has
arystate,andterminatesinthenTS.ThelipidmediatorOEAis at its disposal three effector pathways to activate
producedintheduodenumandactivatesthebrainstem,possibly
when the controlled variable (i.e. body weight)
viathevagusnerve.BoththeArc(viaantagonisticNPY-and
needstobeadjusted:behaviour(i.e.foodintake),the
POMC-expressingcells)andthenTSprojectfurtherintothebrain
inparallelpathwaystoengagehigherbrainregionsintoingestive endocrine system and the autonomic nervous sys-
behaviour.Outputsfromthebrainregulatingenergyexpenditure tem[44]. Importantly, allthreeofthese systems are
includebothbranchesoftheautonomicnervoussystem;the
engaged downstreamoftheArcandnTSstationsto
sympatheticsystemwhosepreganglionicneuronesarelocatedin
provide a synchronized response to fluctuations in
theintermediolateralcellcolumn(IML),whichisdirectlyinner-
vatedbyPOMCneuronesfromtheArc,aswellastheparasym- energy balance; the first primarily in the volitional
patheticsystemwithpreganglionicneuronesfortheefferent control of intake, the latter two regulate energy
portionofthevagusnervelocatedinthedorsalmotornucleusof
expenditure.
thevagus(DMX).Theefferentautonomicinnervationregulates,
e.g.glucosehomeostasisviaactionsinliverandskeletalmuscle.
Seetextfordetails. Peripheral control of feeding behaviour
‘set-point’)mostofthetimeinmostpeople[39].The Metabolic state is reflected in a diverse array of
first step in maintaining this homeostasis is for signalsofthebrain.Recentinvestigationshaveshed
the brain to inform itself of the metabolic status of light on some of the key hormones and the vagal
(cid:1)2005BlackwellPublishingLtdJournalofInternalMedicine258:301–327
304 C. BROBERGER
mechanisms that shape the central response to
nutritional challenges (Fig. 1).
The vagus nerve
Thegastrointestinalcanalisequippedwithamyriad
of sensory receptors along its full crown-rump
extension [45]. Thus, the taste, texture and
mechanic stress of food is reported to the brain to
provide an online description of the immediate
alimentary state. This information is routed to the
nTS primarily via the afferent portion of the vagus
nerve, so that vagal activation causes satiation and
meal termination. (Parallel neural feedback is also Fig.2 Geneticallyleptin-deficientob/obmicetreatedsubcutane-
ously(s.c.)withsaline(left)orwithleptin(right).Thesevere
supplied by sensory neurones innervating the oral
obesityintheseanimalsisabolishedwithleptinreplacement
cavity mediating, e.g. taste, and lesser-studied therapy.FiguregenerouslyprovidedbyDrJeffreyM.Friedman.
splanchnic nerves [46].) Vagal afferents are broadly
sensitive to gastrointestinal signals, including gas- centrally active feeding-inhibitory messenger, as
troduodenal distension, the presence of chemically restitution of the leptin signal in these animals
distinctnutrientswithinthegastrointestinaltractas normalizes food intake and body weight [56]
well as peptides produced by endocrine cells in the (Fig. 2). Serum leptin correlates well to the size of
gutwall,mostprominentlycholecystokinin(CCK),a the body fat deposit, and falls with weight loss [57].
well-characterized satiety signal [47, 48]. Import- This relationship is seen also in obesity, where the
antly, these signals are integrated within the indi- combination of hyperleptinaemia and hyperphagia
vidual vagal sensory neurone prior to the signal has led to the suggestion that overweight is
being relayed in the nTS [49, 50]. The neurochem- characterized by leptin resistance [58]. Central
ical identity of viscerosensory vagal neurones has actions underlie both leptin-mediated feeding sup-
remained enigmatic, but these cells likely signal via pression as well as the extensive peripheral meta-
glutamate [51] and the neuropeptide cocaine- and bolic effects of this hormone; thus, e.g. replacement
amphetamine-regulated transcript [52], which of leptin receptors selectively in the brain of ob/ob
inhibitsfeedinguponbrainstemadministration[53]. mice is sufficient to prevent hepatic steatosis [59].
Leptin Insulin
An appetite-regulating endocrine signal from fat Insulin is well recognized as the key glucostatic
tissue maintaining energy homeostasis had been regulator.Recentdatademonstratethatinadditionto
hypothesized already with parabiosis experiments thecontrolofperipheralglucoseuptake,thisrolealso
in the 1950s [34]. The seminal discovery of leptin, encompasses powerful central effects, in synergism
the adipocyte-derived protein hormone providing with leptin. First, intracerebroventricular (i.c.v.)
this signal, by Friedman and collaborators in 1994 administration of insulin decreases food intake [60]
[54] was a decisive catalyst for much of the current viainsulinreceptorsexpressedonArcneurones[61].
investigation on peripheral modulation of central Theroleofinsulininfeedingiscomplicatedbythefact
networks. A little more than a decade later, leptin that the hypoglycaemia resulting from elevations in
has been shown to modulate several aspects of serum insulin in itself stimulates food intake. How-
energy balance through several different mecha- ever, when blood glucose changes are compensated
nisms and across a wide spectrum of timeframes, for,hypophagiaisseenalsowithincreasesinperiph-
alertingthe braintothe stateofbody adiposity [55] eral insulin [62, 63], suggesting that the central
and acting as a ‘fat-o-stat’. It is now well estab- effectsofinsulinareanabolic.(Thissecondaryhypo-
lished that the pronounced obesity in genetically glycaemiamayalsoexplainwhytheinsulinsecretion
leptin-deficient ob/ob mice is due to the loss of a triggered already at the sight of a palatable-looking
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REVIEW: BRAIN CONTROL OF FOOD INTAKE 305
meal stimulates appetite (‘the cephalic phase’ [64]), peaksharplyinanticipationofamealinhumansas
anindicationthatdirectsensoryinputrelayedviathe well as experimental animals [87], resulting in
cortex can set off powerful appetitive mechanisms.) stimulation of both feeding and gastric emptying
Secondly, and again similar to leptin, insulin also [88] through actions possibly involving the vagus
modulates peripheral energy metabolism via central nerve [89], and may thus provide a meal initiation
effects by inhibiting liver gluconeogenesis [65, 66]. signal. In the hypothalamus, peripherally adminis-
Thus,whilstthebraindoesnotdependoninsulinfor tered ghrelin mainly activates the NPY neurones
glucose uptake, it is very much interested in what [85, 90] and antagonizing the actions of these cells
insulin has to say about the metabolic state of the inhibits the orexigenic effect of ghrelin administra-
body. tion[85,91].Incontrast,themelanocortinpathway
doesnotappeartobeprimarilyinvolved[90].Recent
reportshaveproposedthatghrelinissynthesizedalso
Peptide YY (3-36)
in hypothalamic neurones, but this issue remains
In addition to CCK, several gut-derived peptides controversial,inpartduetothecontradictoryclaims
providealimentaryfeedbacktothecentralmetabolic of the site of central ghrelinergic neurones and the
circuits [67]. Peptide tyrosine-tyrosine (3-36) failuretodemonstrateghrelinmRNAinthebrain(cf.
[PYY(3-36)], a member of the NPY peptide family [92] and [93]).
producedbyenteroendocrinecells[68],hasrecently Importantly,alossofthehungermessagerelayed
been shown to act as an important feedback signal by ghrelin has been suggested as the mechanism
from the gut to the hypothalamus. Following a behind the weight-reducing effects of bariatric sur-
meal, PYY(3-36) is released into the circulation gery [94]. The initial rationale for gastric bypass
[69], specifically stimulated bythe presenceof lipids [95] was that the procedure would produce weight
and carbohydrates in the lumen of the distal ileum lossbymeansofmalabsorption.However,thisturns
andcolon[70,71].Peripheraladministrationofthis out to be a transient effect due to the considerable
hormoneinhibitsfoodintakeandcausesweightloss compensatory potential of the digestive system.
[72, 73]. While some laboratories initially were Nevertheless, weight loss persists, caused instead
unabletoreplicatethiseffect[74],thismaypartlybe by a loss of appetite and hypophagia [96]. Concom-
due to discrepancies in technique [75] and the itant with this effect, a fall in plasma ghrelin is
results have since been independently confirmed observedfollowingthebypassprocedure,incontrast
[76, 77]. The satiety effect of PYY(3-36) is compar- to the ghrelin increase associated with nonsurgical
atively modest but, importantly, is observed also in weight reduction, where weight relapse is common
humans, including obese patients [73, 78]. Plasma [86, 97]. (Note, however, findings that argue
levels of PYY(3-36) rise markedly following ileal against such a relationship, see [67].) Furthermore,
resection [79, 80], an observation that has been clinicaldatatiethehyperphagiaobservedinPrader–
linked to the weight loss observed in patients Willi syndrome to strikingly high plasma ghrelin
undergoing this procedure (S.R. Bloom and C. Le levels[98].Theseresults,coupledwiththediscovery
Roux, personal communication). that elevated plasma ghrelin is a marker for future
weightgain(D.E.CummingsandJ.Krakoff,personal
communication)indicatethatinterferingwithghre-
Ghrelin
lin signalling offers a clinically promising approach
Thus, the gastrointestinal-brain axis has long been to treating eating disorders.
viewed as a key channel subserving meal termin-
ation with CCK and PYY(3-36) as prime mediator
Oleoylethanolamide
examples. Novel findings on the hormone ghrelin
(produced in stomach and small intestine epithelia A role for endogenous cannabinoids in appetite
[81],see[82])arechallengingthisdoctrine.Ghrelin regulation has long been suspected from the carbo-
is unique as the first gut hormone shown to hydrate craving observed in marijuana smoking
stimulate food intake [67]. Both peripheral and [99]; indeed, increased appetite is a diagnostic
central injections of ghrelin result in increased criterion for cannabis intoxication [100]. Neuronal
feeding as well as fat mass [83–86]. Ghrelin levels production of cannabinoids is widespread and these
(cid:1)2005BlackwellPublishingLtdJournalofInternalMedicine258:301–327
306 C. BROBERGER
mediatorsplayanimportantandgeneralroleinthe hormones. This K+ conductance is a priori sensitive
modulationofsynaptictransmission[101],withthe to the availability of metabolic fuel as a fall in
orexigenic effects likely mediated via central cann- intracellular levels of the energy donor ATP causes
abinoid CB1 receptors [102, 103]. However, the the channel to open, leading to K+ influx and
lipid family to which the cannabinoids belong also hyperpolarization;thismechanismenablesneurones
includes other members with opposite and periph- expressingI tovarytheirexcitabilityinresponse
K(ATP)
eral effects on energy metabolism. Piomelli and tochangesinglucoseconcentration[114].Leptinand
colleagueshaveaccumulatedevidencethatthefatty insulin both hyperpolarize Arc neurones by enhan-
acid oleoylethanolamide (OEA), chemically but not cing I [115, 116], by activating a common
K(ATP)
pharmacologically similar to the cannabinoids, is enzyme,phosphoinositide3(PI3)kinase[116,117].
produced in the duodenum and acts via the vagus Itshouldbeemphasizedthatthetransmitterpheno-
nervetodecreasebodyweightthroughactivationof type of Arc neurones expressing I is a contro-
K(ATP)
thenTS[104].OEAincreasestheinter-meallatency, versial issue which remains to be conclusively
an effect distinct from that of, e.g. CCK, which resolved [118–120]. Additional signals likely weigh
primarilydecreasesmealsize[105].However,chan- in on I ; this current is augmented when the
K(ATP)
ges in energy expenditure also underlie the OEA- concentration of fatty acid derivatives is increased
mediated weight reduction and are especially pro- locallywithintheArcbyinhibitionoflipidoxidation,
nouncedinmodelsofobesity,involvinginparticular amessageofenergysurplusthatalsodecreasesfood
increased fat utilization, whereas glucose home- intake [66, 121]. This convergence of nutrient
ostasis is relatively unaffected [106]. The catabolic information makes the PI3-kinase/I a key
K(ATP)
effects are most noticeable as a slowing of body integration node within the metabolic signalling
weight gain in growing rats, with OEA synthesis chain,attractiveasatherapeutictarget.
reduced by food deprivation and stimulated in Modulation of the membrane potential of Arc
responsetoincreaseddemandsonenergyavailability neuroneshasrecentlybeendemonstratedtocontrol
such as cold exposure [104]. The metabolic actions glucose homeostasis. Opening of Arc K(ATP) chan-
of OEA depend selectively and critically on genomic nels via either hyperinsulinaemia or central inhibi-
as well as nongenomic actions of the ubiquitous tion of lipid oxidation inhibits vagal efferent (i.e.
nuclear peroxisome proliferator-activated receptor- parasympathetic)gluconeogenic signalstotheliver,
alpha (PPAR-a) [107]. These results add obesity to promotingtheuseoffatasmetabolicfuel[66,122].
thegrowinglistofpotentialtherapeuticapplications TheArcisalsothesiteofcentralleptinregulationof
fornuclearreceptorpharmaceuticals.Notably,drugs glucose homeostasis as selective restoration of Arc
that target PPAR-a, e.g. gemfibrozil, are already in leptin receptor expression in otherwise leptin recep-
clinicaluse to treat hypercholesterolaemia [108]. tor-deficient mice is sufficient to correct their
hyperglycaemia [123]. These results show that
insulinmodulatesglucosehomeostasisbyindepend-
Integration of peripheral signals in the Arc
ent peripheral and central mechanisms and empha-
Theperipheralsignalsdescribedabovethusactupon size that interconnectivity within brain metabolic
theArc(andnTS,seebelow)toinfluencethecentral regions serve to switch the body between different
pathways regulating energy balance. In the Arc, fuel sources, in parallel to controlling food intake.
receptors for leptin and insulin found on NPY and Interestingly, in obese rats, hypothalamic I
K(ATP)
POMCneuronesservetoinhibittranscriptionofNPY channels fail to respond to leptin and insulin [115,
[109, 55] and increase POMC mRNA levels [110– 116]. Whether similar defects underlie insulin and/
112]viadifferentialsecondmessengersystems[113]. orleptinresistanceinhumandiabetesandobesityis
It is becoming evident that insulin, leptin and other an interesting possibility, which remains to be
metabolically relevant hormones eventually con- investigated.
verge not only on a common set of neurones, but
indeed also on the same molecules. Recent reports
Output from the Arc
highlight the role of the ATP-dependent potassium
current, I , as a molecular target mediating NPY neurones. Neuropeptide Y is one of the most
K(ATP)
rapid, electrophysiological effects, of peripheral potent stimulators of feeding known [124], an
(cid:1)2005BlackwellPublishingLtdJournalofInternalMedicine258:301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE 307
suggests that NPY primarily stimulates appetitive
rather than consummatory behaviour [130].
POMC neurones. Pro-opiomelanocortin is a large
precursor protein which gives rise to several bioac-
tive peptides. Among these, the melanocortin pep-
tides, in particular a- and c-melanocyte-stimulating
hormone, have been shown to exert potent ano-
rexigenic effects when administered i.c.v. [131,
132]. Central melanocortin effects are mediated by
the melanocortin 3 and 4 receptors (MC3R and
MC4R, respectively; Fig. 3b). Deletion of the genes
foreitherPOMC,MC3RorMC4Rresultinobesityin
mice, suggesting that the melanocortin system is
crucial in maintaining body weight [133–135] – as
supportedbysimilarfindingsinhumans(seebelow).
MC4R)/) mice also increase their feeding in
response to a high fat diet, in contrast to wild-type
littermateswhereareductionisseenandob/obmice,
Fig.3 ExpressionofNPYandmelanocortinreceptorsinthe
which maintain the same intake as with regular
mousebrain.Insituhybridizationhistochemistry(a)showsthe
chow [136], underlining the importance of the
distributionofNPYY1receptormRNAdetectedassilvergrainsin
acoronalsection,revealingdenseexpressioninthecerebral melanocortin system for adjusting food intake in
cortexandnucleiintheamygdala,thalamusandhypothalamus. response to caloric variations. In addition, the hall-
Inpanelb,greenfluorescentprotein(GFP)isexpressedina
mark hypophagia seen in disease models as diverse
neuroneundercontrolofthemelanocortin(MC)4receptorpro-
as renal failure, immunological challenge with
moter;notestrongimmunoreactivitythroughoutcellsomaand
dendrites.ANissl-stainedcoronalsection(c)showsneurones lipopolysaccharide (LPS) and tumour implants is
clusteredtoformtheparaventricularhypothalamicnucleus ablated. The obesity in MC4R-deficient animals is
(PVH)alongsidethethirdventricle.ThePVHconstitutesacentral
partlyduetochangesinenergyexpenditure,suchas
integrative‘hub’withinthemetaboliccircuitry.(d)Immunoh-
deficient diet-induced thermogenesis [136]. The
istochemicalforGFP(indicatingthepresenceoftheMC4receptor)
andinsituhybridizationforNPYY1receptormRNAhavebeen anatomical substrate for this effect may be a direct
combinedinasectionfromtheamygdala,revealingthecoexist- projection from the POMC neurones in the Arc to
enceofthesereceptorsinneuronesdownstreamoftheArc.Figure
the preganglionic sympathetic neurones in the spi-
producedbyDrsToshiroKishiandJoelK.Elmquist.Reprinted
nal cord [137–139] constituting a link between the
withpermissionfromMacmillanPublishersLtd.;MolecularPsy-
chiatry2005;10:132–146. metabolic integrator and the autonomic effector
system. Interestingly, the spinal projection sets the
POMC neurones apart from the neighbouring NPY
effect that has been confirmed by various approa- neurones which otherwise exhibit very parallel
ches [40]. While there is conflicting data on whe- innervation patterns. However, it should be pointed
ther deletion of the NPY gene produces hypophagia out, that in humans, the melanocortin system
(cf. [125] and [126]), the obesity of ob/ob mice is appears to be more geared towards regulating feed-
attenuated when combined with an NPY)/) geno- ingbehaviour,withaproportionatelysmallerrolein
type [127], suggesting that NPY is an important peripheral metabolism [140].
mediator of central leptin signalling. Stimulation of
feeding appears to be transduced predominantly via NPY–POMC interactions. Interactions between the
postsynaptic NPY Y1 receptors, as determined from Arc populations allow the NPY neurones to control
pharmacological and genetic engineering studies the activity of the POMC cells via two mechanisms.
(reviewed in [128], Fig. 3a). However, the syner- First, NPY neurones coexpress agouti gene-related
gistic actions of multiple NPY receptor subtypes peptide (AGRP), an endogenous melanocortin ant-
participate to produce orexigenic effects in vivo agonist [141–143]. Thus, at the axon terminal,
[129]. Detailed behavioural analysis of those effects melanocortinactioncanbeblockedbysimultaneous
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308 C. BROBERGER
release of AGRP, and in agreement with such an [153]. Infusion of NMDA antagonists locally within
arrangement, a single i.c.v. administration of AGRP the LHA blocks both agonist-induced and depriva-
causes an impressively long-lasting (one week) tion-inducedfoodintake,indicatingtheinvolvement
suppression of food intake [144]. Secondly, at the ofendogenousglutamatergictoneinnaturalfeeding
cell body level, POMC neurones are innervated by [154].Histochemicalstudiessuggestthatwithinthe
NPY-ergic terminals [145] and express the Y1 Arc, NPY neurones largely contain GABA, whereas
receptor [146], through which NPY causes a POMC neuronessignalvia glutamate [155, 156].
powerfulmembranepotentialhyperpolarization(i.e.
inhibition) [147]. Surprisingly, no reciprocal inner- Downstream targets of the Arc. The downstream
vation has yet been described and Roseberry et al. cellular effects of NPY are still mysterious. It was
[147] did not detect any changes in the electrical initially assumed that ‘feeding-promoting neurones’
properties of NPY neurones using a melanocortin inlocisensitivetoNPYorexigenesiswereexcitedby
analogue. Thus, there may exist an asymmetrical NPY. However, all known members of the NPY
interaction in the Arc favouring the orexigenic receptor family couple to inhibitory second mes-
NPY/AGRP message over anorexigenic melanocor- senger systems [128]. Electrical excitation has been
tinsignalling.However,aninhibitoryinfluenceover proposed to come about in the form of disinhibition
the NPY neurones may be provided by PYY (3-36), via NPY-mediated suppression of GABA-dependent
which is a selective agonist of the inhibitory Y2 inhibitory postsynaptic currents [157, 158], with
autoreceptors [148] expressed by these cells [146]. melanocortin stimulation producing the opposite
Such gastrointestinal negative feedback has been result,i.e.inhibitionviastimulationofGABArelease
proposed as the mechanism whereby PYY(3-36) [157]. However, that does not explain the role of
inhibitsfeedingasnosucheffectisobservedinmice postsynaptic Y1 receptors, which exist throughout
genetically deficient for the Y2 receptor and appli- the hypothalamus [146, 159, 160] (Fig. 3a). The
cationofthepeptideinhibitstheelectricalactivityof most potent orexigenic effects of NPY are seen
Arc NPY terminals [73]. This effect is relatively within the perifornical region/LHA [124], where
selective as disruption of other relevant metabolic NPY/AGRP-ergic terminals appear to target two
pathways does not affect the satiety effect; the separate populations of neurones expressing the
PYY(3-36)effectpersistsbothaftervagotomyandin neuropeptides hypocretin (Hcrt; also known as
MC4)/) mice [76], suggesting that neither the nTS orexin) and melanin-concentrating hormone (MCH;
nor the Arc POMC neurones are directly involved. Fig. 4,[142,161,162]).Thispathwayisofinterest
as Hcrt and MCH potently modulate wakefulness
Classical transmitters: glutamate and GABA. While [163–167],providingameans for metabolic signals
much ofthe current research on the central regula- to control arousal state. Surprisingly, in a recent
tionofenergybalancefocusesontheroleofpeptides, investigation of the electrophysiology of the LHA
itshouldbeemphasizedthatinthehypothalamus,as neurones, melanocortin stimulation did not affect
in the rest of the brain, the key chemical mode of the electrical properties of MCH-expressing cells,
communicationbetweenneuronesisviaaminoacid whereas both these and Hcrt-expressing cells were
transmitters,i.e.excitatoryglutamateandinhibitory inhibited by NPY [168, 169]. Furthermore, micro-
c-aminobutyricacid(GABA).Indeed,intheabsence injection of NPY into the LHA appears to activate a
ofglutamateandGABA-mediatedtransmission,little group of neurones distinct from those expressing
remains of hypothalamic synaptic activity [149, Hcrt or MCH [170]. As with all neural interactions,
150]. The major function of peptides, in addition to it is important to bear in mind that the activity of
their genomic effects, is likely to modulate the syn- neurones can be influenced via several independent
aptic transmission of ‘classical’ transmitters [151] mechanisms, including (but not exclusively) elec-
with which they coexist [152]. Interestingly, glu- trical and transcriptional effects, and that different
tamate N-methyl-d-aspartate (NMDA) receptors changes proceed along different temporal scales.
have been found to stimulate feeding with remark- Thus, a functional Arc-LHA pathway cannot be
able anatomical specificity within the lateral hy- excluded. Nevertheless, these data invite a re-eval-
pothalamic area (LHA), in comparison with other uation of the role of Hcrt and MCH as downstream
hypothalamic regions tested and the amygdala mediators of the NPY and POMC neurones.
(cid:1)2005BlackwellPublishingLtdJournalofInternalMedicine258:301–327
REVIEW: BRAIN CONTROL OF FOOD INTAKE 309
Cerebral Cortex
PFCx
FOOD
INTAKE
Other
AcbSh MCH Hcrt subcortical nuclei,
incl. BST,
MPO, PVT,
LHA DMH,Amgdl,
Raphe, PAG
and PBN
INGESTIVE
PVH (Motivated)
BEHAVIOUR
NPY POMC DMX
Arc
ENERGY
EXPENDITURE
IML
Endocrine
Pituitary regulation Sympathetic
incl. thyroid and ANS
adrenocortical axes Parasympathetic
Fig.4 Integrationinhigherbrainregionsdeterminesthecentralresponsetochangesinperipheralmetabolicstate.Schematicillustration
ofconnectionsbetweenbrainregionsresponsibleforcoordinatingthebehaviouralsomatomotor(i.e.foodintake),autonomicandendocrine
(thelattertworegulatingenergyexpenditure)responsesthattogetherconstitutethemotivatedingestivebehaviourusedbythenervous
systemtomeetnutritionalchallenges.TheantagonisticorexigenicNPYandanorexigenicPOMCneuronesintheArcprojectinparallel
pathstonumeroussubcorticalnuclei[includingthebednucleusofthestriaterminals(BST),themedialpreopticarea(MPO),the
paraventricularnucleusofthethalamus(PVT),severalhypothalamicnuclei,e.g.thedorsomedialnucleus(DMH),theamygdala(Amgdl),
theserotonin-containingsystemintheraphenuclei,theperiacqueductalgreyarea(PAG)andtheparabrachialnucleus(PBN)]distributed
throughoutthebrain.Aprojectiontoneuronesexpressingmelanin-concentratinghormone(MCH)orhypocretin(Hcrt)inthelateral
hypothalamicarea(LHA)providesanindirectpathwaytothecerebralcortexformetabolicsignalsrelayedviatheArc.Thecortexinturn
projectsbackheavilytoboththeLHAandotherfeeding-regulatoryregions.Inaddition,theLHAalsoreceivesaninhibitoryinputfromthe
shellofthenucleusaccumbens(AcbSh),whichinturnismodulatedviaprominentexcitatoryinputsfromtheprefrontalcortex(PFCx).
Thus,theLHAispositionedtointegratebothhomeostaticandreward-relatedsignalsinthegatingoffoodintake.Energyexpenditureis
modulatedviaoutputsfromtheArctoneuroendocrineneuronesintheparaventricularhypothalamicnucleus(PVH),whichcontrol
releaseof,e.g.thyrotropin-releasinghormoneandadrenocorticotropichormonefromthepituitarygland.Energyexpenditureisalso
regulatedbyprojectionsfromPOMCneuronesintheArcanddescendingpathwaysfromthePVHtoautonomicpreganglionicneuronesin,
e.g.thedorsalmotornucleusofthevagus(DMX;parasympathetic)andspinalcordintermediolateralcellcolumn(IML;sympathetic).
Notethatascendingprojectionsfromthebrainstem,whichprovideparallelimportantmetabolicinputstothebrain,havenotbeenincluded
inthefigure.Seetextfordetails.
Circadianregulationofmetabolicprocesses. Inaddition striatedmuscle(aparasympatheticeffect;see[172]).
tothevariouscontrolssummarizedabove,metabolic Buijs et al. [173] have investigated which brain re-
processes also follow strict circadian variations – as gionsareresponsibleforthissynchronization.Using
recently underscored by the demonstration that anatomical tracing they find that the chains of
inactivation of key genes maintaining circadian neuronesinnervatingliverandmuscleareseparated
rhythmicity results in manifest metabolic syndrome allthewaythroughbrainstemandhypothalamusto
in mice [171]. Thus, for example, in rats the active distinct populations of preautonomic master neu-
period of the day is immediately preceded by rones in the suprachiasmatic nucleus [173], the
coordinatedpeaksinhepaticglucoseoutput(viathe brainregionmaintainingcircadianrhythmicityand
sympathetic nervous system) and glucose uptake in entrained by direct retinal input [174, 175]. The
(cid:1)2005BlackwellPublishingLtdJournalofInternalMedicine258:301–327
310 C. BROBERGER
distinct pathways originating in the suprachias- drainage) leads to increases in meal size as well as
matic nucleus are particularly interesting in con- duration [181, 182], although there is a compen-
junction with the discovery that the autonomic satory delay in the latency to meal initiation,
inputs to intra-abdominal and subcutaneous fat possibly mediated by the hypothalamus. These
storesarealsoseparate[176].Inhumans,shiftwork resultsunderscoretheroleoftheArcasametabolic
[177] and sleep deprivation [178] are associated sensor.ItshouldbepointedoutthatanintactArcis
with increased adiposity, findings that have been not necessary for meal initiation – humans and
linkedtothesleep-associatedpeakinleptinsecretion animals with selective lesion of this region not only
[179]. However, this anatomically separate inner- eat, they eat copiously [29, 183–185].
vation indicates that loss of periodicity in the circa- Itisnowbecomingevidentthatthebrainstemcan
dianinputtoadiposetissuemaydisruptthebalance integrate much the same signals as have been
betweendifferentfatcompartmentsleading,inturn, shown to modulate hypothalamic activity. Leptin
to manifestations of the metabolic syndrome, which receptors are expressed at several strategically
is correlated to abdominal but not subcutaneous fat located brainstem sites, and selective stimulation of
accumulation [180]. these receptors suppresses food intake at doses
comparable with those used in forebrain injections
[186, 187]. Here, leptin activates the same medial
Contributions of hind- and forebrain to
region of the nTS that is stimulated by gastric
feeding regulation
distension [188], suggesting an anatomical site of
As mentioned above, the brainstem provides a port integrationoflong-andshort-termfeedingcontrols.
for vagal and other neural sensory signals into the Likewise, melanocortin agonists can reduce feeding
brain. Classical accounts of brain regulation of and body weight by brainstem mechanisms [189].
feedingdescribedtwosystemsbalancingeachother: Interestingly,theneuronesinthenTSmediatingthe
the hypothalamus, monitoring the periphery for viscerosensory signal may also be POMC-encoded
signals alerting central circuits to diminishing [43, 190], a finding that puts our understanding of
energy stores, and the brainstem, receiving oral melanocortin-mediated meal suppression in a new
and gastrointestinal information as an online signal light.Orexigeniceffectsofghrelinarealsoseenwith
of the amounts and qualities of the food that was selective local administration both in the hypotha-
being ingested. This arrangement would allow the lamus [84] and in the brainstem [191] (Fig. 5a,b).
hypothalamus to function as a long-term control Finally,glucosensitive neurones havebeenrecorded
orchestrating meal initiation and the brainstem in the nTS [192]. Thus, the nTS is in no way a
served as a short-term control for meal termination.
Much of our knowledge on the different contribu-
tions of the fore- and hindbrain in meal regulation
comes from a lesion model developed by Grill and
Norgren [33]. Disconnecting the forebrain (which
includes the hypothalamus) produces a rat inca-
pable of the motor activation necessary for normal
feeding. However, if this animal – whose brainstem
remains intact – is provided sucrose solution via an
intraoral cannula, intake can be measured as the
solution consumed until the meal is terminated as
theanimalletssolutiondripoutofthemouth.These
decerebrated rats maintain the ability to terminate
Fig.5 Ghrelinincreasesfoodintakefollowingbrainstemadmin-
theirmealinresponsetochangesingastrointestinal
istration.Unilateralinjectionof10pmol(butnot5)ofghrelin
feedback, but are unable to compensate for varia- (blackbars)intothedorsalvagalcomplex,includingthenucleus
tions in the caloric value of the fed solution, tractussolitarii,resultsinasignificantincreaseoffoodintakeboth
1.5and3hafterdrugadministrationcomparedwithvehicle
resulting in anorexia if the sucrose concentration
(whitebars),inanexperimentbyFaulconbridgeetal.[191].
is reduced. Similarly, removal of the post-oral
ReprintedwithpermissionfromtheAmericanDiabetesAssoci-
feedback (by e.g. vagus nerve transection or gastric ation;Diabetes2003;52:2260–2265.
(cid:1)2005BlackwellPublishingLtdJournalofInternalMedicine258:301–327