STARLING REVIEW Appetite control

28 Pages·2005·0.41 MB·English

291
STARLING REVIEW
. .
Appetite control
Katie Wynne, Sarah Stanley, Barbara McGowan and Steve Bloom
EndocrineUnit,ImperialCollegeFacultyofMedicine,HammersmithHospital,DuCaneRoad,LondonW12ONN,UK
(RequestsforoffprintsshouldbeaddressedtoSRBloom;Email:[email protected])
Abstract
Our understanding of the physiological systems that late these pathways acutely and result in appetite stimula-
regulate food intake and body weight has increased tion or satiety effects. This review discusses central
immensely over the past decade. Brain centres, including neuronalnetworksandperipheralsignalswhichcontribute
thehypothalamus,brainstemandrewardcentres,signalvia energy homeostasis, and how a loss of the homeostatic
neuropeptideswhichregulateenergyhomeostasis.Insulin process may result in obesity. It also considers future
and hormones synthesized by adipose tissue reflect the therapeutic targets for the treatment of obesity.
long-term nutritional status of the body and are able to JournalofEndocrinology(2005)184,291–318
influence these circuits. Circulating gut hormones modu-
Introduction with energy expenditure. The hypothalamus was first
implicated in this homeostatic process over 50 years ago.
Inmostadults,adiposityandbodyweightareremarkably Lesioning and stimulation of the hypothalamic nuclei
constant despite huge variations in daily food intake and initially suggested roles for the ventromedial nucleus as a
energy expended. A powerful and complex physiological ‘satiety centre’ and the lateral hypothalamic nucleus
system exists to balance energy intake and expenditure, (LHA)asa‘hungercentre’(Stellar1994).However,rather
composed of both afferent signals and efferent effectors. than specific hypothalamic nuclei controlling energy
Thissystemconsistsofmultiplepathwayswhichincorpor- homeostasis,itisnowthoughttoberegulatedbyneuronal
ate significant redundancy in order to maintain the drive circuits, which signal using specific neuropeptides. The
to eat. In the circulation, there are both hormones which arcuate nucleus (ARC), in particular, is thought to play a
act acutely to initiate or terminate a meal and hormones pivotalroleintheintegrationofsignalsregulatingappetite.
which reflect body adiposity and energy balance. These The ARC is accessible to circulating signals of energy
signals are integrated by peripheral nerves and brain balance, via the underlying median eminence, as this
centres, such as the hypothalamus and brain stem. The region of the brain is not protected by the blood–brain
integrated signals regulate central neuropeptides, which barrier (Broadwell & Brightman 1976). Some peripheral
modulate feeding and energy expenditure. This energy gut hormones, such as peptide YY and glucagon-like
homeostasis, in most cases, regulates body weight tightly. peptide 1, are able to cross the blood–brain barrier via
However,ithasbeenarguedthatevolutionarypressurehas non-saturable mechanisms (Nonaka et al. 2003, Kastin
resultedinadrivetoeatwithoutlimitwhenfoodisreadily et al. 2002). However, other signals, such as leptin and
available. The disparity between the environment in insulin, are transported from blood to brain by a saturable
whichthesesystemsevolvedandthecurrentavailabilityof mechanism (Banks et al. 1996, Banks 2004). Thus, the
food may contribute to over-eating and the increasing blood–brain barrier has a dynamic regulatory role in the
prevalence of obesity. passage of some circulating energy signals.
There are two primary populations of neurons within
theARCwhichintegratesignalsofnutritionalstatus,and
Current concepts
influence energy homeostasis (Cone et al. 2001). One
neuronalcircuitinhibitsfoodintake,viatheexpressionof
Hypothalamic neuropeptides
the neuropeptides pro-opiomelanocortin (POMC) and
In order to maintain a stable body weight over a long cocaine- and amphetamine-regulated transcript (CART)
period of time, we must continually balance food intake (Elias et al. 1998a, Kristensen et al. 1998). The other
JournalofEndocrinology(2005)184,291–318 DOI:10.1677/joe.1.05866
0022–0795/05/0184–291 (cid:1)2005SocietyforEndocrinology PrintedinGreatBritain Onlineversionviahttp://www.endocrinology-journals.org
292 KWYNNEandothers · Appetitecontrol
Figure1 TheARCandthecontrolofappetite.(cid:1)-MSH,(cid:1)-melanocyte-stimulating
hormone;GHS-R,growthhormonesecretagoguereceptor.
neuronal circuit stimulates food intake, via the expression Although NPY seems to be an important orexigenic
of neuropeptide Y (NPY) and agouti-related peptide signal, NPY-null mice have normal body weight and
(AgRP) (Broberger et al. 1998a, Hahn et al. 1998). See adiposity (Thorsell & Heilig 2002), although they dem-
Figure 1. onstrateareductioninfast-inducedfeeding(Bannonetal.
2000).Thisabsenceofanobesephenotypemaybedueto
NPYNPYisoneofthemostabundantneurotransmitters the presence of compensatory mechanisms or alternative
in the brain (Allen et al. 1983). Hypothalamic levels of orexigenicpathways,suchasthosewhichsignalviaAgRP
NPY reflect the body’s nutritional status, an essential (Marshetal.1999).Itispossiblethatthereisevolutionary
feature of any long-term regulator of energy homeostasis. redundancy in orexigenic signalling in order to avert
ThelevelsofhypothalamicNPYmRNAandNPYrelease starvation. This redundancy may also contribute to the
increasewithfastinganddecreaseafterrefeeding(Sanacora difficulty elucidating the receptor subtype that mediates
etal.1990,Kalraetal.1991,Swartetal.2002).TheARC NPY-induced feeding (Raposinho et al. 2004).
isthemajorhypothalamicsiteofNPYexpression(Morris NPY is part of the pancreatic polypeptide (PP)-fold
1989). ARC NPY neurons project to the ipsilateral family of peptides, including peptide YY (PYY) and
paraventricular nucleus (PVN) (Bai et al. 1985), and pancreatic polypeptide (PP). This family bind to seven-
repeated intracerebroventricular (icv) injection of NPY transmembrane-domain G-protein-coupled receptors,
into the PVN causes hyperphagia and obesity (Stanley designated Y –Y (Larhammar 1996). Y –Y receptors
1 6 1 5
etal.1986,Zarjevskietal.1993).Centraladministrationof havebeendemonstratedinratbrain,butY ,identifiedin
6
NPY also reduces energy expenditure, resulting in mice,isabsentinratsandinactiveinprimates(Inui1999).
reduced brown fat thermogenesis (Billington et al. 1991), The Y , Y , Y and Y receptors, cloned in the hypo-
1 2 4 5
suppression of sympathetic nerve activity (Egawa et al. thalamus, have all been postulated to mediate the orexi-
1991) and inhibition of the thyroid axis (Fekete et al. genic effects of NPY. The feeding effect of NPY may
2002). It also results in an increase in basal plasma insulin indeed be mediated by a combination of receptors rather
level(Moltz&McDonald1985,Zarjevskietal.1993)and than a single one.
morningcortisollevel(Zarjevskietal.1993),independent Administration of antisense oligonucleotides to the Y
5
of increased food intake. receptorinhibitsfoodintake(Schaffhauseretal.1997),and
JournalofEndocrinology(2005)184,291–318 www.endocrinology-journals.org
Appetitecontrol · KWYNNEandothers 293
Y receptor-deficientmicehaveanattenuatedresponseto them susceptible to diet-induced obesity (Challis et al.
5
NPY(Marshetal.1998).However,Y receptordensityin 2004).
5
the hypothalamus appears to be reduced in response Melanocortin 3 (MC3R) and melanocortin 4 receptors
to fasting and upregulated in dietary-induced obesity (MC4R) are found in hypothalamic nuclei implicated
(Widdowsonetal.1997).Inaddition,antagoniststotheY in energy homeostasis, such as the ARC, ventromedial
5
receptor have no major feeding effects in rats (Turnbull nucleus(VMH)andPVN(Mountjoyetal.1994,Harrold
et al. 2002), and Y receptor-deficient mice develop et al. 1999). Lack of the MC4R leads to hyperphagia and
5
late-onset obesity, rather than the expected reduction in obesity in rodents (Fan et al. 1997, Huszar et al. 1997)
body weight (Marsh et al. 1998). It has been postulated and these receptors are implicated in 1–6% of severe
that the Y receptor may maintain the feeding response early-onset human obesity (Farooqi et al. 2000, Lubrano-
5
rather than initiate feeding in response to NPY, as Y Berthelier et al. 2003a, 2003b). Polymorphism of this
5
receptor antisense oligonucleotide decreases food intake receptor has also been implicated in polygenic late-onset
10hafterNPY-orPP-inducedfeeding,buthasnoeffect obesity in humans (Argyropoulos et al. 2002).
on the initial orexigenic response (Flynn et al. 1999). Although the involvement of the MC4R in feeding is
NPY-inducedandfast-inducedfeedingispreventedby established, the function of the MC3R is still unclear. A
antagonists to the Y receptor (Kanatani et al. 1996, selectiveMC3Ragonisthasbeenfoundtohavenoeffect
1
Wieland et al. 1998), and is reduced in Y receptor- on food intake (Abbott et al. 2000), and although the
1
knockout mice (Kanatani et al. 2000). However, like Y MC4R is influenced by energy status, the MC3R is not
5
receptors, ARC Y receptor numbers, distribution and (Harrold et al. 1999). However, there is some evidence
1
mRNA, are reduced during fasting, an effect which is that both the MC3R and MC4R are able to influence
attenuated by administration of glucose (Cheng et al. energy homeostasis. The MC3R/MC4R antagonist,
1998).Furthermore,NPYfragmentswithweakaffinityto AgRP,isabletoincreasefoodintakeinMC4R-deficient
the Y receptor still elicit a similar dose-dependent mice (Butler 2004). Mice which lack the MC3R, al-
1
increase in food intake to NPY, suggesting that the Y though not overweight on a normal diet, have increased
1
receptor may not be mediating its effect (O’Shea et al. adiposity, and seem to switch from fat to carbohydrate
1997). Y receptor-deficient mice are obese, but are not metabolism(Butleretal.2000).However,MC3-nullmice
1
hyperphagic, suggesting that the Y receptor may affect are obese and develop increased adipose tissue when fed
1
energyexpenditureratherthanfeeding(Kushietal.1998). on high-fat chow. MC3R mutations have been found in
The presynaptic Y and Y receptors have an auto- human subjects with morbid obesity (Mencarelli et al.
2 4
inhibitoryeffectonNPYneurons(Kingetal.1999,2000). 2004).
As expected, Y receptor-knockout mice have increased ThemainendogenousligandfortheMC3R/MC4Ris
2
foodintake,weightandadiposity(Naveilhanetal.1999). (cid:1)-melanocyte-stimulating hormone ((cid:1)-MSH), which is
However, Y receptor conditional-knockout mice (per- expressed by cells in the lateral part of the ARC (Watson
2
haps with more normal development of the neuronal & Akil 1979). i.c.v. administration of agonists to the
circuits) have a temporarily reduced body weight and hypothalamic MC4R suppresses food intake, and the
food intake, which returns to normal after a few weeks administration of selective antagonists results in hyper-
(Sainsburyetal.2002).Thereisalsoevidenceforaroleof phagia (Benoit et al. 2000). In addition to its effects on
Y receptors in the orexigenic NPY response. PP has a feeding,(cid:1)-MSHalsostimulatesthethyroidaxis(Kimetal.
4
relativespecificityfortheY receptorandcentraladmini- 2000b) and increases energy expenditure, as measured by
4
strationhasbeenshowntoelicitfoodintakeinbothmice oxygen consumption (Pierroz et al. 2002), sympathetic
(Asakawa et al. 1999) and rats (Campbell et al. 2003). nerveactivityandthetemperatureofbrownadiposetissue
(Yasuda et al. 2004).
The melanocortin system Melanocortins, including The agouti mouse is hyperphagic and obese, and
adrenocorticotrophin and melanocyte-stimulating hor- expressestheagoutiproteinectopically,whichisnormally
mones (MSHs), are peptide-cleavage products of the restricted to the hair follicle. The agouti protein is a
POMCmoleculeandexerttheireffectsbybindingtothe competitive antagonist of (cid:1)-MSH and melanocortin
melanocortinreceptorfamily.LevelsofPOMCexpression receptors (Lu et al. 1994). The antagonist effect on the
reflect the energy status of the organism. POMC mRNA peripheralMC1Rresultsinayellowcoat,anditseffecton
levelsarereducedmarkedlyinfastedanimalsandincreased thehypothalamicMC4Rresultsinobesity(Luetal.1994,
by exogenous administration of leptin, or restored by Fan et al. 1997).
refeeding after 6h (Schwartz et al. 1997, Swart et al. Although the agouti protein is not normally expressed
2002).MutationswithinthePOMCgeneorabnormalities in the brain, a partially homologous peptide, AgRP, is
in the processing of the POMC gene product result in expressed in the medial part of the ARC (Shutter et al.
early-onset obesity, adrenal insufficiency and red hair 1997). AgRP mRNA increases during fasting (Swart
pigmentation in humans (Krude et al. 1998). The loss of et al. 2002) and the peptide is a potent selective antago-
onecopyofthePOMCgeneinmiceissufficienttorender nist at the MC3R and MC4R (Ollmann et al. 1997).
www.endocrinology-journals.org JournalofEndocrinology(2005)184,291–318
294 KWYNNEandothers · Appetitecontrol
AgRP(83–132),theC-terminalfragment,isabletoblock control of energy homeostasis (Kristensen et al. 1998,
the reduction in food intake seen with the icv admini- Lambertetal.1998).CART(1–102)andCART(82–103)
stration of (cid:1)-MSH and increase nocturnal food intake injected icv into rats inhibit both the normal and NPY-
(Rossi et al. 1998). stimulated feeding response, but result in abnormal
Transgenic mice with ubiquitous over-expression of behavioural responses at high dose (Kristensen et al.
AgRP are obese, but with no alteration of coat colour as 1998, Lambert et al. 1998). However, administration of
AgRP is inactive at the MC1R (Ollmann et al. 1997). A CART(55–102)intodiscretehypothalamicnucleisuchas
polymorphism in the AgRP gene in humans is associated theARCandventromedialnucleusisabletoincreasefood
with lower body weight and fat mass (Marks et al. 2004). intake(Abbottetal.2001).Thus,theremaybemorethan
Consistentwithitsroleinenergyhomeostasis,AgRPand onepopulationofCART-expressingneuronswhichhave
AgRP(83–132) administered icv result in hyperphagia different roles in feeding behaviour. For instance, NPY
which can persist for a week (Hagan et al. 2000, Rossi release could stimulate a population of CART neurons
etal.1998).AlthoughNPYmRNAlevelsarereduced6h in the ARC which are orexigenic, producing positive
after refeeding, AgRP levels remain elevated (Swart et al. orexigenic feedback (Dhillo et al. 2002).
2002).Thisprolongedresponseresultsinagreatercumu-
lative effect on food intake than NPY, and probably
Downstream pathways
involves more diverse signalling pathways than the
melanocortin pathway alone (Hagan et al. 2000, 2001, Hypothalamic nuclei such as the PVN, dorsomedial
Zheng et al. 2002). hypothalamus(DMH),LHAandperifornicalareareceive
Consistent with the role of AgRP as an orexigenic NPY/AgRP and POMC/CART neuronal projections
peptide, the reduction of hypothalamic AgRP RNA by from the ARC (Elias et al. 1998b, Elmquist et al. 1998b,
RNAinterferenceresultsinlowerbodyweight,although Kalra et al. 1999). These areas contain secondary neurons
this may partly be an effect of increased energy expendi- which process information regarding energy homeostasis.
ture(Makimuraetal.2002).Independentofitsorexigenic A number of signalling molecules which are expressed in
effects, chronic icv administration of AgRP suppresses these regions have been shown to be physiologically
thyrotropin-releasinghormone,reducesoxygenconsump- involved in energy homeostasis (see Figure 2).
tion and decreases the ability of brown adipose tissue to
expend energy (Small et al. 2001, 2003). PVN The PVN integrates NPY, AgRP, melanocortin
AgRPandNPYarepotentorexigenicmoleculeswhich andothersignalsviaprojectionsitreceivesfromanumber
are 90% co-localized in ARC neurons (Hahn et al. 1998, ofsitesinthebrain,includingtheARCandnucleusofthe
Broberger et al. 1998a). NPY may inhibit the arcuate solitary tract (NTS) (Sawchenko & Swanson 1983). The
POMC neuron via ARC NPY Y receptors (Fuxe et al. PVNishighlysensitivetoadministrationofmanypeptides
1
1997, Roseberry et al. 2004). Activation of ARC NPY/ implicated in feeding, e.g. cholecystokinin (CCK)
AgRP neurons therefore potently stimulates feeding via (Hamamura et al. 1991), NPY (Lambert et al. 1995),
activation of PVN NPY receptors, inhibition of the ghrelin (Lawrence et al. 2002), orexin-A (Edwards et al.
melanocortin system by ARC Y receptors and antagon- 1999, Shirasaka et al. 2001), leptin (Van Dijk et al. 1996,
1
ism of MC3R/MC4R activation by AgRP in the PVN. Elmquistetal.1997)andglucagon-likepeptide1(GLP-1)
However, it has been demonstrated that NPY/AgRP- (Van Dijk et al. 1996). Administration of a melanocortin
knockout mice have no obvious feeding or body-weight agonist directly into the PVN results in potent inhibition
defects. Furthermore, AgRP is absent from hypothalamic offoodintake(Giraudoetal.1998,Kimetal.2000a),and
nuclei known to be involved in energy homeostasis, such inhibits the orexigenic effect of NPY administration
as the VMH (Broberger et al. 1998a). This suggests there (Wirth et al. 2001), whereas, the administration of a
must be other signalling pathways which are capable of melanocortin antagonist to the PVN results in a potent
regulating energy homeostasis (Qian et al. 2002). increase in food intake (Giraudo et al. 1998). Electro-
physiologicalstudiesinthePVNhaveshownthatneurons
CARTCARTisco-expressedwith(cid:1)-MSHintheARC expressingNPY/AgRPattenuateinhibitoryGABA-ergic
(Elias et al. 1998a, Kristensen et al. 1998). Neurons signalling, whereas POMC neurons potentiate GABA-
expressing CART are also found in the LHA and PVN ergic signalling (Cowley et al. 1999). GABA-ergic signal-
(Couceyro et al. 1997). Food-deprived animals show a lingalsooccursinasubpopulationofARCNPYneurons
pronounced reduction in CART mRNA within the which release GABA locally and inhibit POMC neurons.
ARC, whereas peripheral administration of leptin to Neuropeptides involved in appetite regulation in the
leptin-deficient ob/ob mice results in a stimulation of PVN may also signal via AMP-activated protein kinase
CART mRNA expression (Kristensen et al. 1998). An (AMPK), a heterodimer consisting of catalytic (cid:1)-subunits
antiserum against CART peptide (1–102) and CART andregulatory(cid:2)-and(cid:3)-subunits.Multipleanorecticfactors
peptide fragment (82–103), injected icv in rats, increases including leptin, insulin and MT-II (an MC3R/MC4R
feeding, suggesting that it is part of the physiological agonist) suppress (cid:1)2 AMPK activity in the ARC and
JournalofEndocrinology(2005)184,291–318 www.endocrinology-journals.org
Appetitecontrol · KWYNNEandothers 295
Figure2 Schematicofthehypothalamicnuclei(coronalsection).BDNF,brain-derivedneurotrophicfactor;
CRH,corticotrophin-releasinghormone;MCH,melanin-concentratinghormone;ME;medianeminence;
PFA,perifornicalarea;TRH,thyrotropin-releasinghormone.
PVN, whereas the (cid:1)2 AMPK activity is stimulated by order signalling. Indeed, the perifornical area has been
orexigenic factors such as AgRP (Andersson et al. 2004, found to be more sensitive to NPY-elicited feeding than
Minokoshi et al. 2004). A pharmacologically induced thePVN(Stanleyetal.1993).TheLHA/perifornicalarea
increase in the level of AMPK in the PVN results in contains neurons expressing melanin-concentrating
increased food intake (Andersson et al. 2004). (cid:1)2 AMPK hormone (MCH) (Marsh et al. 2002). Fasting increases
activity may be regulated by the MC4R, as peripheral MCH mRNA, and repeated icv administration of MCH
signalsofenergystatusareunabletomodulate(cid:1)2AMPK increases food intake (Qu et al. 1996) and results in mild
activityinMC4R-knockoutmice(Minokoshietal.2004). obesity in rats (Marsh et al. 2002). Conversely, MCH-1
The integration of signals within the PVN intiates receptor antagonists reduce feeding and result in a
changes in other neuroendocrine systems. NPY/AgRP sustainedreductioninbodyweightifadministeredchroni-
and melanocortin projections from the ARC innervate cally (Borowsky et al. 2002). Transgenic mice over-
thyrotropin-releasing hormone neurons in the PVN expressing precursor MCH are hyperphagic and develop
(Legradi & Lechan 1999, Fekete et al. 2000). These central obesity (Marsh et al. 2002), whereas mice with
projections have an inhibitory effect on pro-thyrotropin- a disruption of the MCH gene are hypophagic, lean
releasing hormone gene expression in the PVN (Fekete and have increased energy expenditure, despite reduced
et al. 2002), whereas (cid:1)-MSH projections have a stimula- ARCPOMCandcirculatingleptin(Shimadaetal.1998,
tory effect and prevent fasting-induced inhibition of Marsh et al. 2002). Crosses of leptin-deficient ob/ob mice
thyrotropin-releasing hormone (Fekete et al. 2000). NPY with MCH-null mice result in an attenuation in weight
projections to the PVN also act on corticotrophin- gain and adiposity compared with ob/ob mice (Segal-
releasinghormone-expressingneuronsinfluencingenergy Liebermanetal.2003).ThisperhapsinfersthatMCHacts
homeostasis (Sarkar & Lechan 2003). downstream of leptin and POMC, and demonstrates that
not all orexigenic peptides show redundancy.
DMH The DMH has extensive connections with other Orexin A and B (or hypocretin 1 and 2) are peptide
hypothalamic nuclei, including the ARC, from which it products of prepro-orexin. The peptides are produced in
receives AgRP/NPY projections (Kalra et al. 1999). the LHA/perifornical area and zona incerta by neurons
Integration of signals may also take place in the DMH, as distinctfromthosewhichproduceMCH(DeLeceaetal.
(cid:1)-MSH-positive fibres are in close proximity to NPY- 1998, Sakurai et al. 1998). Orexin neurons exert their
expressing cells in the DMH, and melanocortin agonists effects via wide projections throughout the brain, for
attenuate DMH NPY expression and suckling-induced example to the PVN, ARC, NTS and dorsal motor
hyperphagia in rats (Chen et al. 2004b). nucleus of the vagus (De Lecea et al. 1998, Peyron et al.
1998). The orexin-1 receptor, which is highly expressed
LHA/perifornicalareaOtherhypothalamicsitessuchas in the VMH, has a much greater affinity for orexin A,
the LHA/perifornical area are also involved in second- whereas the orexin-2 receptor, which is highly expressed
www.endocrinology-journals.org JournalofEndocrinology(2005)184,291–318
296 KWYNNEandothers · Appetitecontrol
inthePVN,hascomparableaffinityforbothorexinAand fromarcuateNPY-,AgRP-andPOMC-immunoreactive
B(Sakuraietal.1998).Theprepro-orexinmRNAlevelis neurons and in turn VMH neurons project to other
increasedinthefastingstateandcentraladministrationhas hypothalamicnuclei(e.g.DMH)andtobrainstemregions
been found to result in both orexigenic behaviour and such as the NTS. NPY expression is altered in the VMH
generalizedarousal(Sakuraietal.1998,Haganetal.1999). ofobesemice(Guanetal.1998)andMC4Rexpressionis
Central administration of orexin A has a potent effect on upregulated in the VMH of diet-induced obese rats
feeding (Haynes et al. 1999) and vagally mediated gastric (Huang et al. 2003). Recent work has demonstrated
acid secretion (Takahashi et al. 1999), whereas orexin B that brain-derived neurotrophic factor (BDNF) is highly
does not. However, although icv administration of orexin expressed within the VMH, where its expression is
A results in increased daytime feeding, there is no overall reduced markedly by food deprivation (Xu et al. 2003),
changein24-hfoodintake(Haynesetal.1999).Further- and also regulated by melanocortin agonists. Mice with
more, chronic administration of orexin A alone does not reduced BDNF receptor expression or reduced BDNF
increase body weight (Yamanaka et al. 1999). signalling have significantly increased food intake and
Orexin neurons project to areas associated with arousal body weight (Rios et al. 2001, Xu et al. 2003). Thus,
andattentionaswellasfeeding,andorexin-knockoutmice VMH BDNF neurons may form another downstream
arethoughttobeamodelofhumannarcolepsy(Chemelli pathwaythroughwhichthemelanocortinsystemregulates
et al. 1999). In circumstances of starvation, the orexin appetite and body weight.
neuropeptides may mediate both an arousal response
and a feeding response in order to initiate food-seeking The brainstem pathways
behaviour.
There are extensive reciprocal connections between the
Orexin may also play a role as a peripheral hormone
hypothalamus and brainstem, particularly the NTS
involved in energy homeostasis. Orexin neurons, expres-
(Ricardo&Koh1978,vanderKooyetal.1984,TerHorst
singbothorexinandleptinreceptors,havebeenidentified
et al. 1989). In addition to interacting with hypothalamic
in the gastrointestinal tract, and appear to be activated
circuits, the brainstem also plays a principal role in the
during starvation (Kirchgessner & Liu 1999). Orexin is
regulationofenergyhomeostasis.LiketheARC,theNTS
alsoexpressedintheendocrinecellsinthegastricmucosa,
is in close anatomical proximity to a circumventricular
intestine and pancreas (Kirchgessner & Liu 1999) and
organ with an incomplete blood–brain barrier – the area
peripheral administration increases blood insulin levels
postrema (Ellacott & Cone 2004) – and is therefore in
(Nowak et al. 2000).
an ideal position to respond to peripheral circulating
NPY,AgRPand(cid:1)-MSHterminalsareabundantinthe
signals, in addition to receiving vagal afferents from the
LHA and are in contact with MCH- and orexin-
gastrointestinal tract (Kalia & Sullivan 1982, Sawchenko
expressingcells(Brobergeretal.1998b,Eliasetal.1998b,
1983).
Horvath et al. 1999). Central orexin neurons also express
The NTS has a high density of NPY-binding sites
NPY(Campbelletal.2003)andleptinreceptors(Horvath
(Harfstrandetal.1986),includingY receptors(Glassetal.
etal.1999)andarethusabletointegrateadipositysignals. 1
2002)andY receptors(Dumontetal.1998).Extracellular
Furtherintegrationofperipheralsignalsisprovidedbythe 5
NPY levels within the NTS fluctuate with feeding
large number of glucose-sensing neurons in the LHA
(Yoshiharaetal.1996),andNPYneuronsfromthisregion
(Bernardis&Bellinger1996).Somestudieshavehypothe-
project forward to the PVN (Sawchenko et al. 1985).
sized a role for orexin neurons in sensing glucose levels
Thereisalsoevidenceforamelanocortinsysteminthe
within this region, and these have shown that hypogly-
NTS, separate from that of the ARC (Kawai et al. 1984).
caemia induces c-Fos expression in orexin neurons
POMC-derived peptides are synthesized in the NTS of
(Moriguchietal.1999)andincreasesorexinmRNAlevels
the rat (Kawai et al. 1984, Bronstein et al. 1992, Fodor
(Cai et al. 1999). Glucose signalling also occurs in other
et al. 1996), and caudal medulla in humans (Grauerholz
hypothalamic nuclei such as the VMH (Dunn-Meynell
et al. 1998), and these POMC neurons are activated by
et al. 1997) and in the ARC, where glucose-sensing
feeding and by peripheral CCK administration (Fan et al.
neuronsexpressNPY(Muroyaetal.1999).Themechan-
1997). The MC4R is present in the NTS (Mountjoy
ism by which the MCH and orexin neurons exert their
effects on energy homeostasis has not been fully eluci- et al. 1994). Food intake is reduced by the administration
of a MC3R/MC4R agonist to the fourth ventricle
dated. However, it is clear that major targets are the
or dorsal motor nucleus of the vagus nerve, whereas
endocrine and autonomic nervous system, the cranial
MC3R/MC4Rantagonistsincreaseintake(Williamsetal.
nerve motor nuclei and cortical structures (Saper et al.
2000).
2002).
The reward pathways
VMH The VMH has long been known to play a role in
energy homeostasis. Bilateral VMH lesions produce The rewarding nature of food may act as a stimulus
hyperphagia and obesity. The VMH receives projections to feeding, even in the absence of an energy deficit.
JournalofEndocrinology(2005)184,291–318 www.endocrinology-journals.org
Appetitecontrol · KWYNNEandothers 297
Thesensationofrewardis,however,influencedbyenergy via 5-hydroxytryptamine receptors (Heisler et al. 2002).
status, as the subjective palatability of food is altered in See Figure 3.
the fed, compared with the fasting, states (Berridge
1991). Thus, signals of energy status, such as leptin,
Peripheral signals of adiposity
are able to influence the reward pathways (Fulton et al.
2000). Leptin Leptin (Greek: thin) is a peptide hormone, se-
The reward circuitry is complex and involves inter- creted from adipose tissue, which influences energy
actions between several signalling systems. Opioids play homeostasis, immune and neuroendocrine function.
an important role, as a lack of either enkephalin or Restrictionoffoodintake,overaperiodofdays,resultsin
(cid:2)-endorphin in mice abolishes the reinforcing property a suppression of leptin levels, which can be reversed by
of food, regardless of the palatability of the food tested. refeeding (Frederich et al. 1995, Maffei et al. 1995) or
Thisreinforcingeffectislostinthefastedstate,indicating administration of insulin (Saladin et al. 1995). Production
that homeostatic mechanisms can override the hedonistic of leptin correlates positively with adipose tissue mass
mechanisms (Hayward et al. 2002). In man, opiate antag- (Maffei et al. 1995). Circulating leptin levels thus reflect
onistsarefoundtoreducefoodpalatabilitywithoutreduc- both energy stores and food intake. Exogenous leptin
ing subjective hunger (Yeomans et al. 1990, Drewnowski replacement decreases fast-induced hyperphagia (Ahima
et al. 1992). etal.1996),andchronicperipheraladministrationofleptin
Thedopaminergicsystemisintegraltoreward-induced towild-typerodentsresultsinreducedfoodintake,lossof
feeding behaviour. The influence of central dopamine body weight and fat mass (Halaas et al. 1995).
signallingonfeedingisthoughttobemediatedbytheD In addition to its effects on appetite, circulating leptin
1
and D receptors (Schneider 1989, Kuo 2002). Mice levels also affect energy expenditure in rodents (Halaas
2
which lack dopamine, due to the absence of the tyrosine et al. 1995, Pelleymounter et al. 1995), the hypothalamo-
hydroxylase gene, have fatal hypophagia. Dopamine re- pituitary control of the gonadal, adrenal and thyroid axes
placement, by gene therapy, into the caudate putamen (Ahima et al. 1996, Chehab et al. 1996) and the immune
restores feeding, whereas replacement into the caudate response(Lordetal.1998).Areplacementdoseofleptinis
putamen or nucleus accumbens restores preference for a able to reverse the starvation-induced changes of the
palatable diet (Szczypka et al. 2001). neuroendocrine axes in both rodents (Ahima et al. 1996)
The nucleus accumbens is an important component of and humans (Chan et al. 2003). Thus, leptin signalling is
reward circuitry. Injections of opioid agonists and able to integrate the body’s response to a decrease in
dopamineagonistsintothisregionpreferentiallystimulate energy stores.
theingestionofhighlypalatablefoodssuchassucroseand Leptin is a product of the ob gene expressed predomi-
fat(Zhang&Kelley2000,Zhangetal.2003).Conversely, nantlybyadipocytes(Zhangetal.1994)butalsoatlower
opioid receptor antagonists injected into the nucleus levelsingastricepithelium(Badoetal.1998)andplacenta
accumbensreducetheingestionofsucroseratherthanless (Masuzakietal.1997).Amutationintheobgene,resulting
palatable substances (Zhang et al. 2003). The reciprocal in the absence of circulating leptin, leads to the hyper-
GABA-ergicconnectionsbetweenthenucleusaccumbens phagicobesephenotypeoftheob/obmouse,whichcanbe
andLHAmaymediatehedonisticfeedingbydisinhibition normalized by the administration of leptin (Campfield
of LHA neurons (Stratford & Kelley 1999). The MCH etal.1995,Halaasetal.1995,Pelleymounteretal.1995).
neuronsintheLHAmayreciprocallyinfluencethereward Similarly, mutations resulting in the absence of leptin
circuitry, as the nucleus accumbens is a site which in humans cause severe obesity and hypogonadism
expresses MCH receptors (Saito et al. 2001). (Montague et al. 1997, Strobel et al. 1998), which can be
Other systems, including those mediated by endocan- ameliorated with recombinant leptin therapy in both
nabinoids and serotonin, may also be able to modulate children (Farooqi et al. 1999) and adults (Licinio et al.
both reward circuitry and homeostatic mechanisms con- 2004). There is a higher prevalence of obesity than
trolling feeding. Endocannabinoids in the hypothalamus expected in humans with heterozygous leptin deficiency,
may maintain food intake via CB1 receptors, which comparedwithcontrols.Thesesubjectsalsohaveagreater
co-localizewithCART,MCHandorexinpeptides(Cota percentage of body fat, but a lower than expected leptin
et al. 2003). Defective leptin signalling is associated with level(Farooqietal.2001).Studiesfromanimalmodelsalso
highhypothalamicendocannabinoidlevelsinanimalmod- demonstratethatonedeficientcopyoftheleptingenecan
els (Di et al. 2001). CB1 receptors are also present on affect body weight (Chung et al. 1998, Coleman 1979).
adipocytes where they appear to act directly in order to Theleptinreceptorhasasingletransmembranedomain
increase lipogenesis (Cota et al. 2003). CB1 receptor andisamemberofthecytokinereceptorfamily(Tartaglia
antagonists are currently in phase III clinical trials, and et al. 1995). The leptin receptor (Ob-R) has multiple
have been found to reduce appetite and body weight in isoformswhichresultfromalternativemRNAsplicingand
humans (for a review see Black 2004). Serotonin may post-translational processing (Chua et al. 1997, Tartaglia
directly influence the melanocortin pathway in the ARC 1997). The different splice forms of the receptor can
www.endocrinology-journals.org JournalofEndocrinology(2005)184,291–318
298 KWYNNEandothers · Appetitecontrol
Figure3 Thecentralcontrolofappetite.AP,areapostrema;ME;medianeminence;NAc,nucleus
accumbens;PFA,perifornicalarea.
be divided into three classes: long, short and secreted across the blood–brain barrier (Kastin & Pan 2000). The
(Tartaglia1997,Geetal.2002).Thelong-formOb-Rb short forms of the receptor have been proposed to have a
receptor differs from the other forms of the receptor by roleinthetransportofleptinacrosstheblood–brainbarrier
having a long intracellular domain, which is necessary for (El Haschimi et al. 2000), whereas the secreted form is
the action of leptin on appetite (Lee et al. 1996). This thought to bind to circulating leptin thus modulating its
intracellulardomainbindstoJanuskinases(JAK)(Leeetal. biological activity (Ge et al. 2002).
1996)andtoSTAT3(signaltransductionandactivatorsof The Ob-Rb receptor is expressed within the hypotha-
transcription 3) transcription factors (Vaisse et al. 1996) lamus (particularly ARC, VMH, DMH and LHA) (Fei
requiredforsignaltransduction.TheJAK/STATpathway et al. 1997, Elmquist et al. 1998a). Ob-Rb mRNA is
inducesexpressionofasuppressorofcytokinesignalling-3 expressed in the ARC by NPY/AgRP neurons (Mercer
(SOCS-3),oneofafamilyofcytokine-inducibleinhibitors et al. 1996) and POMC/CART neurons (Cheung et al.
of signalling. 1997).TheorexigenicNPY/AgRPneuronsareinhibited
Obesity in the db/db mouse is the result of a mutation by leptin, and therefore activated in conditions of low
within the intracellular portion of the Ob-Rb receptor, circulating leptin (Stephens et al. 1995, Schwartz et al.
which prevents signalling (Chen et al. 1996, Lee et al. 1996, Hahn et al. 1998, Elias et al. 1999). Conversely,
1996). Similarly, mutations within the human leptin leptin activates anorexigenic POMC/CART neurons
receptor result in early-onset morbid obesity, though less (Schwartz et al. 1997, Thornton et al. 1997, Kristensen
severe than that seen with leptin deficiency, and a failure etal.1998,Cowleyetal.2001).Theanorexicresponseof
to undergo puberty (Clement et al. 1998). leptinisattenuatedbyadministrationofanMC4Rantag-
Circulating leptin is transported across the blood–brain onist, demonstrating that the melanocortin pathway is
barrier via a saturable process (Banks et al. 1996). Regu- perhaps an important downstream mediator of leptin
lation of transport may be an important modulator of the signalling (Seeley et al. 1997). Mice lacking leptin signal-
effects of leptin on food intake. Starvation reduces trans- ling in POMC neurons are mildly obese and hyperlepti-
port, whereas refeeding increases the transport of leptin naemic,butlesssothanmicewithacompletedeletionof
JournalofEndocrinology(2005)184,291–318 www.endocrinology-journals.org
Appetitecontrol · KWYNNEandothers 299
the leptin receptor (Balthasar et al. 2004). This suggests be a potential target for the treatment of leptin-resistant
that POMC are important, but not essential, for leptin obesity.
signalling in vitro. Leptin resistance seems to occur as a result of obesity,
ThePVN,LHAVMHandmedialpreopticareamaybe but a lack of sensitivity to circulating leptin may also
direct targets for leptin signalling as leptin receptors are contribute to the aetiology of obesity. Leptin sensitivity
found in these nuclei (Hakansson et al. 1998). Chronic can predict the subsequent development of diet-induced
hypothalamic over-expression of the leptin gene, using a obesity when rodents are placed on a high-energy diet
recombinant adeno-associated virus vector, has demon- (Levin & Dunn-Meynell 2002). Furthermore, it may be
strated distinct actions of leptin in different hypothalamic thatthehigh-fatdietitselfinducesleptinresistancepriorto
nuclei. Leptin over-expression in the ARC, PVN and any change in body composition, as rodents on a high-fat
VMH results in a reduction of food intake and energy diet rapidly demonstrate an attenuated response to leptin
expenditure,whereasleptinover-expressioninthemedial administration before they gain weight (Lin et al. 2001).
preoptic area results in reduced energy expenditure alone Althoughleptindeficiencyhasprofoundeffectsonbody
(Bagnasco et al. 2002). weight, the effect of high leptin levels seen in obesity are
The NTS, like the ARC, contains leptin receptors much less potent at restoring body weight. Thus, leptin
(Merceretal.1998)andleptinadministrationtothefourth may be primarily important in periods of starvation, and
ventricle results in a reduction in food intake and body- have a lesser role in times of plenty.
weight gain (Grill & Kaplan 2002). Peripheral admini-
stration of leptin also results in neuronal activation within InsulinInsulinisamajormetabolichormoneproducedby
the NTS (Elmquist et al. 1997, Hosoi et al. 2002). Thus the pancreas and the first adiposity signal to be described
leptin appears to exert its effect on appetite via both the (Schwartzetal.1992a).Likeleptin,levelsofplasmainsulin
hypothalamus and brainstem. vary directly with changes in adiposity (Bagdade et al.
Althoughasmallsubsetofobesehumansubjectshavea 1967) so that plasma insulin increases at times of positive
relative leptin deficiency, the majority of obese animals energy balance and decreases at times of negative energy
and humans have a proportionally high circulating leptin balance (Woods et al. 1974). Levels of insulin are deter-
(Maffei et al. 1995, Considine et al. 1996), suggesting mined to a great extent by peripheral insulin sensitivity,
leptinresistance.Indeed,recombinantleptinadministered and this is related to total body fat stores and fat distri-
subcutaneouslytoobesehumansubjectshasonlyshowna bution,withvisceralfatbeingakeydeterminantofinsulin
modest effect on body weight (Heymsfield et al. 1999, sensitivity (Porte et al. 2002). However, unlike leptin,
Fogteloo et al. 2003). Administration of peripheral leptin insulin secretion increases rapidly after a meal, whereas
to rodents with diet-induced obesity fails to result in a leptin levels are relatively insensitive to meal ingestion
reductioninfoodintake,althoughtheserodentsretainthe (Polonsky et al. 1988).
capacity to respond to icv leptin (Van Heek et al. 1997). Insulin penetrates the blood–brain barrier via a satura-
Exogenous leptin in mice is transported across the blood– ble, receptor-mediated process, at levels which are pro-
brain barrier less rapidly in obese animals (Banks et al. portional to the circulating insulin (Baura et al. 1993).
1999). Leptin resistance may be the result of a signalling Recentfindingssuggestthatlittleornoinsulinisproduced
defect in leptin-responsive hypothalamic neurons, as well in the brain itself (Woods et al. 2003, Banks 2004). Once
as impaired transport into the brain. Resistance to the insulin enters the brain, it acts as an anorexigenic signal,
effects of leptin has been shown to develop in NPY decreasingintakeandbodyweight.Aninfusionofinsulin
neurons following chronic central leptin exposure (Sahu intothelateralcerebralventriclesinprimates(Woodsetal.
2002). Furthermore, the magnitude of hypothalamic 1979) or third ventricle in rodents (Ikeda et al. 1986)
STAT3 activation in response to icv leptin is reduced in results in a dose-dependent decrease in food intake and,
rodents with diet-induced obesity (El Haschimi et al. over a period of weeks, decreases body weight. Injections
2000). Leptin upregulates expression of SOCS-3 in of insulin directly into the hypothalamic PVN also
hypothalamic nuclei expressing the Ob-Rb receptor. decrease food intake and rate of weight gain in rats
SOCS-3 acts as a negative regulator of leptin signalling. (Menendez&Atrens1991).Consistentwiththesedata,an
Therefore,increasedorexcessiveSOCS-3expressionmay injection of antibodies to insulin into the VMH of rats
be an important mechanism for obesity-related leptin increasesfoodintake(Strubbe&Mein1977)andrepeated
resistance. Consistent with this, neuron-specific condi- antiserum injections increase food intake and rate of
tional SOCS-3-knockout mice are resistant to diet- weightgain(McGowanetal.1992).Thus,theVMHand
induced obesity (Mori et al. 2004). Mice with hetero- PVN seem therefore to play an important part in the
zygousSOCS-3deficiencyarealsoresistanttoobesityand ability of centrally administered insulin to reduce food
demonstrate both enhanced weight loss and increased intake.
hypothalamic leptin receptor signalling in response to Male mice with neuron-specific deletion of the insulin
exogenous leptin administration (Howard et al. 2004). receptor in the CNS are obese and dyslipidaemic with
Although as yet untested, SOCS-3 suppression may increasedperipherallevelsofinsulin(Bruningetal.2000).
www.endocrinology-journals.org JournalofEndocrinology(2005)184,291–318
300 KWYNNEandothers · Appetitecontrol
Reduction of insulin receptor proteins in the medial The mechanisms by which insulin acts as an adiposity
ARC, by administration of an antisense RNA directed signalremaintobefullyelucidated.Earlierstudiespointed
against the insulin receptor precursor protein, results in to hypothalamic NPY as a potential mediator of the
hyperphagia and increased fat mass (Obici et al. 2002). regulatoryeffectsofinsulin.i.c.v.administrationofinsulin
i.c.v. administration of an insulin mimetic dose- during food deprivation in rats prevents the fasting-
dependently reduces food intake and body weight in rats, induced increase in hypothalamic levels of both NPY in
andalterstheexpressionofhypothalamicgenesknownto the PVN and NPY mRNA in the ARC (Schwartz et al.
regulate food intake and body weight (Air et al. 2002). 1992b). NPY expression is increased in insulin-deficient,
Treatment of mice with orally available insulin mimetics streptozocin-induced diabetic rats and this effect is re-
decreases the weight gain produced by a high-fat diet as versed with insulin therapy (Williams et al. 1989, White
well as adiposity and insulin resistance (Air et al. 2002). et al. 1990). More recently, the melanocortin system has
If insulin elicits changes in feeding behaviour at the been implicated as a mediator of insulin’s central actions.
levelofthehypothalamus,thenlevelsofcirculatinginsulin Insulin receptors have been found on POMC neurons in
should reflect the effect of centrally administered insulin. the ARC (Benoit et al. 2002). Administration of insulin
Studiesofsystemicinsulinadministrationhavebeencom- into the third ventricle of fasted rats increases POMC
plicated by the fact that increasing circulating insulin mRNAexpressionandthereductionoffoodintakecaused
causes hypoglycaemia which in itself potently stimulates by i.c.v. injection of insulin is blocked by a POMC
food intake. Experiments where glucose levels have been antagonist (Benoit et al. 2002). Furthermore, POMC
controlledinthefaceofelevatedplasmainsulinlevelshave mRNAisreducedby80%inratswithuntreateddiabetes,
indeed shown a reduction in food intake in both rodents andthiscanbeattenuatedbyperipheralinsulintreatment
and baboons (Nicolaidis & Rowland 1976, Woods et al. which partially reduces the hyperglycaemia (Sipols et al.
1984).Thusperipheralandcentraldataareconsistentwith 1995). Taken together, these experiments suggest that
the insulin system acting as an endogenous controller of both the NPY and melanocortin systems are important
appetite. downstreamtargetsfortheeffectsofinsulinonfoodintake
The insulin receptor is composed of an extracellular and body weight.
(cid:1)-subunit which binds insulin, and an intracellular
(cid:2)-subunit which tranduces the signal and has intrinsic Adiponectin Adiponectin is a complement-like protein,
tyrosinekinaseactivity.Theinsulinreceptorexistsastwo secreted from adipose tissue, which is postulated to
splice variants resulting in subtype A, with higher affinity regulate energy homeostasis (Scherer et al. 1995). The
forinsulinandmorewidespreadexpression,andsubtypeB plasmaconcentrationofadiponectinisinverselycorrelated
with lower affinity and expression in classical insulin- withadiposityinrodents,primatesandhumans(Huetal.
responsive tissues such as fat, muscle and liver. There are 1996, Arita et al. 1999, Hotta et al. 2001). Adiponectin is
several insulin receptor substrates (IRSs) including IRS-1 significantly increased after food restriction in rodents
andIRS-2,bothidentifiedinneurons(Baskinetal.1994, (Berg et al. 2001) and after weight loss induced by a
Burks et al. 2000). The phenotype of IRS-1-knockout calorie-restricteddiet(Hottaetal.2000)orgastricpartition
mice does not show differences in food intake or body surgery in obese humans (Yang et al. 2001). Peripheral
weight (Araki et al. 1994), but that of IRS-2-knockout administrationofadiponectintorodentshasbeenshownto
mice is associated with an increase in food intake, in- attenuate body-weight gain, by increased oxygen con-
creasedfatstoresandinfertility(Burksetal.2000).IRS-2 sumption, without affecting food intake (Berg et al. 2001,
mRNA is highly expressed in the ARC, suggesting that Fruebis et al. 2001, Yamauchi et al. 2001). The effect of
neuronal insulin may be coupled to IRS-2 (Burks et al. peripheraladiponectinonenergyexpenditureseemstobe
2000). There is also evidence to suggest that insulin mediatedbythehypothalamus,sinceadiponectininduced
and leptin, along with other cytokines, share common expression of the early gene c-fos in the PVN, and may
intracellular signalling pathways via IRS and the enzyme involve the melanocortin system (Qi et al. 2004). It is
phoshoinositide 3-kinase, resulting in downstream perhaps counterintuitive for a factor that increases energy
signal transduction (Niswender et al. 2001, Porte et al. expenditure to increase following weight loss; however,
2002). reduced adiponectin could perhaps contribute to the
Insulin receptors are widely distributed in the brain, pathogenesis of obesity.
with highest concentrations found in the olfactory bulbs Studies show that plasma adiponectin levels correlate
and the hypothalamus (Marks et al. 1990). Within the negatively with insulin resistance (Hotta et al. 2001), and
hypothalamus, there is particularly high expression of treatmentwithadiponectincanreducebody-weightgain,
insulinreceptorsintheARC;theyarealsopresentinthe increase insulin sensitivity and decrease lipid levels in
DMH, PVN, and suprachiasmatic and periventricular rodents (Berg et al. 2001, Yamauchi et al. 2001, Qi et al.
regions (Corp et al. 1986). This is consistent with the 2004). Adiponectin-knockout mice demonstrate severe
hypothesis that peripheral insulin acts on hypothalamic diet-induced insulin resistance (Maeda et al. 2002) and a
nuclei to control energy homeostasis. propensity towards atherogenesis in response to intimal
JournalofEndocrinology(2005)184,291–318 www.endocrinology-journals.org