Melanin-concentrating hormone functions in the nervous system: food intake and stressGuillaume HervieuDrug Discovery, GlaxoSmithKline plc, Neurology Centre of Excellence for Drug Discovery (CEDD),NFSP-North, H17-L1-130-H04, Third Avenue, Harlow, Essex CM19 5AW, UK
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, which cen-trally regulates food intake and stress. MCH induces food intake in rodentsand, more generally, acts as an anabolic signal in energy regulation. In addi-tion, MCH seems to be activatory on the stress axis. Two receptors for MCH inhumans have very recently been characterised, namely, MCH-R1 and MCH-R2.MCH-R1 has received considerable attention, as potent and selective antago-nists acting at that receptor display anxiolytic, antidepressant and/or anorecticproperties. Feeding and affective disorders are both debilitating conditionsthat have become serious worldwide health threats. There are as yet no effi-cient and/or safe cures that could contain the near-pandemia phenomen ofboth diseases. Thus, the discovery of MCH-R1 antagonists may lead to thedevelopment of valuable drugs to treat obesity, anxiety and depressive syn-dromes. In addition, it opens wide avenues to probe additional functions ofthe peptide, both in the brain and in the peripheral nervous system.
The prevalence of both feeding and affective disorders has skyrocketed since themid-twentieth century in the Western world and has continued to rise dramaticallyduring the last two decades. It has now become a huge burden on patient quality oflife and public health expenditure.
In the US, it is estimated that > 30 and 65% of US adults are obese or over-weight, respectively [1]. Trends for an increase in obesity are also rising considerablyamongst children and adolescents, which is worrying because poor eating habits areoften established during childhood [1]. The number of overweight people increasesby 1.5% every year in developing countries [2]. Comorbidity with obesity is associ-ated with a number of chronic and potentially lethal diseases such as stroke, heartdisease, diabetes, hypertension, osteoarthritis, and hypercholesterolaemia. Obesityincreases the likelihood of death from all causes by 20%.
Equally, the prevalence of major depression and anxiety syndromes has increaseddramatically over the past 20 years. The prevalence of depression/anxiety disorders isestimated to be 3 – 7% of the adult population, with 15% of patients eventuallydying by committing suicide. In the US, approximately one in ten adults suffersfrom depression each year. Affective disorders, including various anxiety and mooddisorders, are amongst the top ten leading causes of disability in the US and otherdeveloped countries.
Finding efficient cures to fight obesity and depression is of prime importancebecause of these tremendous health concerns, and it has received genuine
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considerable attention from public health services as well aspharmaceutical companies.
Obesity is due to an imbalance between energy expendi-ture and food intake, but the exact reason for that imbalanceis still unclear. The aetiology of obesity is a complex interac-tion of dietary, genetic, metabolic and physical healthcauses. Similarly, it is still not understood how an imbalancein serotonin and noradrenaline neurotransmitter circuitriescan translate to depression.
The therapeutic market for depression and obesity is rela-tively unmet and therefore offers considerable opportunitiesto companies and academia with a focus on those illnesses.
Safe and bioactive melanin-concentrating hormone (MCH)mimetics acting as antagonists at the receptor MCH-R1 mayrepresent a novel way of treating both disorders, as MCH is acritical regulator of food intake and stress response.
The purpose of this review is to present the most recentfindings on the neurobiology of MCH, with special emphasison its role in food intake/energy regulation and its interven-tion in the stress axis, and how this could translate into poten-tial therapeutic benefits.
A long-standing and important achievement in the field isthe cloning, functional characterisation and neuronal distri-bution of at least two MCH receptors, namely, MCH-R1 andMCH-R2, in the late 1990s [3,4], and the very recent develop-ment of MCH-R1 antagonists that show potential anxiolytic,antidepressant and/or anorectic actions [5,6].
1.1 Melanin-concentrating hormoneMCH was first isolated in 1983 from fish Teleost pituitaries byvirtue of its hypophysiotropic role on melanin concentration[7], and was later shown to intervene in the fish stress axis [8-10].
Immunochemical studies using an antisalmonMCH antiserum indicated the existence of an MCH-like fac-tor in the rat [10,11]. The rat orthologue peptide was biochem-ically isolated from rat hypothalamic extracts at The SalkInstitute, California in 1989 [12]. Rat and salmon MCH areboth cyclic neuropeptides and display strong sequence iden-tity mainly within the loop structure. Cloned mammalianforms of MCH (mouse, rat, human) display total sequenceidentity (Figure 1A). MCH is produced by post-translationalcleavage from a protein precursor, prepro-MCH. The precur-sor can also release other bioactive peptides. In the rat, thesepeptides are named NEI and NGE (Figure 1B) [13-15]. Anecdo-tally, the amidated C-terminal tail of NEI led to theMCH neuronal population being called the α-2 system, or‘second α-MSH’ system. α-MSH is also amidated, and theconfusion arose because of crossreactivity of the amideepitope analysed by immunochemical detection [16]. An inter-action between both MCH and α-MSH systems cannot beignored. MCH and α-MSH are functional antagonists inmany bioactivities of both peptides in both fish and mam-mals, including stress and food intake [4,8-10,17-18].
Localisation studies show a dramatic region-specificMCH gene expression pattern in the CNS; the
prepro-MCH gene is quasi-exclusively expressed in the lateralhypothalamus area (LHA) (Figure 2A’ and C), whilstMCH-containing processes are found widely throughout theCNS (Figure 2A) [19]. Another marker of the LHA is the recentlydiscovered family of orexin peptides [20-21]. Orexins are alsomajor players in energy balance. Antagonists to the orexin-1receptor promote weight loss in rodents. In addition, com-pounds manifest psychoactive properties, in particular for sleepregulation [22]. The LHA, traditionally viewed as a phylogeneticcontinuation of the nervous reticular formation, governs manyfunctions such as feeding, blood pressure, neuroendocrine axis,thermoregulation, sleep–waking cycle, emotion, sensorimotorintegration, and reward processes [23]. This is reflected by itsextensive projections throughout the nervous system. Of thesediverse roles of the LHA, feeding behaviour regulation is a majorone. The LHA is often branded as the brain ‘feeding centre’. Italso shows exquisite anatomical relationships with the majorstress-regulating nuclei within the hypothalamus itself, the lim-bic system and the brainstem (serotonergic raphe nuclei andnoradrenergic locus coeruleus). This is why it is perhaps not sur-prising that MCH is a major player in regulating both stress andfood intake.
In the peripheral nervous system, the main tissues express-ing the MCH gene are part of the enteric, nervous, reproduc-tive and immune systems [24-28].
Surprisingly, the fact that MCH is a potent orexigenic fac-tor was not initially discovered as the first function of themammalian peptide. Rather, sporadic and sometimes con-troversial evidence attributed to the peptide a psychoactiverole in epileptogenesis [29], sensory gating [30], passive avoid-ance [31], aggression and anxiety [32,33], and in the regulationof the hypothalamo–pituitary axis [34-37]. Peripheral nervoussystem actions of the peptide were concerned with digestivehydro-mineral balance [27]. More recent evidence concernsthe involvement of MCH in reproduction [38-42] and mem-ory retention [43], perhaps linked to hippocampal increase ofsynaptic transmission [44].
Thorough studies on the intracellular pathways activatedby MCH upon binding to its receptors have begun to bedescribed [45], including the isolation of a specificMCH-R1-interacting zinc-finger protein called MIZIP [46], aswell as effects of MCH on neuronal excitability [47-48].
1.2 Melanin-concentrating hormone receptorsA truncated form of the human orphan G-protein-coupledreceptor (GPCR) called SLC-1 (GPR24), identified by Kola-kowski et al. as most homologous to the somatostatin receptorfamily [49], was later characterised as being a receptor forMCH [3,4,50-54]. Rodent orthologues were cloned in the rat [55]
and mouse [56]. Some of the approaches used a method bestdescribed as a ‘reverse pharmacology approach’ (RPMA) [57],relying on systematic agonist compound bank screening orbiochemical purification of ligands that can activate the trans-fected receptor in heterologous cell lines. Within a year, a sec-ond GPCR-related family receptor with low sequence identity
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to that of MCH-R1 was identified as a biologically-relevantsecond MCH receptor subtype or a paralogue to MCH-R1,named MCH-R2 [4,18,58-64]. Other MCH receptor subtypesmay have been identified in a keratinocyte cell line [65].
MCH-R1 is widely expressed in the rat brain (Figure 2B,2D and 2E) and its distribution overlaps with MCH immuno-reactive zones (compare with Figure 2A) [4,64].
2. Reviewing the evidence for implication of melanin-concentrating hormone in energy balance and stress regulation
2.1 Melanin-concentrating hormone and food intakeMCH potently promotes food intake in rodents [4,18,66-70].
Genetic models, pharmacological intervention, geneexpression, structure–activity relationship and neuroanatomi-cal studies have all pointed to MCH being a critical regulatorin feeding behaviour and energy regulation, not only in theCNS but also in the peripheral nervous system.
2.1.1 Pharmacological evidenceImportantly, the appetite-stimulating effect of MCH occursboth in the light and dark phases of the day [67] and is compa-rable to that of orexins and galanin [68]. Twice-daily adminis-tration of MCH only caused a transient increase in foodintake for 5 consecutive days, after which time the effect waslost. Daily food intake and weight were also not altered [67].However, continuous infusion of MCH in Wistar orSprague–Dawley rats (8 µg/animal/day) stimulated feedingand increased body weight after 5 days. Long-term infusion ofthe peptide still resulted in a feeding-promoting effect ofMCH after 12 days of administration in both Wistar andSprague–Dawley rats [69].
Intriguingly, the dipeptide H-NEI–MCH-OH is a ‘super-agonist’ version of MCH. It has a more potent feeding-inducing effect than MCH itself (Figure 1B) [15]. NEI–MCHhas been biochemically identified by chromatography cou-pled to immunological detection [4], so it may well havephysiological relevance.
Figure 1. MCH and prepro-MCH structure. A. The rat MCH is a cyclic nonadecapeptide. Amino acid residues that differ from the fishsequence are dark grey and additional residues for the mammalian peptide are mid grey. The disulfide bridge is light grey. The peptide isparticularly sensitive to degradation by the endopeptidase 24.11 (neutral endopeptidase) [145]. The peptide is matured from a prepro-MCHprotein by pro-hormone convertase proteolysis. The precursor, which contains a signal peptide, could also release NEI and possibly NGE(B). Basic cleavage sites are indicated by arrows. MCH and NEI have been biochemically characterised, whilst NGE has not. Convertaseenzymes responsible for the proteolysis have been identified [146]. The naturally-occurring NEI–MCH dipeptide is more potent than MCHitself in inducing food intake [16].MCH: Melanin-concentrating hormone.
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Figure 2. MCH and MCH-R1 localisation in the rat brain. In the CNS, the MCH is quasi-exclusively expressed as a protein (A’) andmRNA (C) in the lateral hypothalamus. MCH efferent projections are sent throughout the brain (A) [19,147]. The MCH antiserum wasproduced in white New Zealand rabbits using rat MCH coupled to Keyhole Limpet Haemocyanin by glutaraldehyde. The receptor MCH-R1(B, D, E) is localised to MCH-immunopositive areas (A) as demonstrated by immunohistochemistry using an affinity-purified rabbitpolyclonal antiserum raised against the C terminus of the protein (B, D, E, where E is a pre-adsorption control). The distribution of thesubtype receptor is widespread and may underlie the fact that MCH-R1 is well placed to mediate many of the pleiotropic activities ofMCH. MCH-R1 immunosignals were recorded in the CTX, the olfactory regions (AON, OB and OT), the basal ganglia (CP, ACB, HDB), thehippocampal formation (hi, SUB), the diencephalon (LHA, VP) and various midbrain and hindbrain areas (Pn, SC, IC, LL, NTS, PSV, SPV, Cbincluding infracerebellar nuclei Int, PRN, GRN, MDRN, MV) [4,5,110,111].ACB: Nucleus accumbens; AON: Anterior olfactory nucleus; Cb: Cerebellum; CP: Caudate-putamen; CTX: Neocortex; GRN: Gigantic reticular nuclei; HDB: Horizontallimb of the diagonal band; hi: Hippocampus; IC: Inferior colliculus; LHA: Lateral hypothalamic area; LL: Lateral lemniscus; MCH: Melanin-concentrating hormone;MDRN: Medullary reticular nuclei; MV: Medial vestribular nuclei; NTS: Nucleus of the solitary tract; OB: Olfactory bulb; OT: Olfactory tube; Pn: Pons; PRN: Pontinereticular nuclei; PSV: Principal sensory trigeminal; SC: Superior colliculus; SPV: Nucleus of the trigeminal nerve; SUB: Subiculum; VP: Ventro–posteriorthalamus complex.
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2.1.2 Genetic animal modelsGenetic models have strongly confirmed the involvement ofMCH in energy regulation. Mice deleted for theprepro-MCH gene display a hypophagic and lean phenotypewith virtually no fat deposit and an altered metabolism [70].However, as the prepro-MCH gene also encodes for the NEI,NGE, and MGOP peptides as well as the nuclear factorAROM, it cannot therefore be concluded that the observedphenotype is entirely due to the MCH absence alone. Con-versely, MCH overexpression in transgenic mice leads to obes-ity as well as insulin resistance [71]. Importantly, targeteddisruption of the MCH-R1 gene results in resistance to diet-induced obesity and hyperphagia [72,73], leanness, hyperactiv-ity and altered metabolism [72].
Intriguingly, mice that lack the M3 muscarinic acetylcho-line receptor are hypophagic and lean. Levels of MCH geneexpression are dramatically downregulated in that model [74].Other evidence would advocate for a close relationshipbetween cholinergic and MCH signalling [4,18].
2.1.3 Quantitative gene expression studiesNumerous variations in the level of MCH gene expression havebeen linked to feeding behaviour and possibly obesity. First,activation of MCH neurons was observed following insulin and2-deoxyglycose injections in the rat [75] or lesions of the ventro-medial hypothalamic nuclei (VMN) [76]. Importantly, energymetabolism is also thought to be critically controlled by theLHA, as it contains a population of neurons that is sensitive toglucose levels and is activated by hypoglycaemia. The identityof these cells has remained elusive, probably because the lateralhypothalamus is not as topologically organised as other majornuclei of the hypothalamus. In addition, the medial forebrainbundle, the most prominent brain fibre network bundle, passesthrough the LHA. This has clearly added complexity to thedesign of experiments to study the LHA that would not dam-age the medial forebrain bundle itself [23].
An increase in MCH mRNA levels is observed following fooddeprivation in rats [75] and mice [66]. Finally, overexpression ofMCH mRNA- and/or pro-MCH-derived peptides was found invarious obese rodents, including ob/ob mice [66,78-80], db/db mice[79-80], fat/fat mice [81] and Ay/a (agouti) mice [82]. Impairedprocessing of pro-MCH in fat/fat mice may well account for theobese phenotype [81]. Alteration in adiposity may also have someinfluence on MCH expression. This was exemplified by thedecrease in MCH mRNA observed in brown adipose tissue-defi-cient mice that developed both obesity and hyperleptinaemia[83], and the higher levels of MCH mRNA found in thin ewes incomparison with the fat animals [77]. MCH is critically involvedwith leptin, an adipocyte-derived hormone acting as a majorsatiety signal [22]. Leptin decreases MCH gene expression follow-ing acute injection in rats [84] and, conversely, stimulatesMCH mRNA peptide expression during chronic treatment inlean and ob/ob mice [80]. The increase in hypothalamic expres-sion and circulating release of MCH observed in obese hyper-phagic Zucker rats associates with the phenotypic absence of
leptin signalling. It is likely to contribute to their obesity syn-drome [86]. Finally, Shimokawa et al. reported that the fatty acidsynthase inhibitor, C75, injected intraperitoneally, markedlyincreased expression of MCH and MCH-R1 in both lean andobese mice hypothalami [87].
Using canine distemper virus (CDV), which can targethypothalamic nuclei and lead to obesity syndrome in the latestages of infection, Verlaeten et al. showed a surprising specificdownregulation of MCH precursor mRNA (ppMCH) ininfected obese mice [88].
A possible pathophysiological implication of MCH inhuman feeding disorders was indicated by an observed 3-foldincrease in MCH mRNA and peptide in human obese ascompared to lean subjects [89]. Quite importantly, MCH geneexpression is decreased in adult male rats treated with lipopol-ysaccharide (LPS), an inflammatory agent. Anorexia is often aconsequence of inflammatory processes, and the downregula-tion of MCH gene expression may contribute to hypophagicbehaviours [90]. In addition, in oestrogen-induced weight loss,an accepted model of anorexia, MCH signalling is decreasedand MCH appears critically positioned to counteract the anti-feeding properties of oestrogens. This may well have clinicalimplications in cancer- and AIDS-related anorexia [91].
2.1.4 Interaction of melanin-concentrating hormone with other critical food intake modulatorsFunctional interactions of MCH with other peptidic systemsinvolved in feeding control and energy balance homeostasisare now well-documented. MCH acts as a functional antago-nist of α-MSH in food intake [17,36]. Other anorectic pep-tides, such as glucagon-like peptide (GLP)-1 or neurotensin,also prevent the appetite-stimulating effect of MCH.
Galanin [92], orexin [93] and opioids [94], compared toMCH, control food intake behaviour by using separate, paral-lel neuronal circuits.
2.1.5 Neurochemical signallingNeurochemical signalling of hypothalamic MCH neurons hasrecently received considerable attention. The phenotypic neu-rochemical identity of afferents to and efferents from theMCH neurons, as well as receptors harboured by theMCH neurons, include a plethora of factors involved in energyregulation such as CART, orexin, glutamate, NPY, AgRP,α-MSH, leptin receptor, NK3 receptor, VIP, and AVP. Thereader is referred to [4,17,18]. It re-emphasises the critical role ofthe brain in mediating the orexigenic property of MCH.
2.1.6 Neuroendocrine studiesNeuroendocrine studies also point to the role of MCH in theoverall management of energy balance.
MCH is first implicated in the stress axis [34-37]
(see Section 2.2). Partial inhibition of CRF release byMCH [34] could be critical for MCH to contain the potentanorectic action of CRF. Stress axis and energy balance areclosely related (see Section 3.3). In addition, MCH suppresses
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TRH release from hypothalamic explants as well as decreasingplasmatic levels of thyroid-stimulating hormone [95]. The thy-roid axis is important in energy homeostasis, and starvationleads to profound suppression of the hypothalamo–pituitary–thyroid axis. Finally, MCH-R1-deleted mice have higher cor-ticosterone relative to wild-type animals [73].
2.1.7 Peripheral action of melanin-concentrating hormone on energy balance regulationIt has emerged very recently that MCH does act within theperiphery to regulate energy balance in at least both the endo-crine pancreas and fat tissues.
MCH regulates insulin secretion in established ratMCH-R1-immunopositive insulinoma cell lines [96]. Miceoverexpressing the MCH gene have an enlarged pancreas [71].In addition, specific vagal and sympathetic denervation com-bined with injection of a retrograde trans-synaptic tracer,pseudorabies virus, into the pancreas showed that hypotha-lamic MCH neurons project to both the dorsal motor nucleusof the vagus and in preganglionic spinal cord neurons, respec-tively, which indicates a direct association between behav-ioural and autonomic functions [97]. These findings set thescenery for MCH to be a possible critical factor in regulatingendocrine pancreatic hormone release and thus to be poten-tially involved in diabetes.
MCH also acts on adipocytes as MCH stimulates leptinrelease [98] and activates adipocyte signalling pathways [99].Tracing of neural pathways from the brain to brown adiposetissue in the rat have established a clear involvement of thehypothalamic MCH neurons [100].
2.1.8 Structure–activity studies on ligand/receptorsPhysiological structure–activity studies with a variety ofMCH peptide analogues indicated a strong correlation betweentheir effects upon food intake and their potency obtained at therat SLC-1 receptor. This would indicate the relevance of theSLC-1 receptor in feeding behaviour [101]. The reader here isdirected to a number of recent studies on the pharmacophoreregions of the MCH peptide conferring selectivity forMCH-R1 and/or MCH-R2 preferential binding [4,18,101-109].
2.1.9 MCH-R1 is implicated in mediating the orexigenic effect of MCHNon-peptide antagonists of MCH to MCH-R1 have beendeveloped by a number of pharmaceuticals such as the carbox-amide GlaxoSmithKline (GSK) compound [109], the Takedacompound T-226296 [108] and the Synaptic compoundSNAP-7941 [6].
Haynes et al. showed that a GSK MCH-R1 antagonistreduced MCH- and fast-induced food intake and bodyweight in both rats and mice [5]. Borowsky et al. went on toshow that the pyrimidine-derived SNAP-7941, anotherMCH-R1 antagonist, inhibited food intake stimulated bycentral administration of MCH, reduced consumption ofpalatable food and, after chronic administration to rats with
diet-induced obesity, resulted in a marked, sustaineddecrease in body weight [6].
MCH-R1 is found in key brain areas that regulate foodintake such as the hypothalamic ventromedial and dorsome-dial nuclei (Figure 3A and 3B) as well as nuclei involved in therewarding properties of food (Figure 3C) [3,4,51,110-113].
The anorectic property of non-peptidic and specificMCH-R1 antagonists [5,6] and the lean phenotype of inde-pendent models of MCH-R1 knockout mice [72,73], as well asthe complete resistance of MCH-R1-deficient mice to chronicintracerebroventricular infusion of MCH [72,73], are furtherserious proofs-of-concept that MCH-R1 is at least involved inmediating the orexigenic effect of its ligand, and consequentlyis a receptor essential to energy balance homeostasis. It nowremains to check the actions of MCH-R1 antagonists on foodintake in the MCH-R1-deficient mice.
2.2 Melanin-concentrating hormone and stressMCH is activatory on the stress axis in fish. The reader is par-ticularly referred to a series of thorough studies conducted byBaker and co-workers [4,8-10,16].
In mammals, the first studies have led to controversy. Thedirect inhibitory action of salmon MCH on ACTH release fromisolated rat pituitary cells observed by Baker et al. [115] could notbe reproduced using the rat MCH by Navarra et al. [116].
In vivo studies by Jezova et al. reported a central stimulatoryeffect of rat MCH on basal ACTH release after intracerebroven-tricular administration of MCH in conscious rats [34]. Anotherstudy, however, found that intracerebroventricular injection ofrat MCH (and NEI) did not modify the basal secretion ofACTH during the day or at night [35]. On the contrary, MCHappears to inhibit ACTH secretion after an ether stress [35] orafter a mild handling stress [36]. This would indicate that regula-tory actions of MCH on the stress axis are circadian rhythm-dependent [4,8-10,18]. Interestingly, NEI [35] or α-MSH [36] canprevent the inhibitory action of MCH on ACTH release.
In vivo studies by Ashmeade et al., who administered ratMCH intravenously in rats, showed a strong and significantdose-dependent increase in the plasma corticosterone level [37].
It has been shown that endogenous glucocorticoids inadrenalectomised rats or addition of dexamethasone in vivo[117] or in hypothalamic cells in culture [118], stimulate the syn-thesis of MCH mRNA- and pro-MCH-derived peptides(MCH and NEI). Conversely, CRF is reported to suppressMCH release in vitro [118].
Behavioural studies first showed that MCH antagonises theeffects of the melanocortin on grooming and locomotor activ-ities in the rat [9,17,119]. Excessive grooming is a mark of anx-ious behaviour. In fact, MCH is reported to be anxiogenicwhen injected into the hypothalamic pre-optic area [32],although it is reported to be anxiolytic followingintracerebroventricular administration [33]. In addition,Gonzalez et al. have provided a role for MCH in the modula-tion of amine release, thereby reducing serotonergic activityand inhibiting dopamine release [120].
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Figure 3. MCH-R1 and food intake. MCH-R1 is found in key brain areas regulating food intake such as the hypothalamicventromedial and dorsomedial nuclei (A, B) as well as nuclei involved in the rewarding properties of food (C). Strong immunostainingwas found in the basal ganglia as illustrated with a sagittal section; dense immunosignals were seen in the substantia nigra, STN, andlateral segment of the GPl. Immunosignals were also observed in the CP, sACB, VPal and ic. The OT and isl are also immunostained[4,5,110,111].CP: Caudate-putamen; GPl: Globus pallidus; ic: Internal capsula; isl: Islands of Calleja; MCH: Melanin-concentrating hormone; OT: Olfactory tube; sACB: Shell of thenucleus accumbens; STN: Subthalamic nucleus; VPal: Ventral pallidum.
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Gene expression studies have also linked changes ofMCH gene expression levels in a variety of neurogenic andosmotic stress paradigms [4,8-10,18,121].
In particular, a low level of MCH mRNA expression wasfound to be associated with short-term footshock stress [118]
and dehydration or hypertonic saline regimen [122], suggestingan inhibitory function for the MCH system in the stressresponse and fluid homeostasis. Importantly, MCH mRNAexhibits a marked circadian variation which closely followsthat of plasma corticoids [10]. MCH neurons possibly receivedirect afferents from the hypothalamic suprachiasmaticnucleus, acting as a paramount circadian pacemaker [123].
It is not yet known exactly how and where MCH interactsin the stress axis. However, MCH is partially responsible forCRF release as shown by MCH immunoneutralisation [34]. Inaddition, Parkes and Vale showed that a population of thehypothalamic paraventricular nucleus (PVN) was activated byMCH injected intracerebroventricularly as seen by c-fos neuro-nal activation [124]. This may well be the CRF neuronal popu-lation. c-fos neuronal activation in both the PVN and the locuscoeruleus/Barrington nucleus has been confirmed(Cluderay et al., Figure 4A). The latter dorso–lateral ponsregion is a major CRF-synthesising nucleus [125]. MCH-R1 hasbeen detected in the PVN, locus coeruleus and the pituitary[51,110-111]. In addition, MCH-R1-deleted mice have highercorticosterone relative to wild-type animals [72], which wouldimplicate MCH-R1 in stress axis regulation. As for energy reg-ulation, the actions of MCH-R1 antagonists on the stress axisin the MCH-R1-deficient mice remain to be investigated.
Colocalisation studies in the rodents are needed to revealwhether or not anterior pituitary cells and the adrenal glandharbour MCH-R1. Conversely, do the MCH neurons colo-calise with the CRF, melanocortin and glucocorticoid recep-tors? A hypothetical model placing MCH in the rodent stressaxis is presented in Figure 4B. In addition to common endo-crine/paracrine mechanisms of action, MCH could transducethrough the choroid plexus and the blood vessel walls, bothMCH-R1-immunopositive (Figure 4C and 4D).
3. Expert opinion
3.1 Melanin-concentrating hormone andenergy regulationMCH is a critical anabolic regulator of energy balance, andprospects of MCH-R1 antagonists in diminishing foodintake are currently highly attractive and may well translateinto the clinic.
New treatments for obesity are urgently needed. Patientstreated with orlistat (Xenical®, Roche) are poorly compliant asorlistat inhibits fat absorption, which then means that fat iseliminated in stools. Thus, episodes of oily diarrhoea are fre-quent. One of the most effective treatments using fenflu-ramine–phentermine (blocking the neuronal re-uptake ofserotonin) had to be withdrawn from the market because ofits high cardiovascular toxicity. On the other hand, lower-risk
treatments tend to have poorer long-term results. Potentialavenues for the development of drugs to treat obesity are mol-ecules that decrease food intake (such as NPY and galaninantagonists, melanocortin-4 receptor agonists and CCK ago-nists, enterostatin and leptin), molecules that modify metabo-lism (such as insulin, glucagon/GLP-1) and molecules thatincrease energy expenditure (β3-agonists, leptin, uncouplingproteins) [22]. However, it is clear that they are not yet treat-ments. It would rather seem that interventions targeted atmultiple levels in the energy homeostasis system might benecessary to achieve weight loss.
Obesity and Type II diabetes (non-insulin dependent dia-betes mellitus) are sufficiently closely interrelated for the neol-ogism ‘diabesity’/‘diobesity’ to have appeared in the medicalcommunity. MCH may be one of those critical factors bridg-ing both obesity and Type II diabetes.
3.2 Melanin-concentrating hormone and stress regulationThe fact that both activatory and inhibitory actions ofMCH on the stress axis are reported could appear to be a con-fusing situation, but it is highly likely that the marked diurnalcircadian pattern of MCH gene expression, as well as theresponse heterogeneity of hypothalamic MCH neuronalgroups to osmotic stress [123], are both key areas that deserveto be looked into further.
SNAP-7941, an MCH-R1 antagonist, produced effectssimilar to clinically used antidepressants and anxiolytics inthree animal models of depression/anxiety: the rat forced-swim test, rat social interaction and guinea-pig maternal-sepa-ration vocalisation tests [6]. Given these observations, anMCH1-R antagonist may offer novel approaches to depres-sion and/or anxiety. MCH may be key in triggering depres-sion and/or anxiety. CRH mediates very wide and profoundstress-induced changes in the autonomic nervous system, neu-roendocrine function and behaviour [125]. Hyperactivity of thestress axis in the aetiology of affective illnesses is overwhelm-ingly documented. Two-thirds of drug-free depressed patients(depression, post-traumatic stress disorder, anxiety and ano-rexia nervosa) show signs of hypercortisolaemia, enlargedadrenal and pituitary glands, elevated cerebrospinal fluid lev-els of CRH and blunted neuroendocrine responses to syn-thetic glucocorticoid (dexamethasone) challenge. Comorbidcognitive impairments may be consistent with a toxic activityof the chronically high levels of brain cortisol and the down-regulation of its receptors in the hippocampal formation [125].
MCH is a regulator in the stress axis. An immediate ques-tion is how much MCH influences the profound anxiogenic,anorectic, anhedonic properties of CRF.
Classical antidepressants such as the tricyclic antidepres-sants (TCAs) and monoamine oxidase inhibitors (MAOIs),and more recent developments such as selective serotonin re-uptake inhibitors (SSRIs), noradrenaline re-uptake inhibitors(NARIs), and serotonin and noradrenaline re-uptake inhibi-tors (SNARIs) will need replacements, as their use is
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CRFneurone
MCHneurone
Periphery
ACTHcell
• Adrenal gland
+
+
Glucocorticoidcell
Hypothalamus
• Pituitary
+
-
+
Locus coeruleus
Hypothalamus
A
B
C D
Choroid plexus Brain blood vessel
PVH
MCH-R1 protein
3v
4v
c-fos protein activation upon intracerebroventricular administration of MCH or vehicle
Figure 4. MCH/MCH-R1 in the rodent stress axis. Neuronal activation triggers the activation of IEGs, such as the proto-oncogenec-fos. Stereotypic inducibility of that transcription factor is the most widely used functional anatomical mapping tool.Intracerebroventricular administration of MCH provoked a dramatic increase in c-fos neuronal expression in the PVH and locus coeruleusas compared to vehicle. MCH-R1 was detected in both those major CRF-synthesising regions. It is therefore highly likely that MCH-R1mediates the effect of MCH on stress (A). A hypothetical model placing MCH in the stress axis is presented in B. MCH would activateCRF release, which would lastly result in adrenal glucocorticoid release. Glucocorticoids and CRF enhance and inhibit MCH synthesis andsecretion, respectively [117,118]. MCH is partly involved in the CRF-induced pituitary ACTH release [34]. In rodents, colocalisation studieswith MCH-R1 may help in knowing whether MCH could act directly on hypothalamic CRF cells, pituitary corticotrophs and adrenalmedulla, to directly control the release of CRF, ACTH and corticoids. There may be MCH-R1 protein harboured by MCH cells, as MCH-R1is reported in the LHA [110-111]. (+) indicates an activatory action, whilst (-) indicates an inhibitory action. In addition to commonendocrine/paracrine mechanisms of action, MCH could transduce through the human choroid plexus (C) and the blood vessel walls (D),both MCH-R1-immunopositive. Autofluorescence, as shown in the choroid plexus case, is often encountered in post-mortem humantissues. Kastin et al. have discussed the properties of MCH passing through the blood–brain barrier [148,149].IEG: Immediate-early genes; LHA: Lateral hypothalamic area; MCH: Melanin-concentrating hormone; PVH: Hypothalamic paraventricular nucleus; veh: Vehicle.
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associated with a wide range of non-acceptable side effects anda high rate of non-respondance.
It is of considerable interest, therefore, that SNAP-7941exhibits anxiolytic/antidepressant properties. MCH-R1antagonists may represent a highly exciting advance in psychi-atric therapeutics. Other neuropeptide receptor antagonistshave displayed antidepressant/anxiolytic properties (e.g., theneurokinin-1 receptor antagonist MK-869) [126].
3.3 Melanin-concentrating hormone as a central link between stress and energy balance?It is well-established that the nutritional status of mammalsand activity of the stress axis are interrelated. Human clinicaldata have long since accumulated about the effect of glucocor-ticoid treatment on inducing obesity and depression inpatients as well as immune disorders, amongst many otherdysregulations. In pathological situations, the overactivity ofthe HPA axis (elevated circulating ACTH and glucocorticoidblood levels) is a hallmark of comorbidity with obesity[127,128]. Glucocorticoid excess induces abdominal obesity,insulin resistance, diabetes and hypertension.
All this may suggest a pathophysiological role for MCH asa primer of obesity and depression, given the link betweenMCH and the stress axis. Worse, a feedforward mechanismmay trigger the onset of depression in obese people. Con-versely, a benefit for MCH-R1 antagonists in a subpopulationof obese people would be that they are treated with the samedrug for both physical (weight loss) and psychological aspects.It is clear that obese subjects do suffer from some psycho-social discrimination. This may also increase patient compli-ance to take the drug adequately.
3.4 Melanin-concentrating hormone and melanocortins: additional therapeutic opportunities for melanin-concentrating hormone?MCH and α-MSH have opposite actions on epileptogenesis[29], sensory gating [30], passive avoidance (McBride et al.),aggression and anxiety [32], and regulation of the hypotha-lamo–pituitary axis and feeding behaviour [36].
Many other biological functions for α-MSH have beendocumented. In particular, α-MSH is critically involved ininflammation, nerve regeneration, opiate self-administrationand analgesia, AIDS cachexia, and temperature control. Inaddition, melanocortin administration usually improvedperception and consciousness [16,129]. These functions havenot yet been fully probed for MCH. In particular, MCH-R1is densely localised to a number of brain reward areas, suchas the ventral tegmental area and the nucleus accumbens[4,6,110,111]. Activation of reward systems is a component offeeding behaviour and probably mediates the self-reinforc-ing properties of palatable food [130] (Figure 3C).Drug-addiction may thus be a particular area for MCH thatdeserves further attention.
Anecdotally, both MCH and α-MSH derive their namefrom their melanotropic properties in the fish. But evidence
of MCH involvement in mammalian melanogenesis couldnot be demonstrated until very recently. MCH-R1 is anauto-antigen associated with vitiligo, a common depig-menting disorder resulting from the loss of melanocytes inthe skin [131].
A current area of interest is that MCH can act onMC receptors but at micromolar concentrations [18,36,40]. Thefact that MCH may be a genuine ligand at melanocortinreceptors should not be disregarded. Peptide levels canincrease in many paradigms, including those directly linked tobrain pathologies [132-133]. It may also explain some stillunsolved discrepancies regarding the pharmacology and func-tion of MCH [18].
3.5 A very intriguing evolutionary systemApart from all physiological significance, MCH and its recep-tor system have a very intriguing genetic evolution history.
MCH-R2 [58-63] is a late evolutionary acquisition. Non-pri-mate species (at least rat, mouse, hamster, guinea-pig and rab-bit) do not have functional MCH-R2 receptors or encode anon-functional MCH-R2 pseudogene whilst retainingMCH-R1 functional expression [4,18,64,134].
MCH-R1 has three functional isoforms in the human [54],whilst it is restricted to one in the rodents [55-56]. The originalhuman SLC-1 sequence (Kolakowsky) includes an intron andis not functional [50,55].
In addition, there are two very distinct loci for humanMCH gene chromosomal localisation. Amongst the pri-mates, it is now only restricted to the Hominidae [135-136]. Itpresents as a truncated version of the MCH gene [135-136]
with a different chromosomal localisation to that of the‘authentic’ MCH gene. Moreover, this gene may code for aputative nuclear protein [136]. Any potential nuclear bioac-tivity would be a serious shift from currently characterisedneuropeptide mechanisms of action. Coincidentally per-haps, MCH-like immunoreactivity was localised in thenuclei of germ cells [26]. Sporadic evidence of nuclear actionof neuropeptide action has been reported. The reader isreferred to a summary of those intriguing phylogenetic find-ings to Courseaux and Nahon [137].
Near-transcriptional events of MCH gene expression couldbe regulated naturally by an antisense mechanism, as prepro-MCH antisense transcripts have been characterised in vivo inthe rat [25], the human [138], and in vitro in cell lines [139].
Another fact is that the prepro-MCH gene is subject togene-overprinting, a much rarer mechanism than just alterna-tive mRNA splicing to provide more chemical diversity. Tou-maniantz et al. characterised a peptide called MGOP derivedfrom the prepro-MCH gene [140], and mapped its immunore-active distribution within the rat brain [141]. It is claimed thatthe MCH gene-overprinted peptide (MGOP) product, whichshows differential neuronal distribution with MCH in the ratbrain, has immunomodulatory functions [209].
Such a late evolutionary process for a peptide system linkedto a diversity of functions is a rare occurrence.
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4. Competitor activity
The growing interest and focus in the MCH field can beappreciated by the sheer number of patents and publications,which have been skyrocketing in the last 3 years.
Feeding disorders represent a therapeutic disease area withconsiderable market potential. This is probably why pharma-ceuticals and biotechs entered a race to characterise the recep-tor(s) and design assays to screen substances against the clonedreceptor(s) (legacy SmithKline Beecham, legacy Glaxo-Well-come, GSK, Schering-Plough, Synaptic, Merck Sharp Dohme,Neurogen, Synaptic, Banyu, Yamamouchi, AstraZeneca,Takeda) and, consequently, to develop a mimetics ligand ofMCH (legacy SmithKline Beecham, GSK, Schering-Plough,Servier, Synaptic, Neurogen, Takeda). Non-profitable govern-mental research agencies (Centre National de la Recherche Sci-entifique, France; University of California, USA;US Department of Health and Human Services) have alsoissued WO patents on the MCH receptor.
The author refers here only to the patents issued on non-peptide MCH mimetics acting at the MCH-R1 protein asantagonists. Schering has developed urea [201] and piperidinederivatives [202]. SmithKlineBeecham has developed carboxa-mide derivatives [5,109,202], whilst Synaptic has developedpyrimidine compounds [6,203]. Takeda has patented amine[204-206] and aromatic [207] derivatives, whilst Neurogen hasconcentrated on phenylalkennylamine compounds [208].Apart from the SmithKlineBeecham and Synaptic com-pounds, the physiological effects of most of those currentlypublished MCH-R1 antagonists have yet to be evaluated inanimal models as well as in MCH-R1-deficient mice. Thera-peutic use, not surprisingly, lists eating disorders in all pat-ents, whilst affective disorders are included in some.Importantly, compounds that show therapeutic benefits inanimal preclinical models are orally bioavailable.
5. Conclusion and perspectives
This review has provided physiological, pharmacological,genetic and anatomical evidence supporting a crucial role forMCH in food intake and stress regulation. This may repre-sent an integrative mechanism aimed at producing the mostappropriate and coordinated response to ancestral food-seek-ing behaviour. Display of that behaviour may not be requiredso much now. Depression and anxiety syndromes have proba-bly been underdiagnosed historically because of political andreligious reasons, but clearly obesity has not been a problemuntil recently. Both have become a worldwide epidemic, aris-ing mainly from mixed causes of sedentary lifestyles and thecompetitive nature of modern life.
It is thus of importance that MCH-R1 antagonists potentiallydisplay both antiobesity and antianxiety/depression effects, ascurrent cures will need replacing in the near future. Traditionally,GPCRs are the easiest targets to block with small-molecule drugsand have a proven history of being excellent therapeutic targets.
Unravelling how much MCH interacts with CRF to mani-fest the profound anxiogenic, anorectic, and anhedonic proper-ties of CRF may bring a molecular mechanistic understandingof these highly complex and epidemic pathologies.
In addition, this should provide an impetus to determine thefunctions of the many other MCH-associated peptides. In par-ticular, further information about the functions of the NGE,NEI, MGOP and potential human variant MCH/AROM iseagerly awaited.
Other important roles for MCH may also be discovered. Inparticular, and pertinent to stress regulation, possible develop-ments could be expected in MCH regulating the immune sys-tem, as a recent report has shown that MCH decreasesCD3-stimulated peripheral blood mononuclear cells throughMCH-R1 [142]. In the fish, supernatants from leucocytestreated with MCH have a stimulatory effect on rainbow troutphagocytes in vitro [143].
That the MCH-R2 gene is functional only in primateswill certainly restrict knowledge of the potential ofMCH mimetics acting at MCH-R2, as rodents are themost widely used preclinical animal models of disease.Consequently, this impacts the development of MCH-R1-selective compounds for human therapies. There is a clearconcern that MCH receptor blockade may have adverseeffects not detected in animal studies using rodents. How-ever, primate, dog and ferret species, which all possessfunctional MCH-R2 receptors, are alternative animal mod-els potentially amenable to development, and they shouldprove useful for unravelling the relative contribution ofeach MCH receptor paralogue in the modulation of energybalance and stress. Indeed, it is not yet known whether ornot functional compensation exists between MCH-R1 andMCH-R2 in species that express both receptor subtypes.For instance, the complexity of the system NPY/NPYreceptors in the control of appetite is instructive. WhilstNPY Y1 receptors are clearly required to mediate short-term food intake, there are still many issues surroundingthe role of the subtypes NPY Y2 and Y5 [144]. Consequently,MCH-R1 antagonists that are effective for modulatingMCH-mediated behaviours in rodents may not workequivalently in species that possess both MCH receptorsubtypes. However, there is now good evidence thatMCH-R1 is a paramount paralogue receptor that at leastintervenes in food intake and stress response. A drug thatcould decrease food intake and increase psychological well-being is definitely worth the effort of translating the basicfindings into clinical use.
Acknowledgements
The author is thankful to J Cluderay, Psychiatry CEDD, GSKfor her excellent scientific and critical contribution, andC Hanham, Information Management, GSK. The author isalso grateful to DR Witty, CN Johnson, JRS Arch andKA Al-Barazanji, GSK.
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60. SAILER AW, SANO H, ZENG Z et al.: Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc. Natl. Acad. Sci. USA (2001) 98:7564-7569.
61. AN S, CUTLER G, ZHAO JJ et al.: Identification and characterization of a melanin-concentrating hormone receptor. Proc. Natl. Acad. Sci. USA (2001) 98:7576-7581.
62. WANG S, BEHAN J, O’NEILL K et al.: Identification and pharmacological characterization of a novel human melanin-concentrating hormone receptor, MCH-R2. J. Biol. Chem. (2001) 276(37):34664-34670.
63. RODRIGUEZ M, BEAUVERGER P, NAINME I et al.: Cloning and molecular characterization of the novel human melanin-concentrating hormone receptor MCH2. Mol. Pharmacol. (2002) 60(4):632-639.
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its receptors: state of the art. Can. J. Physiol. Pharmacol. (2002) 80(5):388-395.
65. AUDINOT V, LAHAYE C, SUPLY T et al.: SVK14 cells express an MCH blinding site different from the MCH1 or MCH2 receptor. Biochem. Biophys. Res. Commun. (2002) 295(4):841-848.
66. QU D, LUDWIG DS, GAMMELTOFT S et al.: A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature (1996) 380:243-244.
• A seminal paper reporting that MCH stimulates food intake.
67. ROSSI M, BLOOM SR: MCH acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology (1997) 138(1):351-355.
68. EDWARDS CMB, ABUSNANA S, SUNTER D, MURPHY KG, GHATEI MA, BLOOM SR: The effect of the orexins on food intake: comparison with NPY, MCH and galanin. J. Endocrinol. (1999) 160:R7-R12.
69. DELLA-ZUANA O, PRESSE F, ORTOLA C, DUHAULT J, NAHON JL, LEVENS N: Acute and chronic administration of MCH enhances food intake and body weight in Wistar and Sprague–Dawley rats. Int. J. Obesity (2002) 26:1-7.
70. SHIMADA M, TRITOS NA, LOWELL BB, FLIER JS, MARATOS-FLIER E: Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature (1998) 396:670-674.
• The first example that the deletion of a single prepro-neuropeptide protein can trigger hypophagia, leanness and altered metabolism.
71. LUDWIG DS, TRITOS NA, MASTAITIS JW et al.: MCH overexpression in transgenic mice leads to obesity and insulin resistance. J. Clin. Invest. (2001) 107(3):379-386.
• MCH does not only act centrally to regulate energy regulation. It also acts at the pancreatic level, and overexpression of MCH leads to pancreatic islet hypertrophy.
72. MARSH DJ, WEINGARTH DT, NOVI DE et al.: Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive and hyperphagic, and have altered metabolism. Proc. Natl. Acad. Sci. USA (2002) 99(5):3240-3245.
• MCH-R1 is involved in energy balance.
73. CHEN YY, HU CZ, HSU CK et al.: Targeted disruption of the melanin-concentrating hormone receptor-1
results in hyperphagia and resistance to diet-induced obesity. Endocrinology (2002) 143(7):2469-2477.
• MCH-R1 is involved in energy balance.
74. YAMADA M, MIKAYAMA T, DUTTAROY A et al.: Mice lacking the M3 muscarinic receptor are hypophagic and lean. Nature (2001) 410:207-212.
• An intriguing M3 knockout phenotype which may underlie the very close link between the cholinergic and MCH systems.
75. PRESSE F, SOROKOVSKI I, MAX JP, NICOLAIDIS S, NAHON JL: MCH is a potent anorectic peptide regulated by food-deprivation and glucopenia in the rat. Neuroscience (1996) 71(3):735-745.
76. GRIFFOND B, DERAY A, NGUYEN NU, COLARD C, FELLMAN D: The synthesis of melanin-concentrating hormone is stimulated by ventromedial hypothalamic lesions in the rat lateral hypothalamus: a time-course study. Neuropeptides (1995) 28:267-275.
77. HENRY BA, TILBROOK AJ, DUNSHEA FR et al.: Long-term alterations in adiposity affect the expression of melanin-concentrating hormone and enkephalin but not proopiomelanocortin in the hypothalamus of ovariectomized ewes. Endocrinology (2000) 141(4):1506-1514.
78. MONDAL MS, NAKAZATO M, MATSUKARA S: Characterization of orexins (hypocretins) and melanin-concentrating hormone in genetically obese mice. Regul. Pept. (2002) 104:21-25.
79. MIZUNO TM, KLEOPOULOS SP, BERGEN HT, ROBERTS JL, PRIEST CA, MOBBS CV: Hypothalamic POMC mRNA is reduced by fasting in ob/ob and db/db mice, but is stimulated by leptin. Diabetes (1998) 47:294-297.
80. HUANG Q, VIALE A, PICARD F, NAHON JL, RICHARD D: Effects of leptin on MCH expression in the brain of lean and obese mice. Neuroendocrinology (1999) 69:145-153.
81. ROVERE C, VIALE A, NAHON JL, KITABGI P: Impaired processing of brain pro-neurotensin and pro-melanin-concentrating hormone in obese fat/fat mice. Endocrinology (1996) 137:2954-2958.
82. HANADA R, NAKAZATO M, MUTSUKURA S, MURAKAMI N, YOSHIMATI H, SAKATA T: Differential regulation of MCH and orexin genes in the AgRP/MC4 receptor system.
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Biochem. Biophys. Res. Commun. (2000) 268:88-91.
83. TRITOS NA, ELMQUIST JK, MASTAITIS, FLIER JS, MARATOS-FLIER E: Characterization of expression of hypothalamic appetite-regulating peptides in obese hyperleptinemic brown adipose tissue-deficient (uncoupling protein-promoter-driven diphteria toxin A) mice. Endocrinology (1998) 139:4634-4641.
84. SAHU A: Evidence suggesting that galanin, MCH, neurotensin, POMC and NPY are targets of leptin signalling in the hypothalamus. Endocrinology (1998) 139(2):795-798.
85. SAHU A: Interactions of neuropeptide Y, hypocretin-I (orexin A) and melanin-concentrating hormone on feeding in rats. Brain Res. (2002) 944(1-2):232-238.
86. STRICKER-KRONGRAD A, DIMITROV T, BECK B: Central and peripheral dysregulation of melanin-concentrating hormone in obese Zucker rats. Mol. Brain Res. (2001) 92(1-2):43-48.
87. SHIMOKAWA T, KUMA MV, LANE MD: Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc. Natl. Acad. Sci. USA (2002) 99(1):66-71.
88. VERLAETEN O, GRIFFOND B, KHUTH ST et al.: Downregulation of melanin concentrating hormone in virally-induced obesity. Mol. Cell. Endocrinol. (2001) 181(1-2):207-219.
89. ZHANG P, LIAND JD, SANDUSKY GE et al.: Hypothalamic MCH mRNA protein are increased in human obesity. Satellite Symposium; 9th International Congress of Obesity, France, Proceedings of the Symposium. Int. J. Obesity (1999) P51.
90. SERGEYEV V, BROBERGER C, HOCKFELT T: Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus. Mol. Brain Res. (2001) 90:93-100.
91. MYSTKOWSKI P, SEELEY RJ, HAHN TM et al.: Hypothalamic MCH and estrogen-induced weight loss. J. Neurosci. (2000) 20(22):8637-8642.
• Is MCH a main regulator of the hypophagic effect of oestrogens?
92. ROSSI M, BEAK SA, CHOI S-J et al.: Investigation of the feeding effects of MCH on food intake – action independent of
galanin and the melanocortin receptors. Brain Res. (1999) 846:164-170.
93. LOPEZ M, SEOANE LM, GARCIA MD, DIEGUEZ C, SENARIS R: Neuropeptide Y, but not agouti-related peptide or melanin-concentrating hormone, is a target peptide for orexin-A feeding actions in the rat hypothalamus. Neuroendocrinology (2002) 75(1):34-44.
94. CLEGG DJ, AIR EL, WOODS SC, SEELEY RJ: Eating elicited by orexin-A, but not melanin-concentrating hormone, is opioid mediated. Endocrinology (2002) 143(8):2995-3000.
95. KENNEDY AR, TODD JF, STANLEY SA et al.: Melanin-concentrating hormone (MCH) suppresses thyroid stimulating hormone (TSH) release, in vivo and in vitro, via the hypothalamus and the pituitary. Endocrinology (2001) 142(7):3265-3268.
96. TADAYYON M, WELTERS HJ, HAYNES AC, CLUDERAY JE, HERVIEU G: Expression of melanin-concentrating hormone receptors in insulin-producing cells: MCH stimulates insulin release in RINm5F and CRI-G1 cell-lines. Biochem. Biophys. Res. Commun. (2000) 275(2):709-712.
97. BUIJS RM, CHUN SJ, NIIJIMA A, ROMINJ HJ, NAGAI K: Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J. Comp. Neurol. (2001) 431(4):405-423.
98. BRADLEY RL, KOKKOTOU EG, MARATOS-FLIER E, CHEATAM B: MCH regulates leptin synthesis and secretion in rat adipocytes. Diabetes (2000) 49:1073-1077.
• The first report that MCH may act directly on fat tissues.
99. BRADLEY RL, MANSFIELD JPR, MARATOS-FLIER E, CHEATAM B: Melanin-concentrating hormone activates signaling pathways in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol. Metab. (2002) 283(3):E584-E592.
100. OLDFIELD BJ, GILES ME, WATSON A, ANDERSON C, COLVILL LM, MACKINLEY MJ: The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience (2002) 110(3):515-526.
101. SUPLY T, DELLA-ZUANA O, AUDINOT V et al.: SLC-1 receptor mediates effect of melanin-concentrating
hormone on feeding behavior in rat: a structure–activity study. J. Pharmacol. Exp. Ther. (2001) 299(1):137-146.
102. MACDONALD D, MURGOLO N, ZHANG RM et al.: Molecular characterization of the melanin-concentrating hormone/receptor complex: identification of critical residues involved in binding and activation. Mol. Pharmacol. (2000) 58:217-225.
103. AUDINOT V, LAHAYE C, SUPLY T et al.: [I-125]-S36057: a new and highly potent radioligand for the melanin-concentrating hormone receptor. Br. J. Pharmacol. 133(3):371-378.
104. AUDINOT V, LAHAYE C, SUPLY T et al.: Structure–activity relationship studies of melanin-concentrating hormone (MCH)-related peptide ligands at SLC-1, the human MCH receptor. J. Biol. Chem. (2001) 276(17):13554-13562.
105. BEDNAREK MA, FEIGHNER SD, HRENIUK DL et al.: Short segment of human melanin-concentrating hormone that is sufficient for full activation of human melanin-concentrating hormone receptors 1 and 2. Biochemistry (2001)40(31):9379-9386.
106. BEDNAREK MA, HRENIUK DL, TAN C et al.: Synthesis and biological evaluation in vitro of selective, high affinity peptide antagonists of human melanin-concentrating hormone action at human melanin-concentrating hormone receptor 1. Biochemistry (2002) 41(20):6383-6390.
107. BEDNAREK MA, TAN C, HRENIUK DL et al.: Synthesis and biological evaluation in vitro of a selective, high potency peptide agonist of human melanin-concentrating hormone action at human melanin-concentrating hormone receptor 1. J. Biol. Chem. (2002) 277(16):13821-13826.
108. TAKEKAWA S, ASAMI A, ISHIHARA Y et al.: T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur. J. Pharmacol. (2002) 438(3):129-135.
109. WITTY DR, HADLEY MS, HERVIEU GJ et al.: Biphenyl carboxamide antagonists of the human melanin-concentrating hormone receptor 11CBy (SLC-1); discovery and SAR. Medicinal Chemistry Symposium, Barcelona, Spain (2002).
110. HERVIEU GJ, CLUDERAY JE, HARRISON D et al.: The distribution of the mRNA and protein products of the melanin-concentrating hormone (MCH)
Melanin-concentrating hormone functions in the nervous system: food intake and stress
510 Expert Opin. Ther. Targets (2003) 7(4)
receptor gene, slc-1, in the central nervous system of the rat. Eur. J. Neurosci. (2000) 12:1194-1216.
• A neuroanatomical study of the MCH-R1 distribution in the rat brain analysed by mRNA in situ hybridisation and immunohistochemistry.
111. SAITO Y, CHENG M, LESLIE FM, CIVELLI O: Expression of the melanin-concentrating-hormone receptor mRNA in the rat brain. J. Comp. Neurol. (2001) 435:26-42.
• A thorough neuroanatomical study of the MCH-R1 distribution in the rat brain analysed by mRNA in situ hybridisation.
112. SAWCHENCKO PE: Toward a new neurobiology of energy balance, appetite and obesity. The anatomists weigh-in. J. Comp. Neurol. (1998) 402:435-441.
• A comment making sense of the plethora of hypothalamic neuromediators regulating energy balance.
113. KILDUFF TS, DE LECEA L: Mapping of the mRNAs for the hypocretin/orexin and MCH receptors: network of overlapping peptide systems. J. Comp. Neurol. (2001) 435:1-5.
114. SCHWARTZ MW, GELLING RW: Rats lighten up with MCH antagonist. Nat. Med. (2002) 8(8):779-781.
116. NAVARRA P, TSAGARAKIS S, COY DH, REES LH, BESSER GP, GROSSMAN AB: Rat melanin concentrating hormone does not modify the release of CRH-41 from rat hypothalamus or ACTH from the anterior pituitary in vitro. J. Endocrinol. (1990) 127:R1-R4.
117. PRESSE F, HERVIEU G, IMAKI T, SAWCHENKO PE, VALE W, NAHON JL: Rat melanin-concentrating hormone messenger ribonucleic acid expression: marked changes during development and after stress and glucocorticoid stimuli. Endocrinology (1992) 131:1241-1250.
118. PARKES DG, VALE W: Secretion of melanin-concentrating hormone and neuropeptide-EI from cultured rat hypothalamic cells. Endocrinology (1992) 131:1826-1831.
119. SANCHEZ M, BAKER BI, CELIS M: Melanin-concentrating hormone (MCH) antagonizes the effects of α-MSH and neuropeptide E-I on grooming and
locomotor activities in the rat. Peptides (1997) 18:393-396.
120. GONZALEZ MI, KALIA V, HOLE DR, WILSON CA: α-MSH and MCH modify monoaminergic levels in the preoptic area of the rat. Peptides (1997) 18(3):387-392.
121. NAHON JL, PRESSE F, BRETON C, HERVIEU G, SCHORP M: Melanotropic peptides. In: Structure and regulation of the melanin-concentrating hormone gene. Ann. NY Acad. Sci. (1993) 680:111-129.
122. NAHON JL, PRESSE F: Differential regulation of melanin-concentrating hormone gene expression in distinct hypothalamic areas under osmotic stimulation in rat. Neuroscience (1993) 55:709-720.
• A study showing that the hypothalamic neuronal MCH population is heterogenous.
123. ABRAHAMSON EE, LEAK RK, MOORE RY: The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport (2001) 12(2):435-440.
• A link with the brain time pace-maker, which may be a basis to investigate the clear circadian rhythm of the MCH system.
124. PARKES DG, RIVEST S, RIVIER C, SAWCHENKO PE, VALE W: MCH and NEI activate hypothalamic CRF neurons in conscious rats, Soc. Neurosci. San Diego (1992) 18 56.3:120.
126. KRAMER MS, CUTLER N, FEIGHNER J et al.: Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science (1998) 281:1640-1645.
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128. PEEKE PM, CHROUSOS GP: Hypercortisolism and obesity. In: Stress: basic mechanisms and clinical implications. Ann. NY Acad. Sci. (1995) 711:665-676.
• A summary of evidence for how feeding and depressive disorders may be related.
129. ADAN RAH, GIPSEN WH: Brain melanocortin receptors: from cloning
to function. Peptides (1997) 18(8):1279-1287.
130. SAPER CB, THOMAS C, CHOU TC, ELMQUIST JK: The need to feed: homeostatic and hedonic control of eating. Neuron (2002) 36:199-211.
131. KEMP EH, WATERMAN EA, HAWES BE et al.: The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. J. Clin. Invest. (2002) 109(7):923-930.
• MCH was thought to have no role in mammal pigmentogenesis. This paper clearly shows that this is no longer the case.
132. HOCKFELT T: Neuropeptides in perspective: the last ten years. Neuron (1991)7:867-879.
• A classical review on neuropeptides.
133. HOCKFELT T, BROBERGER C, XU D Z-Q, SERGEYEV V, UBINK R, DIEZ M: Neuropeptides, an overview. Neuropharmacology (2000) 39:1337-1356.
• An update of the current knowledge in neuropeptidergy, 10 years after [132].
134. TAN C, SANO H, IWAASA H et al.: Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression. Genomics (2002) 79:785-792.
135. VIALE A, ORTOLA C, RICHARD F et al.: Emergence of a brain-expressed variant melanin-concentrating hormone gene during higher primate evolution: a gene ‘in search of a function’. Mol. Biol. Evol. (1998) 15:196-214.
136. VIALE A, COURSEAUX A, PRESSE F et al.: Structure and expression of the variant melanin-concentrating hormone genes: only PMCHL1 is transcribed in the developing human brain and encodes a putative protein. Mol. Biol. Evol. (1999) 17:1626-1640.
137. COURSEAUX A, NAHON JL: Birth of two chimeric genes in the Hominidae lineage. Science (2001) 2921:1293-1295.
• A summary on the puzzling late primate evolution of the MCH system. Published in the Science issue reporting the Human genome sequencing data by C Venter and Celera, Inc.
138. MILLER CL, BURMEISTER M, THOMPSON RC: Antisense expression of the human prepro-MCH gene. Brain Res. (1998) 803:86-94.
139. BORSU L, PRESSE F, NAHON JL: The AROM gene, spliced mRNAs encoding new DNA/RNA-binding proteins are transcribed from the opposite strand of the
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MCH gene in mammals. J. Biol. Chem. (2000) 275(51):40576-40587.
• A complex natural antisense case.
140. TOUMANIANTZ G, BITTENCOURT JC, NAHON JL: The rat MCH gene encodes an additional protein in a different reading frame. Endocrinology (1996) 137(10):4518-4521.
• A quasi-unique case of gene overprinting.
141. TOUMANIANTZ GFERREIRA PC, ALLAEYS I, BITTENCOURT JC, NAHON JL: Differential neuronal expression and projections of MCH and MGOP in the rat brain. Eur. J. Neurosci. (2000) 12:4367-4380.
142. VERLAET M, ADAMANTIDIS A, COUMANS B et al.: Human immune cells express ppMCH mRNA and functional MCHR1 receptor. FEBS Lett. (2002) 527(1-3):205-210.
143. HARRIS J, BIRD DJ: Supernatants from leucocytes treated with MCH and α-MSH have a stimulatory effect on rainbow trout phagocytes in vitro. Vet. Immunol. Immunopathol. (2000) 76:117-124.
144. CHAMORRO S, DELLA-ZUANA O, FAUCHERE JL et al.: Appetite suppression based on selective inhibition of NPY receptors. Int. J. Obesity (2002) 26(3):281-298.
145. CHECLER F, DAUCH P, BARELLI H, NAHON JL, VINCENT JP: Hydrolysis of
rat melanin-concentrating hormone by endopeptidase 24.11 (neutral endopeptidase). Biochem. J. (1992) 286(1):217-221.
146. VIALE A. ORTOLA C, HERVIEU G et al.: Cellular localisation and role of prohormone convertases in the processing of pro-melanin concentrating hormone. J. Biol. Chem. (1999) 274(10):6536-6545.
147. KNIGGE KM, BAXTER-GRILLO D, SPECIALE J, WAGNER J: Melanotropic peptides in the mammalian brain: the melanin-concentrating hormone. Peptides (1996) 17(6):1063-1073.
• A comparative neuroanatomical review of MCH distribution in the mammalian brain.
148. KASTIN AJ, PAN WH, MANESS LM, BANKS WA: Peptides crossing the blood–brain barrier: some unusual observations. Brain Res. (1999) 848(1-2):96-100.
149. KASTIN AJ, AKERSTROM V, HACKLER L, ZADINA JE: [Phe(13),Tyr(19)]-melanin-concentrating hormone and the blood–brain barrier: role of protein binding. J. Neurochem. (2000) 74(1):385-391.
Patents201. SCHERING CORP.:
WO02057233 (2002).
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203. SMITHKLINE BEECHAM CORP.: WO02010146 (2002).
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AffiliationGuillaume Hervieu PhDGlaxoSmithKline R&D, Drug Discovery, Neurology Centre of Excellence for Drug Discovery, New Frontiers Science Park - North, HW1713 Building H17, L1-130 C06 Third Avenue, Harlow, Essex CM19 5AW, UKTel: +44 (0)1279 622 931; Fax: +44 (0)1279 622 555;E-mail: [email protected]
