Melanina y Emocion

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Peptides 25 (2004) 16051611

Review

Beyond skin color: emerging roles of melanin-concentrating hormonein energy homeostasis and other physiological functions

Yuguang Shi

Endocrine Research, Lilly Research Laboratories, DC 0545, Eli Lilly and Company, Lilly Corporate Center, Indianapo lis, IN 46285, USA

Received 23 January 2004; accepted 24 February 2004

Available online 11 September 2004

Abstract

Melanin-concentrating hormone (MCH) is a cyclic peptide that mediates its effects by the activation of two G-protein-coupled seven

transmembrane receptors (MCHR1 and MCHR2) in humans. In contrast to its primary role in regulating skin color in fish, MCH has evolved

in mammals to regulate dynamic physiological functions, from food intake and energy expenditure to behavior and emotion. Chronic infusion

or transgenic expression of MCHstimulates feeding and increasesadipocity, whereas targeted deletion of MCH or its receptor (MCHR1) leads

to resistance to diet-induced obesity with increased energy expenditure and thermogenesis. The involvement of MCH in energy homeostasis

and in brain activity has also been validated in mice treated with non-peptide antagonists, suggesting that blockade of MCHR1 could provide

a viable approach for treatment of obesity and certain neurological disorders. This review focuses on emerging roles of MCH in regulating

central and peripheral mechanisms.

Published by Elsevier Inc.

Keywords: Melanin-concentrating hormone; Obesity; Agonist; Antagonist; Hyperphagia; Energy expenditure; Melanocyte-stimulating hormone; Anxiety

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1605

2. MCH and pigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1606

3. MCH and energy homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1607

4. MCH receptor as a drug target for obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1608

5. MCH and social behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1609

1. Introduction

Melanin-concentrating hormone (MCH) is a cyclic pep-

tide originally isolated from the teleost fish as a pituitary

hormone that regulates skin color [35,54]. In teleost fish,

MCH causes aggregation of melanin granules thus lighten-

Tel.: +1 317 276 6753; fax: +1 317 276 9574.

E-mail address: shi [email protected].

ing the skin, and its action is antagonized by -melanocyte

stimulating hormone (-MSH) that causes melanin granule

dispersion. The mammalian MCH is a 19-amino acid peptide

that shares high homology with fish MCH, and is fully con-

served in all mammals analyzed thus far [46,47,82]. MCH is

generated via a proteolytic cleavage of the preprohormone of

165 residues, generating two additional peptides, neuropep-

tide E-I (NEI) and neuropeptide G-E (NGE). Two related

peptides are also generated from the Pmch gene that en-

0196-9781/$ see front matter. Published by Elsevier Inc.

doi:10.1016/j.peptides.2004.02.023


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codes the MCH hormone. One is the MCH-gene-overprinted-

polypeptide (MGOP peptide) produced by alternative frame

reading to theMCH codingregion, whereas theother is a pep-

tide named antisense RNA overlapping from MCH (AROM)

generated by transcription of the DNA partially overlapping

with the Pmch gene [13,21,52,78]. The function of those

MCH related peptides remains to be identified.Biological function of MCH is mediated by two G-

protein-coupled receptors known as MCHR1 and MCHR2.

MCHR1 was simultaneously identified by several groups, us-

ing different biochemical and pharmacological approaches,

and the encoding gene was found to be identical to that of the

previously cloned orphan receptor SLC-1 [4,19,38,63,64].

Human MCHR1 is closely related to the somatostatin re-

ceptor family (35% homology), and is highly homologous

with MCHR1 from other mammalian species. MCHR2 was

later identified by its limited sequence homology with a core

region of MCHR1 [2,31,45,56,61,84]. In contrast to MCHR1

that is conserved among all mammals, functional MCHR2 is

only expressed in carnivores and primates, but not in rodents[77]. The multifunctional role of MCH is accomplished

in part by the coupling of MCH receptors with different

G-proteins. MCHR1 is primarily coupled to Gi and Gq, as

evidenced by the fact that MCHR1 activation leads to

suppression of forskolin-stimulated cAMP and reduction of

intracellular Ca2+ [29]. In addition, MCHR1 activation was

also found to stimulate other signal transduction pathways,

including those mediated by protein kinase C, phospholipase

C, and extracellular signal-regulated kinase [29,51]. In

contrast, MCHR2 is believed to be exclusively coupled

to Gq [2,31,61]. The two receptors share similar tissue

distribution patterns within the CNS [68], although MCHR1is more abundant and exhibits a wider distribution pattern

than MCHR2, whose function has yet to be determined due

to its absence in rodents [77].

Physiological function of MCH and its receptors was

subjected to intensive investigation in recent years that was

stimulated by an initial observation that over-expression of

MCH was associated with the onset of obesity in ob/ob mice

[53]. Cumulative evidence suggests that MCH contributes to

a variety of physiological functions, from pigmentation and

energy homeostasis to cognation and emotion (Fig. 1).

2. MCH and pigmentation

Although MCH was originally discovered in the pitu-

itary of teleost fish for its regulation of skin melanocyte

aggregation [35,54], its function in regulating skin color

in higher mammals has not been confirmed. Coat color

in mice is controlled by complex genetic traits [83]. The

agouti protein is a major regulator of pigmentation in mice,

which antagonizes the binding of melanocyte stimulating

hormone (-MSH) to melanocortin 1 receptor (MC1R),

switching melanin synthesis from eumelanin (black/brown)

to pheomelanin (red/yellow). Dominant mutations in the

Fig. 1. Schematic representation of MCH circuitry in the brain, and its pro-

posed regulation of peripheral physiology. The arcuate nucleus (ARC) con-

tains neurons that co-express-melanocyte-stimulating hormone (-MSH),

an antagonist for MCH function, and cocaine and amphetamine-related tran-

script (CART) that are activated when there is a positive energy balance or

stimulated by leptin and insulin. The arcuate nucleus also contains neu-

rons that are responsive to food restriction through the action of neuropep-

tide Y (NPY) and agouti-related protein (AgRP). Neurons in the arcuate

nucleus project to other brain nuclei that are involved in regulation of en-

ergy balance, including lateral hypothalamus where melanocortin receptor-

containing neurons that express orexigenic neuropeptide MCH and orexin

are located, and paraventicular nucleus that contains neurons, which ex-

press anorexigenic neuropeptides corticotropin-releasing factor (CRF) and

thyroid-releasing hormone (TRH). Catabolic projections from the paraven-

ticular nucleus and anabolic input from the lateral hypothalamus determine

thenet neuronal output from thenucleus of thesolitarytract (NTS).Alterna-

tively, MCH could also have direct local action as depicted by dashed lines.

WAT, white adipose tissue; and BAT, brown adipose tissue.

non-coding region of the mouse agouti gene results in

yellow coat color, whereas ectopic expression in brain

causes obesity and type II diabetes resulting from antago-

nistic action of agouti on MC3 and MC4 receptors [55,83].

Loss-of-function mutations at the MC1R are associated

with a switch from eumelanin to pheomelanin production,

resulting in a red or yellow coat color. In man, a number

of loss-of-function mutations in MC1R are associated with

red-hair and lightening of skin color, although activating

mutations of the MC1R in man have not been reported [67].

Like agouti in mice and agouti signal protein (ASIP) in hu-

man, MCH also functionally antagonizes the action of MSH

in fish and mammals, thus expecting some effects on coat and

skin color. Yet, this has not been confirmed in animal models

of MCH physiology. Mice, with targeted deletion of MCH or

MCHR1, developed normal coat and skin color, suggesting

that the MCH is not obligated to normal development of skin


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Y. Shi / Peptides 25 (2004) 16051611 1607

color in rodents. However, due to some differences in MCH

function between rodents and humans, the possible regula-

tory role of MCH on skin and hair color in humans cannot be

ruled out. For example, MCH binding sites were identified in

human SVK14 keratinocytes, and both MCH and its recep-

tor are expressed and functional in human skin [18,32,65], as

demonstrated by inhibition of the melanogenic actions of-MSH by MCH in cultured human melanocytes. Furthermore,

autoantibodies against the MCHR1 were recently identified

in patients with vitiligo, a common depigmentation disorder

resulting from the destruction of functional melanocytes in

the affected skin [25,37], although a causative role of the

autoantibodies remains to be elucidated. Since MCH is al-

most exclusively expressed in the brain, and melanocytes are

mainly derived from the neural crest cells [85], it is not yet

clear whether the MCHeffect on melanocytes is of peripheral

or central origin (Fig. 1). Nevertheless, these findings neces-

sitate further investigation to confirm a role of MCH on skin

and hair pigmentation.

3. MCH and energy homeostasis

Although MCH was originally named as a melanin-

concentrating hormone for its involvement in regulating skin

color, it plays an even greater role in regulating physiological

functions in the CNS of both fish [1,28,49] and higher mam-

mals [34,47,50]. Cumulative evidence suggests that MCH

plays an important role in maintaining energy homeostasis

by regulating satiety, energy expenditure, and thermogenesis.

The expression of both MCH and MCHR1 is up-regulated by

genetic obesity and fooddeprivation [27,30,39,53]. Intracere-broventricular (ICV)injectionof MCHstimulatesfood intake

in rats, which can be functionally antagonized by MSH, an

inhibitor of appetite [39,58,79]. Chronic infusion of MCH or

a peptide agonist induces hyperphagia and body weight gain

[33], whereas continuous treatment of mice with a MCHR1

peptide antagonist suppresses appetite and adipocity [72].

Further evidence regarding a role of MCH in regulating

energy homeostasis comes from animal models with genetic

manipulation of MCH or MCHR1 expression. Transgenic

expression of MCH leads to increased susceptibility to obe-

sity and insulin resistance [40]. Targeted deletion of MCH

and MCHR1 also supports a role for MCH in regulating en-

ergy homeostasis. Mice lacking MCH are lean as a result

of hypophagia and a slightly increased metabolic rate [73].

Likewise, knockout mice with MCHR1 deficiency are resis-

tant to obesity with increased energy expenditure [20,41].

However, in comparison with hypophagia in MCH knock

out mice, MCHR1-null mice present hyperphagia and hy-

peractivity. Such differences are likely caused by deletion

of MCH related peptides such as NEI, NGE, AROM, and

MGOP [13,21,52,78], since MCHR1 has been demonstrated

to be the only functional receptor for MCH-mediated activity

in mice [77]. Consistent with a role for these peptides in con-

tributing to the MCH knockout phenotype, NEI is reported

to stimulate exploratory behavior, increase anxiety, and re-

duce dopamine release [24]. NEI is also shown to antagonize

the action of MCH on stress-induced release of adrenocorti-

cotropin [11].

As part of the complex central network involved in regula-

tion of satiety and energy expenditure [5,16,22,66,70], MCH

plays an important role in mediating the effects of leptin onenergy homeostasis [34,69]. As such, leptin deficiency in

ob/ob mice was demonstrated to significantly increase MCH

expression, whereas leptin administration leads to a dramatic

decrease of MCH [53,60]. Ablation of MCH expression in

ob/ob mice corrects the obese phenotype by increasing rest-

ing energy expenditure and locomotive activity [71]. The

data suggest that MCH functions downstream in the leptin-

mediated signal transduction pathway. However, ablation of

MCH expression only partially corrects the defective physio-

logical effects of leptin deficiency, since the double-null mice

still exhibit hyperphagia and hyperinsulinemia [71]. MCH is

exclusively expressed in the lateral hypothalamus and zona

incerta in close proximity with orexin containing neurons.MCH-expressing neurons project to nucleus of the solitary

tract (NTS) (Fig. 1), parabrachial nucleus, and medial pre-

frontal cortex regions, establishing connections throughout

the brain [9,10,62]. Thus, alteration in MCH expression is ex-

pected to change orexigenic peptide expression in the arcuate

nucleus (ARC), such as neuropeptide Y (NPY) and agouti-

related protein (AgRP), or orexin in the lateral hypothalamus.

As a result of MCHdeficiency, POMC expression in the ARC

is markedly diminished to counterbalance the diminution in

satiety and body weight [71]. Such a compensatory change in

POMC expression is not caused by lack of direct antagonism

at the melanocortin receptors, as MCH and -MSH do notcompete with each other in receptor binding [39,57].

In addition to a role in the central regulation of the feed-

ing response, MCH also plays a role in regulating the levels

of insulin, glucocorticoid, and thermogenesis (Fig. 1). Trans-

genic over-expression and targeted deletion of MCH have

reciprocal effects on glucocorticoid and insulin levels. In ad-

dition to hyperinsulinemia, transgenic mice over-expressing

MCH also developed islet cell hyperplasia, suggesting a se-

vere insulin resistance. In supporting a role of MCH in reg-

ulating thermogenesis, chronic infusion of MCH was shown

to significantly decrease rectal temperatures and the expres-

sion of uncoupling protein-1 expression in brown adipose

tissue [33], whereas mice deficient both in leptin and MCH

demonstrated an increase in basal body temperature and re-

sistance to cold exposure [71]. As part of changes elucidated

by MCH infusion, there is a significant reduction in mRNA

expression of key molecules involved in fatty acid oxida-

tion in the brown adipose tissue (BAT), including acyl-CoA

oxidase and carnitine palmitoyltransferase, suggesting that

MCH infusion might impair BAT functions [33]. Addition-

ally, MCH deficiency in ob/ob mice causes a reduction in

the expression of stearoyl-CoA desaturase-1, another medi-

ator of the obese phenotype in ob/ob mice [48]. MCH is

also reported to stimulate leptin mRNA expression and lep-


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tin secretion [14], and activates signaling pathways in 3T3-

L1 adipocytes [14,15], suggesting a role in regulating white

adipocyte function. In addition, MCHR1 expression is also

reported in insulin-producing RINm5F and CRI-G1 cell-lines

that are responsive to MCH-stimulated insulin release [75].

It is not clear whether these peripheral effects are centrally

mediated by local synthesis of MCH or through paracrineregulation. For example, second-order neurons in both vagal

and sympathetic innervation of the pancreas are reported to

contain neuropeptides that control food intake [17].

4. MCH receptor as a drug target for obesity

Obesity is a common problem in Western societies and

is associated with significant morbidity and mortality. Due

to limited treatment options, the disease represents a large

unmet medical condition. As a result, pharmaceutical and

biotech companies have invested significant amount of ef-

forts and resources in the search for a novel treatment.

As one of the orexigenic neuropeptides involved in central

regulation of energy homeostasis, MCH has been subjected

to intensive scrutinization for its potential as a target for obe-

sity drug development. A number of highly potent cyclic

peptide analogs were developed as peptide agonists and an-

tagonists from structureactivity relationship studies of MCH

and MCHR [3,68,74]. It was demonstrated that an MCH

analog consisting of the cyclic core with arginine attached

to the N-terminus of the disulfide ring was sufficient to acti-

vate both MCHR1 and MCHR2 as effectively as full-length

MCH [6] (Fig. 2). The analog was equally effective as MCH

in inducing food intake in short-term treatment, and adipoc-ity with chronic administration when compared with MCH

[72,74]. Similarly, a series of analogs with antagonist activ-

ity were also generated [7]. A potent antagonist was devel-

oped by replacement of Leu9-Gly10 and Arg14-Pro15 with

Fig. 2. The structure of MCH and its peptide analogs. Ava, 5-aminovaleric

acid.

5-aminovaleric acid, and the analog demonstrated antago-

nistic activity against MCH [7,72]. When tested in rats, the

antagonist attenuated the orexigenic effects of an agonist,

but was ineffective on food intake when given alone [72].

Development of these peptide analogs provides useful tools

for exploring physiology mediated by MCHR1, and for fur-

ther validation of the receptor as a drug target for obesity.However, development of peptide antagonists as a potential

treatment for obesity faces significant challenges due to their

required route of delivery acrossthe blood brain barrier, since

no direct peripheral MCH effects have been reported thus far.

As a member of the G-protein-coupled receptor super

family that are amenable to drug screening, cloning of both

MCHR1 and MCHR2 hasfacilitated the development of cell-

based assays for high-throughput screening of small MCH

antagonist molecules. Development of non-peptide antago-

nists affords direct testing of those compounds for efficacy

by peripheral injection or feeding without the complica-

tion associated with ICV injection. Two of the non-peptide

MCHR1 antagonists discovered by high throughput and tar-geted screenings were recently reported to be effective in

treating diet-induced obesity in rodents [23] (Fig. 3). The

first non-peptide antagonist, T-226296, is an orally active

compound that demonstrated a high affinity and selective

binding to MCHR1 (Ki = 5.5 nM), but not MCHR2 and

other homologous receptors [76]. The compound inhibites

MCH-stimulated arachidonic acid release in heterologous

expression systems, and also reverses the MCH-mediated in-

hibition of forskolin-stimulated cAMP accumulation as well

as MCH-induced Ca2+ release. T-226296 exhibits a good

oral bioavailability and brain penetrability, and oral admin-

istration in rats reverses the hyperphagia induced by ICVinjection of exogenous MCH [76]. No further analysis was

Fig. 3. Chemical structures of two MCHR1 antagonists.


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reported on the potential of T-226296 on energy expenditure

and its effectiveness in treating diet-induced obesity.

A second non-peptide antagonist compound, SNAP-7941,

was identified by screening of a GPCR-biased compound li-

brary against MCHR1 in a functional assay measuring in-

tracellular Ca2+ mobilization [12]. The compound possesses

more than 1000-fold selectivity for MCHR1 compared withthe human MCHR2 and other related GPCRs. Radio-labeled

SNAP-7941 specifically binds to MCHR1 in brain sections

in a pattern that parallels that of the MCHR1 expression in

differentregions of the brain, including cerebral cortex, olfac-

tory tubercle, claustrum, and piriform cortex. Chronic injec-

tion of the compound decreases food intake and body weight,

andblocks theonset of diet-inducedobesity [12]. The anorec-

tic effect of SNAP-7941 was unlikely caused by malaise, as

verified by a taste aversion study. In comparison with fenflu-

ramine, an antiobesity drug with significant toxic side effects

[59], the compound causes more sustained weight reduction

in diet-induced obesity that is much less reversible in weight

gain after termination of treatment.

5. MCH and social behaviors

One of the surprising observations from the treatment of

rats with SNAP-7941 is the antipsychotic effect of the com-

pound on mood and emotion, which is supported by binding

sites of the compound in areas such as the amygdala, accum-

bens nucleus, dorsal raphe, and locus coeruleus [12,26,62].

Rats treated with a single oral dose of SNAP-7941 spend

much less immobile time in the forced-swim test, which

is comparable with the effect of the typical antidepressantdrug, fluoxitine. The compound is also effective in treating

anxiety, as evidenced by a significant increase in social

time of rats treated with 30 mg/kg SNAP-7941 or 5 mg/kg

chlordiazepoxide, an anxiolytic drug, when compared with

vehicle-treated controls. These results are consistent with

hyperactivity observed in MCHR1 knockout mice [20,41],

but contrast to a previous reports that central administration

of MCH caused anxiolytic activity [36,42,44]. Further

analysis is needed to verify whether the antipsychotic

activity of SNAP-7941 is caused by blocking of the MCH

activity, or by its off target activity on other unknown brain

targets. This can be examined by comparing the compound

with other antagonists of equal efficacy, or by testing the

compound in MCHR1 knockout mice. In addition, MCH

has been reported to affect other brain activities, such as

learning ability and memory retention in rats [42,43,80,81],

which remain to be validated in the MCHR1 knockout mice

or with the small molecular antagonists.

6. Conclusions

Characterization of MCH in genetically obese rodent

models and in mice with targeted deletion of MCH and

MCHR1 firmly establishes a role of the hormone in regulat-

ing energy homeostasis. MCH, the only neuropeptide in the

hypothalamus that gives rise to significant changes in energy

metabolism when ablated in mice, hasattracted significant at-

tention by the pharmaceutical industry in an effort to develop

non-peptide antagonists as a treatment for obesity. Demon-

stration of two small molecular weight antagonists, effectivein treating animal models of obesity, have partially validated

such an approach, although specificity of these compounds

remains to be confirmed in mice deficient in MCHR1 expres-

sion. However,major questions remain aboutthe mechanisms

regarding the regulatory roles of MCH in energy homeostasis

and neurological functions. For example, significant differ-

ences exist between the MCH and MCHR1 knockout mice

as to the causes for weight loss. There are also differences

between human and rodents in MCH function as evidenced

by the lack of a functional MCHR2 receptor in mice and rats.

Thus, precautions have to be taken when interpreting data

from rodents in relation to human physiology of MCH me-

diated events, such as changes in energy expenditure and be-haviors observed in mice with targeted deletion of MCHR1or

mice treated with antagonist compounds. Furthermore, due

to a lack of an animal model, it remains a challenge to in-

vestigate the physiological function of MCHR2 in humans.

Finally, the wide distribution of MCHR1 expressing neurons

in the brain suggests multifunctional roles for MCH in regu-

lating brain activity, such as behavior, olfaction, memory, and

emotions, which remain to be investigated in future studies.

Acknowledgements

The author would like to thank Drs. Jose Caro, Lawrence

Slieker, and Mark Heiman for insightful comments and help-

ful suggestions, and John Lockwood for critically reading the

manuscript.

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