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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 yuguang@lilly.com.
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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1606 Y. Shi / Peptides 25 (2004) 16051611
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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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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