1 Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109; and 2 Merck Research Laboratories, Rahway, New Jersey 07065
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ABSTRACT |
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The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.
inflammation; obesity; pigmentation; sexual function; receptor
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INTRODUCTION |
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THE MELANOCORTIN SYSTEM consists of
1) the melanocortin peptides -,
-, and
-melanocyte-stimulating hormone (
-,
-,
-MSH) and
adrenocorticotropic hormone (ACTH), 2) a family of five
seven-transmembrane G protein-coupled melanocortin receptors,
and 3) the endogenous melanocortin antagonists agouti and
agouti-related protein (AGRP). In addition, two ancillary proteins,
mahogany and syndecan-3, have been found that modulate the activity of
the melanocortin peptides (melanocortins). This minireview is meant to
introduce the melanocortin system to the unacquainted reader.
The melanocortins are involved in an extraordinarily diverse number of physiological functions, including pigmentation, steroidogenesis, energy homeostasis, exocrine secretion, sexual function, analgesia, inflammation, immunomodulation, temperature control, cardiovascular regulation, and neuromuscular regeneration. On the basis of their prominent regulatory role in many of these functions, the development of melanocortin-based drugs is currently being considered, or is presently in the developmental phase, for the treatment of skin cancer and other cutaneous disorders, obesity, anorexia nervosa and cachexia, erectile dysfunction, inflammatory diseases, pain, and nerve injury. The physiological basis for considering melanocortins as central participants in some of the aforementioned processes will be discussed.
The first portion of this minireview will present, largely in isolation, the various elements of the melanocortin system. These elements will then be discussed in the context of four physiological functions: pigmentation, inflammation, energy homeostasis, and sexual behavior. With the use of this approach, however, there is an inevitable overlap of organization.
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COMPONENTS OF THE MELANOCORTIN SYSTEM |
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Proopiomelanocortin Prohormone
The melanocortins are posttranslational products of the proopiomelanocortin (POMC) prohormone. This prohormone also gives rise to the opiate peptideThe POMC gene is expressed primarily in the central nervous system (CNS), where it is expressed in the pituitary, arcuate nucleus of the hypothalamus, and nucleus of the solitary tract in the brain stem. The POMC gene is also expressed by cutaneous keratinocytes and melanocytes. In addition, POMC mRNA and immunoreactivity have been reported in a number of peripheral human tissues, including genitourinary tract, gastrointestinal tract, adrenal, spleen, lung, and thyroid and in cells of the immune system (52).
Melanocortin Receptors
There are five G protein-coupled melanocortin receptors (MCRs), which are all linked to cAMP generation via the stimulatory G protein Gs and adenylate cyclase. However, MCR signaling has also been associated with increases in intracellular Ca2+ concentration secondary to activation of inositol trisphosphate (25), influx of extracellular Ca2+ (24), and activation of the MAP kinase (15), janus kinase/signal transducer and activator of transcription (7), and PKC pathways (23). Importantly, the five MCRs have differing affinities for the melanocortins and the endogenous antagonists agouti and AGRP (Table 1).
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MC1R is the "classical" melanocyte -MSH receptor. It is
expressed by cutaneous melanocytes, where it has a key role in
determining skin and hair pigmentation. However, other cell types in
the skin also express MC1R, including keratinocytes, fibroblasts,
endothelial cells, and antigen-presenting cells (31).
Other tissues and cell types have also been found to express MC1R
(9). In this respect, it is notable that MC1R is expressed
by leukocytes, where it mediates the anti-inflammatory and
immunomodulatory properties of melanocortins.
MC2R is the classical adrenocortical ACTH receptor. It is expressed in
the adrenal cortex zona reticularis and zona fasiculata, where it
mediates the effects of ACTH on steroid secretion. Notably, it is
distinguished pharmacologically from the other MCR subtypes in that it
is activated only by ACTH and has no affinity for -,
-, or
-MSH (Table 1). A rare human autosomal recessive disorder, hereditary isolated glucocorticoid deficiency, is caused by mutations in MC2R (44). Attention has been paid to the fact that
MC2R is also expressed by adipose tissue in mice and humans
(52). Although ACTH is lypolytic in mice, it is not so in
humans, and the function of MC2R in human adipose tissue is presently unclear.
MC3R is expressed in many areas of the CNS and in several peripheral
tissues, including the gastrointestinal tract and placenta (9). All of the melanocortins are roughly equipotent at
MC3R (Table 1). Notably, among the MCR subtypes, -MSH has its
greatest affinity at MC3R, an observation that is assumed to be of
physiological significance. Of importance, MC3R is involved in energy
homeostasis (see The Melanocortin System and Energy
Homeostasis).
MC4R is expressed predominantly in the CNS. As is the case with MC3R, it is involved in energy homeostasis. More recently, MC4R has been shown to be involved in sexual function (see Melanocortins and Sexual Function).
MC5R is expressed in numerous human peripheral tissues, including adrenal gland, adipocytes, leukocytes, and many others (9). It also has a very limited distribution in the CNS. The only firmly established function of MC5R, which was discovered by targeted deletion of that receptor, is its participation in exocrine function, particularly sebaceous gland secretion (11). Although the role of melanocortins in sebaceous gland function had been reported some 20 years earlier (42), their role in that process received little attention until this recent discovery. The role of MC5R in exocrine secretion has the potential to be exploited for the treatment of skin disorders such as acne and dermatitis.
Endogenous Antagonists
Perhaps one of the most interesting aspects of the melanocortin system is that it has two endogenous antagonists, agouti and AGRP. These proteins are unique in that no inhibitory proteins have been identified for any of the seven-transmembrane receptor family. Agouti and AGRP are paracrine signaling molecules, which are endogenous antagonists of the MCRs (13). Of physiological significance, agouti and AGRP have MCR subtype selectivity (Table 1). Interestingly, agouti and AGRP both have a cysteine-rich COOH-terminal domain. Although the structure of agouti has not been resolved, nuclear magnetic resonance studies demonstrate that the cysteine residues in AGRP adopt a structural motif called an inhibitor cystine knot (32). This motif is common to invertebrate toxins, but in mammals this structure is unique to AGRP and, presumably, agouti. Another commonality is that agouti and AGRP have both been shown in vitro to be inverse agonists (33). Thus they have the potential in vivo to regulate their respective MCRs, even in the absence of melanocortins.The term agouti refers to a hair color pattern commonly seen in
mammals, which is characterized by a subapical yellow band on an
otherwise black or brown background. Historically, scientific interest
in the agouti locus extended beyond its effect on coat color. Dominant mutations of the agouti gene cause
mice to develop yellow fur, obesity, insulin resistance, increased
somatic growth, and a predispostion to tumorigenesis. With the
isolation of the gene encoding agouti, it was noted that these
pleiotropic effects were associated with a deregulated expression of
agouti in all tissues (6). Subsequent investigations have
demonstrated that the obesity displayed by these mutant mice is
secondary to the ectopic expression of agouti in the hypothalamus,
where it acts as an antagonist of -MSH at MC4R (30). In
light of recent discoveries that hypothalamic
-MSH is a major
satiety factor that transmits its message by activating MC4R, the
hyperphagia and resultant obesity of those animals are readily understood.
The normal role of agouti, however, is to act in conjunction with
-MSH and MC1R to determine mammalian coat color. Agouti is produced
by the dermal papillae cell and acts on the adjacent melanocyte to
block melanocortin action at MC1R. This interaction has a major effect
on pigmentation (see Melanocortins and Pigmentation). Pharmacologically, agouti is a high-affinity, competitive antagonist of
the melanocortin peptides at MC1R and MC4R. In rodents, agouti is
expressed only in skin. The human homolog of agouti, called agouti-signaling protein (ASP), has a wider pattern of expression, including adipose tissue, testis, ovary, and heart and lower levels of
expression in foreskin, kidney, and liver (54). However, humans do not have a banded agouti-like hair pattern, and the role of
ASP in hair and skin pigmentation in humans is doubtful. At the present
time, the physiological function(s) of ASP in humans is unknown.
Subsequent to the discovery of agouti, AGRP was identified by database searches for molecules with homology to agouti (34). AGRP is a competitive antagonist of MC3R and MC4R that is equipotent at both of those receptors. AGRP has little activity at the other MCRs. AGRP is expressed primarily in the arcuate nucleus of the hypothalamus, the subthalamic region, and the adrenal cortex, with a small amount of expression observed in the lung and kidney. However, its major physiological function is in the hypothalamus, where AGRP acts as a potent orexigenic (appetite-stimulating) factor due to its ability to antagonize melanocortins at MC3R and MC4R. Very low levels of circulating AGRP have been found in both rat and human (40). An interesting question that remains to be answered is the physiological role of AGRP in the adrenal. The adrenal is the tissue with the second highest concentration of AGRP. However, human and rat adrenals have been reported to express only the MC2R and MC5R receptors with no affinity for AGRP, and the adrenal is apparently not the origin of blood-borne AGRP in rats, since adrenalectomy does not affect blood levels.
Ancillary Proteins
Mahogany and syndecan-3 are proteins that modulate the activity of agouti and AGRP, respectively. Although both have convincingly been shown to interact with agouti and AGRP, important questions remain to be answered about those interactions.Mahogany is a single-pass transmembrane protein that is expressed primarily in brain, including the hypothalamus, and skin (18). It is clear that mahogany is involved in mammalian coat coloration. In mice, there is an absolute requirement for functional mahogany protein for the action of agouti. The mahogany mutation completely suppresses the obesity and yellow hair coloration of dominant agouti mutations. Mahogany has been shown to be a low-affinity receptor for agouti but not AGRP (19). However, it is difficult to reconcile the dramatic effect that mahogany mutations have on dominant agouti mutations simply in terms of the loss of a low-affinity receptor. In addition, mahogany appears to have effects on metabolic rate independent of its suppression of agouti mutations (14). Therefore, it would seem that the convergence of mahogany with the melanocortin pathway is still incompletely understood.
Syndecan-3 is a heparan sulfate proteoglycan, a class of single-pass
transmembrane molecules whose ectodomain is shed from the cell surface
in response to defined stimuli. Importantly, syndecans are molecules
that bind extracellular ligands. Awareness of the involvement of
syndecan-3 with the melanocortin system arose from the observation that
transgenic mice that overexpress the related molecule syndecan-1
display obesity similar to that of transgenic mice that overexpress
AGRP or mice with dominant agouti mutants (37).
It was hypothesized that misexpression of syndecan-1 in the
hypothalamus mimicked a physiological modulator of feeding behavior.
Because syndecan-1 is not normally found in the hypothalamus, attention
was drawn to syndecan-3, which is. Indeed, syndecan-3 has been shown in
pharmacological assays to augment AGRP antagonism of -MSH at MC4R.
The data suggest that syndecan-3 might act as an AGRP coreceptor. The
affinity of this interaction is presently unknown. However,
syndecan-3-null mice do not have a phenotype, and the only feeding
abnormality that they display is decreased reflex hyperphagia after
fasting. This raises some question about the importance of the
syndecan-3-AGRP interaction, although compensatory mechanisms could
certainly be called into account. Nonetheless, it is noteworthy that
food deprivation increases hypothalamic syndecan-3 more than fourfold. According to one model, in the food-deprived state, syndecan-3 is
upregulated on the surface of hypothalamic neurons expressing MC3R and
MC4R. This would increase local concentrations of AGRP and promote an
orexigenic state. In the fed state, the ectodomain of syndecan-3 is
shed and the local concentrations of AGRP fall. This allows increased
activity of
-MSH at MC3R and MC4R and promotes a sated state. Of
course, regulation of AGRP release occurs independently in those
states, and the relative contribution of syndecan-3 to AGRP function is
presently unknown.
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SELECTED FUNCTIONS |
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The four functions of the melanocortins that are perhaps most heavily studied at the present time are their role in pigmentation, inflammation, energy homeostasis, and sexual function. These functions are briefly discussed below.
Melanocortins and Pigmentation
In mammals, skin, coat, and hair color are determined by the relative ratio of phaeomelanin (yellow/red pigment) to eumelanin (brown/black pigment) produced by the melanocyte. In fur-bearing mammals, both MC1R and agouti affect this ratio. Activation of MC1R byMutations of MC1R also have profound effects on pigmentation. Both gain-of-function and loss-of-function mutations of MC1R have been shown to alter pigmentation in a range of species (38). MC1R is also highly polymorphic in humans (39). Certain allelic variants of the gene in humans are associated with red hair and pale skin (46). Although human pigmentation is genetically complex, to date only polymorphism at MC1R has been associated with phenotypic changes. The relationship of MC1R variants to melanoma and nonmelanoma skin cancer has been the subject of controversy.
In humans, -MSH and ACTH produced locally in the skin have a major
role in pigmentation (41). The production of both peptides is upregulated in the keratinocyte by UV radiation, and they act as
paracrine factors that stimulate the melanocyte to produce eumelanin.
-MSH is also produced by the melanocyte and may act as an autocrine
factor that affects eumelanin synthesis and melanocyte morphology and
as a paracrine factor that protects the melanocyte against immune
system damage. MC1R has also been reported to be upregulated by UV
radiation. The contribution of centrally produced
-MSH, which
circulates at an extremely low level in humans, and serum ACTH to
pigmentation in humans in nonpathological states has yet to be determined.
Melanocortins and Inflammation
The melanocortins have significant anti-inflammatory properties (8, 31). The administration ofThe Melanocortin System and Energy Homeostasis
Although earlier publications had firmly implicated melanocortins in the inhibition of food intake on the basis of the observation that injection of ACTH (1-24) into the lateral ventricle or ventromedial hypothalamic nucleus inhibited food intake in rats (48) and that POMC mRNA levels were regulated by metabolic state (3), it was not until 1994 that researchers took greater notice of the melanocortin system as a mediator of feeding behavior. By that time, the MCRs had been cloned, and it was known that MC3R and MC4R were expressed in the hypothalamus, a CNS region that controls many physiological functions, including feeding behavior. Importantly, that year it was discovered that agouti was a potent antagonist of MC4R (30). It was hypothesized that the obesity of mice with dominant mutations of the agouti gene was due to overexpression of agouti in the hypothalamus and its antagonism of MC4R. Several publications in 1997 (16, 21, 34) solidified these observations into a coherent framework. First, it was demonstrated that the newly developed MC4R antagonist SHU-9119 could block the inhibition of food intake induced by the nonspecific melanocortin agonist MT-II (16). Second, it was reported that targeted deletion of MC4R resulted in obesity associated with hyperphagia (21). Finally, the endogenous agouti-like orexigenic factor AGRP was discovered (34).These observations set the stage for a multitude of studies that have
continued up to the present, which have established the hypothalamic
melanocortin system (MC4R, POMC peptides, and AGRP) as one of the
convergence points for peripheral and central factors that regulate
feeding behavior and metabolism. Although -MSH is presumed to be the
most relevant melanocortin involved in energy regulation within the
hypothalamus, POMC neurons probably release a complex soup of POMC
peptides (35). More recently, it has been demonstrated
that MC3R is also involved in energy homeostasis. MC3R-null mice have a
loss of lean body mass and an increase in subcutaneous fat while
maintaining a relatively normal body weight (10).
Notably, the aforementioned observations extend to humans. It has been estimated that MC4R mutations occur in 4% of severely obese French individuals (45). Not only is the hypothalamic melanocortin system involved in obesity, it has also been implicated in cachexia (27) and anorexia (5) in rodents.
Whole animal, neuroanatomical, and electrophysiological studies
continue to confirm the importance of the melanocortin system in
feeding behavior and metabolism. POMC-containing neurons have been
shown to be the site of convergence of a variety of peripheral and
central hormones, neurotransmitters, and nutrients involved in feeding
behavior. By use of an electrophysiological slice preparation, it has
been shown that the activity of POMC neurons can be affected either
directly or indirectly by leptin, insulin, glucose, ghrelin, peptide
YY, neuropeptide Y, -endorphin, serotonin, GABA,
melanin-concentrating hormone, and orexins (12, 17, 20).
In turn, projections of POMC and AGRP neurons project to other
hypothalamic centers that modulate feeding and metabolism
(4). In this respect, it is notable that the dopaminergic
system, which has been implicated in both energy homeostasis and sexual
function (see Melanocortins and Sexual Function), is
modulated by melanocortin receptor agonists (28, 29).
Although the aforesaid describes a hypothalamic centric melanocortin feeding model, the hindbrain is also an important site of melanocortin action (53). POMC peptides and MC3R and MC4R are expressed in the hindbrain, and it has been shown that subnanomolar concentrations of MT-II or SHU-9119 administered into that region have effects on feeding behavior similar to those observed in the hypothalamus.
Although in vivo experimental evidence indicates the importance of AGRP in energy homeostasis, recently it was shown that AGRP-null mice have no phenotype and display normal feeding behavior (36). The majority of obesity researchers at the present time think that this observation is due to compensatory mechanisms and that it highlights the redundancy of orexigenic pathways.
The central role of the melanocortin system in feeding behavior has made it an attractive target for the development of antiobesity agents. This is particularly true for MC4R.
Melanocortins and Sexual Function
The involvement of the melanocortin system in sexual function has been known since the 1960s, when it was observed that injection of ACTH orImportantly, in small (10 subjects), double-blind, placebo-controlled crossover studies, subcutaneous administration of the nonselective MCR agonist MT-II evoked spontaneous penile erections in men with either psychogenic or organic erectile dysfunction (50, 51). The percentage of responders who had erections of sufficient rigidity for sexual intercourse (as determined by penile tumescence monitoring and patient self-reporting) was 94% (psychogenic) and 70% (organic), although subjects did not necessarily respond to both of the injections administered.
-MSH has been reported to influence female sexual behavior in rats
(43). However, its influence on female sexual behavior is
less clear, because, depending on receptivity levels, ACTH-MSH peptides
increased or decreased sexual behavior. There is presently no
information on the effects of melanocortins on human female sexual response.
Recently, the role of MC4R in mediating the peripheral actions of melanocortin effects on erectile function and copulatory behavior in male rodents was elucidated in studies using a highly selective tetrahydroisoquinoline (THIQ) MC4R agonist and MC4R-null mice (47). THIQ was shown to augment electrically evoked intracavernosal pressure in mice, an effect that was absent in MC4R-null mice and independent of direct action on cavernosal smooth muscle. The efficacy of this effect is comparable to that of sildenafil (Viagra) in certain rodent models. MC4R-null mice were also found to have impaired copulatory behavior, although a breeding colony of these animals could be established. Of significance, it was demonstrated that MC4R mRNA was expressed in tissues that modulate erectile function, including the spinal cord and pelvic ganglion of rats and the penis of both rats and humans, providing an anatomical basis for melanocortin effects on sexual function. The cellular source of melanocortins mediating these effects is still unknown. In addition, these studies do not prove that MC4R is the only MCR involved in the peripheral action of melanocortins on sexual function. Nonetheless, the studies do demonstrate that administration of an MC4R agonist is sufficient to elicit melanocortin effects on sexual function.
Presently, it is thought that melanocortin modulation of sexual function is due to both central and peripheral actions. Because it appears that the full complement of melanocortin-mediated sexual responses can be elicited by peripheral administration of a selective MC4R agonist, this may become one of the therapeutic uses for such an agent. On the other hand, it may also represent an undesirable side effect to the use of such agonists for the treatment of obesity.
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SUMMARY |
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In the past 10 years, substantial progress has been made in understanding the physiological functions of the melanocortin system. In that time, cloning of the various components of the melanocortin system, the application of gene targeting technology, and the development of selective pharmacological agents have provided insight into the biological basis for the protean effects of the melanocortins.
The role of melanocortins MC3R, MC4R, and AGRP in metabolic regulation
and the role of -MSH and the MC4R in sexual function have received a
great deal of attention and have provided a framework to explore the
melanocortin system for the treatment of obesity, other metabolic
abnormalities, and sexual dysfunction. The role of the melanocortins in
pigmentation can now be understood in the context of MC1R variants and
the competition among ACTH-MSH peptides and agouti. Expression of MC1R
by leukocytes begins to unravel the role of the melanocortins in
inflammation and immunomodulation. The role of MC5R in exocrine
function has opened new avenues for dermatological research. Although
development of highly selective agonists and antagonists for MC1R and
MC5R has lagged behind the pace of drug development directed at MC3R
and MC4R, future identification of such compounds promises to lead to
an even greater understanding of the roles of melanocortins in normal
and pathological physiology.
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ACKNOWLEDGEMENTS |
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We thank Drs. James Lipton and Hunter Wessels for helpful discussions. Because of constraints on the number of references, we apologize to the many researchers who were not cited.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant 1RO1 DK-54032-01 (I. Gantz) and the University of Michigan Gastrointestinal Peptide Research Center (NIDDK Grant P30 DK-34933).
Address for reprint requests and other correspondence: I. Gantz, Univ. of Michigan Medical School, 6504 MSRB I, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0682 (E-mail: Igantz{at}Umich.edu).
10.1152/ajpendo.00434.2002
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