Melanin-concentrating hormone (MCH), also known as pro-melanin stimulating hormone (PMCH), is a cyclic 19-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

orexigenic hypothalamic

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

originally isolated from the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The h ...

teleost fish Teleostei (; Greek ''teleios'' "complete" + ''osteon'' "bone"), members of which are known as teleosts ), is, by far, the largest infraclass in the class Actinopterygii, the ray-finned fishes, containing 96% of all extant species of fish. Tel ...

, where it controls skin pigmentation. In mammals it is involved in the regulation of feeding behavior, mood, sleep-wake cycle and energy balance.

Structure

MCH is a cyclic 19-amino acid

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like t ...

, as it is a polypeptide chain that is able to act as a

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

. MCH neurons are mainly concentrated in the

lateral hypothalamic area The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognit ...

zona incerta The zona incerta (ZI) is a horizontally elongated region of gray matter in the subthalamus below the thalamus. Its connections project extensively over the brain from the cerebral cortex down into the spinal cord. Its function is unknown, though ...

, and the incerto-hypothalamic area, but they are also located, in much smaller amounts, in the paramedian pontine reticular formation (PPRF), medial preoptic area,

laterodorsal tegmental nucleus The laterodorsal tegmental nucleus (or lateroposterior tegmental nucleus) is a nucleus situated in the brainstem, spanning the midbrain tegmentum and the pontine tegmentum. Its location is one-third of the way from the pedunculopontine nucleus ...

, and the

olfactory tubercle The olfactory tubercle (OT), also known as the tuberculum olfactorium, is a multi-sensory processing center that is contained within the olfactory cortex and ventral striatum and plays a role in reward cognition. The OT has also been shown to ...

. MCH is activated by binding to two G-coupled protein receptors ( GCPRs), MCHR1 and

MCHR2 Melanin-concentrating hormone receptor 2 (MCH2) also known as G-protein coupled receptor 145 (GPR145) is a protein that in humans is encoded by the ''MCHR2'' gene. MCH2 is also found in dogs, ferrets, and some other primates and carnivores, but is ...

. MCHR2 has only been identified in certain species such as humans, dogs, ferrets, and rhesus monkeys, while other mammals such as rodents and rabbits do not have the receptor. MCH is cleaved from prepro-MCH (ppMCH), a 165 amino acid polypeptide which also contains the neuropeptides GE and EI.

Tissue distribution

MCH has also been found in peripheral structures outside of the brain. Both the spleen and

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or '' T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders ...

have shown significant levels of MCH in mammals in multiple studies. The bloodstream seems to carry MCH around the body in mammals as well, though it is a very amount in humans. MCH is found in the laterodorsal tegmental nucleus solely in female brains in rat models. MCH has also only been found in the medial preoptic area and the paraventricular hypothalamic nucleus during lactation.

Activation and deactivation

MCH neurons depolarize in response to high glucose concentrations. This mechanism seems to be related to glucose being used as a reactant to form ATP, which also causes MCH neurons to depolarize. The neurotransmitter,

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

, also causes MCH neurons to depolarize, while another neurotransmitter, GABA, causes MCH neurons to hyperpolarize. Orexin also depolarizes MCH neurons. MCH neurons seems to have an inhibitory response to MCH, but does not cause the neurons to become hyperpolarized.

Norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

has an inhibitory effect on MCH neurons as does

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

. MCH neurons hyperpolarize in response to

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

. Cannabinoids have an excitatory effect on MCH neurons. Some research has shown that dopamine has an inhibitory effect on MCH neurons, but further research is needed to fully characterize this interaction.

Function

Sleep

MCH and the hormone

orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy) ...

have an antagonistic relationship with one another with regards to the sleep cycle, with orexin being almost entirely active during wake periods and MCH being more active during sleep periods. MCH also promotes sleep, and within a sleep period increased levels of MCH seem to increase the amount of time spent in REM sleep and slow waves sleep. Increased levels of MCH can also increase the amount of time spent in both

REM Rem or REM may refer to: Music * R.E.M., an American rock band * ''R.E.M.'' (EP), by Green * "R.E.M." (song), by Ariana Grande Organizations * La République En Marche!, a French centrist political party * Reichserziehungsministerium, in Nazi ...

and NREM, which in turn increases total sleep duration. Increased levels of sugar promotes MCH and its effect on sleep and conserving energy.

Maternal behavior

The presence of MCH in specific locations solely during lactation is thought to help to promote maternal behavior in individuals.

Eating behaviors and energy conservation

An increased presence of MCH can cause increased eating levels and has been linked to an increase in body mass. Inversely, a decrease in the amount of MCH present can cause decreased levels in eating. Increased amounts of MCH in olfactory regions, among others, have also been linked to an increased intake of fatty foods with high caloric content. Food that is found to taste good also seems to promote MCH, which reinforces the eating of that food. Sugar, specifically glucose, seems to promote MCH's role in sleep and energy conservation. This promoting of energy conservation has also been linked to higher body mass even when diet is controlled.

Reproduction

It has been postulated that MCH has a modulatory role with the release of

Luteinizing Hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...

(LH) either by directly acting on the pituitary gland or indirectly by affecting Gonadotropin-releasing hormone (GNRH) in the hypothalamus.

Estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

seems to be necessary in order for MCH to affect reproduction.

Skin pigmentation

Though MCH was initially discovered for its role of determining the pigmentation in fish, trying to determine MCH's role in skin pigmentation in mammals has been much more difficult to determine. However, MCHR1 has been found in human

melanocyte Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and hear ...

s and some melanoma cells, so MCH is able to bind to these cells as well as

keratinocyte Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...

s though they do not express MCHR1. In melanocytes, MCH seems to have an antagonistic relationship with

α-MSH α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone and neuropeptide of the melanocortin family, with a tridecapeptide structure and the amino acid sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. It ...

, and decreased melanin production. Though, more information is needed to fully understand MCH's relationship with skin pigmentation in mammals.

Clinical significance

Narcolepsy

While MCH does promote sleep, there has been no research that links MCH to narcolepsy. Research has instead found that in individuals with narcolepsy there is a decrease in orexin neurons, which would promote wakefulness, while the number of MCH neurons do not vary from the average non-narcoleptic individual.

Depression and anxiety

MCH has been linked to depression and anxiety. MCHR1 antagonists have been show to act as antidepressants.

Anorexia

Interactions between MCH and

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...

s that lead to an overall decrease in MCH release and neuron excitability has been linked with infection-induced anorexia. Chemokines and cytokines often appear as the result of inflammation or infection, and they can then damage MCH neurons, which can lead to anorexia in an individual.

Skin cancers

MCH has been identified in both

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

and

squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...

cell lines. However, pro-MCH, a precursor to MCH, has not been found in melanocytes, keratinocytes, or fibroblasts, which might indicate MCH might be brought into these cells by macrophages as part of the immune response. More research is needed to fully determine and understand any relationship between MCH and possible immune responses in skin.

History

MCH was initially discovered in the teleost fish; it was found to help determine the fish's skin color. Later, a mammalian version of MCH was discovered in rats, where most of the functions and localizations are conserved across mammalian species.

References

External links

* {{Orexigenics Peptides