The central melanocortin system is defined anatomically as a collection of

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

circuits which include: *

Neurons A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

that express hypothalamic

neuropeptide Y Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...

and agouti gene-related protein or

proopiomelanocortin Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the r ...

and that originate in the

arcuate nucleus The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...

. *

Brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...

proopiomelanocortic neurons (POMC neurons) originating in the commissural nucleus of the solitary tract (cNTS). *Downstream targets of these proopiomelanocortic and agouti related protein neurons expressing the melanocortin-3 and melanocortin-4 receptors

Mechanism of Action

The melanocortin system is a critical regulator of

energy balance Energy balance may refer to: * Earth's energy balance, the relationship between incoming solar radiation, outgoing radiation of all types, and global temperature change. * Energy accounting, a system used within industry, where measuring and anal ...

, in both feeding behaviors and energy expenditure, as well as peripheral tissues such as skin and hair. This system is a principal nexus of body weight regulation through its role in appetite and energy expenditure via

leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate Energy homeostasis, energy balance by inhib ...

ghrelin Ghrelin (; or lenomorelin, INN) is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highe ...

and

agouti-related protein Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nu ...

. It receives inputs from

hormones A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and beh ...

, nutrients and afferent neural inputs, and is unique in its composition of fibers which express both agonists and antagonists of melanocortin receptors. Much of what is known about brain control's of overall energy balance and fat storage stem from the discoveries about the hypothalamic melanocortin system and leptin. Research into appetite-suppressants have further highlighted the role of the melanocortin system in weight homeostasis.

Nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

's appetite-suppressant effect appears to result from nicotine's stimulation of α3β4 nAChR receptors located in the POMC neurons in the arcuate nucleus and subsequently the melanocortin system via the melatocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus.

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 vas ...

plays an essential role in mediating energy balance, including appetite suppression and weight reduction, by stimulation of the melanocortin-4 receptors, as was previously hypothesized, by a pathway to the brain stem via the hypothalamus, even though there are also peripheral pathways. Circadian rhythm signals also affect the melanocortin system, both directly with melatonin affecting POMC gene expression in the arcuate nucleas, and indirectly via the interdependence between serotonin and melatonin cycles.

Selenoprotein In molecular biology a selenoprotein is any protein that includes a selenocysteine (Sec, U, Se-Cys) amino acid residue. Among functionally characterized selenoproteins are five glutathione peroxidases (GPX) and three thioredoxin reductases, (TrxR/TX ...

s indirectly regulate the melatocortin system via redox homeostasis.

Therapeutic Implications

Due to the essential role of melanocortins in the regulation of body weight and appetite, they are a target of choice for

anti-obesity drug Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control weight. These medications alter one of the fundamental processes of the human body, weight regulation, by altering either appetite, or absorpt ...

s development, such as

setmelanotide Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation. The most common side effects include injection site reactions, skin hyperpigmentation (skin patc ...

and

lorcaserin Lorcaserin, marketed under the brand name Belviq was a weight-loss drug developed by Arena Pharmaceuticals. It reduces appetite by activating a type of serotonin receptor known as the 5-HT2C receptor in a region of the brain called the hypothal ...

, but also

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

cachexia Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart f ...

and

eating disorders An eating disorder is a mental disorder defined by abnormal eating behaviors that negatively affect a person's physical or mental health. Only one eating disorder can be diagnosed at a given time. Types of eating disorders include binge eating ...

such as

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

. Other drugs target the

serotonergic system 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 vas ...

to indirectly affect the melanocortin system for the treatment of obesity. However, it is important to note that this system also elicits effects on cardiovascular and sexual function. Stimulation of the melanocortin-4 receptor causes a decrease in appetite and an increase in metabolism of fat and lean body mass, even in a relatively starved state. Conversely, damage to this receptor has been shown to result in morbid obesity, and is the most commonly known cause of monogenic morbid obesity. Mutation in an allele of the melanocortin-4 receptor causes 2-3% of childhood and adult obesity. Deficiencies and mutations in the melanocortin-4 receptors were also identified in the general population, thus rendering obsolete the distinction between rare monogenic obesity and common polygenic obesity.

References

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Additional bibliography

*Cone (2005) ''Anatomy and Regulation of the Central Melanocortin System'' Nature Neuroscience 7: 1048-54 *Daniel L. Marks, Nicholas Ling and Roger D. Cone (2001) ''Role of the Central Melanocortin System in Cachexia'' Cancer Research 61, 1432- 1438 *Joyce J. Hwa, Lorraine Ghibaudi, Jun Gao, and Eric M. Parker (2001) ''Central melanocortin system modulates energy intake and expenditure of obese and lean Zucker rats'' AJP-Regulatory, Integrative and Comparative Physiology Vol. 281, Issue 2, R444-R451 Central nervous system