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, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

circuits which include: *

Neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

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. It is secreted alongside other neurotransmitters such as GABA and glu ...

and agouti gene-related protein or

proopiomelanocortin Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is Protein biosynthesis, synthesized in Corticotropic cell, corticotrophs of the anterior pituitary from the 267-amino-acid-long Precursor polypeptide, pol ...

(POMC) and that originate in the

arcuate nucleus The arcuate nucleus of the hypothalamus (ARH), or ARC, is also known as the infundibular nucleus to distinguish it from the arcuate nucleus of the medulla oblongata in the brainstem. The arcuate nucleus is an aggregation of neurons in the medio ...

. *

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 conti ...

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, 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"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...

ghrelin Ghrelin (; or lenomorelin, INN) is a hormone primarily 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 ghrel ...

and agouti-related protein. It receives inputs from

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

, 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 melanocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus.

Serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

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 excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and con ...

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 pat ...

and

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

, but also

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

cachexia Cachexia () is a syndrome that happens when people have certain illnesses, causing muscle loss that cannot be fully reversed with improved nutrition. It is most common in diseases like cancer, Heart failure, congestive heart failure, chronic o ...

and

eating disorders An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's health, physical or mental health, mental health. These behaviors may include eating too much food or too little food. Types of eatin ...

such as

anorexia Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. Individuals wit ...

. Other drugs target the serotonergic system 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