Central melanocortin system

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The central melanocortin system is defined anatomically as a collection of central nervous system circuits which include:

Contents

Mechanism of Action

The melanocortin system is a critical regulator of energy balance, in both feeding behaviors and energy expenditure, [1] as well as peripheral tissues such as skin and hair. [2] This system is a principal nexus of body weight regulation through its role in appetite and energy expenditure via leptin, ghrelin and agouti-related protein. [3] [4] It receives inputs from hormones, nutrients and afferent neural inputs, and is unique in its composition of fibers which express both agonists and antagonists of melanocortin receptors. [4] 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. [5]

Research into appetite-suppressants have further highlighted the role of the melanocortin system in weight homeostasis. Nicotine'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. [2] [6] Serotonin plays an essential role in mediating energy balance, [7] including appetite suppression and weight reduction, [8] by stimulation of the melanocortin-4 receptors, [9] as was previously hypothesized, [10] by a pathway to the brain stem via the hypothalamus, even though there are also peripheral pathways. [11] 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. [12] Selenoproteins indirectly regulate the melatocortin system via redox homeostasis. [13]

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 drugs development, [14] [15] such as setmelanotide and lorcaserin, [16] [17] but also diabetes, [18] cachexia and eating disorders such as anorexia. [19] Other drugs target the serotonergic system to indirectly affect the melanocortin system for the treatment of obesity. [18] [20] However, it is important to note that this system also elicits effects on cardiovascular and sexual function.[ citation needed ]

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. [21] Conversely, damage to this receptor has been shown to result in morbid obesity, and is the most commonly known cause of monogenic morbid obesity. [22] Mutation in an allele of the melanocortin-4 receptor causes 2-3% of childhood and adult obesity. [4] [23] [24] 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. [25]

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

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

<span class="mw-page-title-main">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

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 removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

<span class="mw-page-title-main">Leptin</span> Hormone that inhibits hunger

Leptin is a hormone predominantly made by adipose cells and its primary role is likely to regulate long-term energy balance.

Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Appetite has a relationship with every individual's behavior. Appetitive behaviour also known as approach behaviour, and consummatory behaviour, are the only processes that involve energy intake, whereas all other behaviours affect the release of energy. When stressed, appetite levels may increase and result in an increase of food intake. Decreased desire to eat is termed anorexia, while polyphagia is increased eating. Dysregulation of appetite contributes to anorexia nervosa, bulimia nervosa, cachexia, overeating, and binge eating disorder.

<span class="mw-page-title-main">Orexin</span> Neuropeptide that regulates arousal, wakefulness, and appetite.

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, is caused by a lack of orexin in the brain due to destruction of the cells that produce it. It exists in the forms of Orexin-A and Orexin-B.

The melanocyte-stimulating hormones, known collectively as MSH, also known as melanotropins or intermedins, are a family of peptide hormones and neuropeptides consisting of α-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating hormone (β-MSH), and γ-melanocyte-stimulating hormone (γ-MSH) that are produced by cells in the pars intermedia of the anterior lobe of the pituitary gland.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

Ghrelin 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 highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.

<span class="mw-page-title-main">Phentermine</span> Weight loss medication

Phentermine (phenyl-tertiary-butylamine), with several brand names including Ionamin and Sentis, is a medication used together with diet and exercise to treat obesity. It is taken by mouth for up to a few weeks at a time, after which the benefits subside. It is also available as the combination phentermine/topiramate.

<span class="mw-page-title-main">Agouti-related peptide</span> Mammalian protein found in Homo sapiens

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 nucleus in the hypothalamus. AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.

The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in chordates. Melanocortins were originally named so because their earliest known function was in melanogenesis. It is now known that the melanocortin system regulates diverse functions throughout the body, including inflammatory response, fibrosis, melanogenesis, steroidogenesis, energy homeostasis, sexual function, and exocrine gland function.

<span class="mw-page-title-main">Growth hormone secretagogue receptor</span> Protein-coding gene in the species Homo sapiens

Growth hormone secretagogue receptor(GHS-R), also known as ghrelin receptor, is a G protein-coupled receptor that binds growth hormone secretagogues (GHSs), such as ghrelin, the "hunger hormone". The role of GHS-R is thought to be in regulating energy homeostasis and body weight. In the brain, they are most highly expressed in the hypothalamus, specifically the ventromedial nucleus and arcuate nucleus. GSH-Rs are also expressed in other areas of the brain, including the ventral tegmental area, hippocampus, and substantia nigra. Outside the central nervous system, too, GSH-Rs are also found in the liver, in skeletal muscle, and even in the heart.

<span class="mw-page-title-main">Obesogen</span> Foreign chemical compound that disrupts lipid balance causing obseity

Obesogens are certain chemical compounds that are hypothesised to disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity.

<span class="mw-page-title-main">Melanocortin 4 receptor</span> Mammalian protein found in Homo sapiens

Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the MC4R gene. It encodes the MC4R protein, a G protein-coupled receptor (GPCR) that binds α-melanocyte stimulating hormone (α-MSH). In mouse models, MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.

<span class="mw-page-title-main">Melanocortin 3 receptor</span> Mammalian protein found in Homo sapiens

Melanocortin 3 receptor (MC3R) is a protein that in humans is encoded by the MC3R gene.

<span class="mw-page-title-main">Gustatory nucleus</span>

The gustatory nucleus is the rostral part of the solitary nucleus located in the medulla. The gustatory nucleus is associated with the sense of taste and has two sections, the rostral and lateral regions. A close association between the gustatory nucleus and visceral information exists for this function in the gustatory system, assisting in homeostasis - via the identification of food that might be possibly poisonous or harmful for the body. There are many gustatory nuclei in the brain stem. Each of these nuclei corresponds to three cranial nerves, the facial nerve (VII), the glossopharyngeal nerve (IX), and the vagus nerve (X) and GABA is the primary inhibitory neurotransmitter involved in its functionality. All visceral afferents in the vagus and glossopharyngeal nerves first arrive in the nucleus of the solitary tract and information from the gustatory system can then be relayed to the thalamus and cortex.

In biology, energy homeostasis, or the homeostatic control of energy balance, is a biological process that involves the coordinated homeostatic regulation of food intake and energy expenditure. The human brain, particularly the hypothalamus, plays a central role in regulating energy homeostasis and generating the sense of hunger by integrating a number of biochemical signals that transmit information about energy balance. Fifty percent of the energy from glucose metabolism is immediately converted to heat.

Hunger is a sensation that motivates the consumption of food. The sensation of hunger typically manifests after only a few hours without eating and is generally considered to be unpleasant. Satiety occurs between 5 and 20 minutes after eating. There are several theories about how the feeling of hunger arises. The desire to eat food, or appetite, is another sensation experienced with regards to eating.

<span class="mw-page-title-main">Setmelanotide</span> Chemical compound

Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation.

<span class="mw-page-title-main">Pathophysiology of obesity</span>

Pathophysiology of obesity is the study of disordered physiological processes that cause, result from, or are otherwise associated with obesity. A number of possible pathophysiological mechanisms have been identified which may contribute in the development and maintenance of obesity.

References

  1. ↑ Garfield, AS; Lam, DD; Marston, OJ; Przydzial, MJ; Heisler, LK (July 2009). "Role of central melanocortin pathways in energy homeostasis". Trends in Endocrinology and Metabolism (Review). 20 (5): 203–15. doi:10.1016/j.tem.2009.02.002. PMID   19541496. S2CID   28772158.
  2. 1 2 Hu T, Yang Z, Li MD (December 2018). "Pharmacological Effects and Regulatory Mechanisms of Tobacco Smoking Effects on Food Intake and Weight Control". Journal of Neuroimmune Pharmacology (Review). 13 (4): 453–466. doi:10.1007/s11481-018-9800-y. PMID   30054897. S2CID   51727199. Nicotine's weight effects appear to result especially from the drug's stimulation of α3β4 nicotine acetylcholine receptors (nAChRs), which are located on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), leading to activation of the melanocortin circuit, which is associated with body weight. Further, α7- and α4β2-containing nAChRs have been implicated in weight control by nicotine.
  3. ↑ Yeo, GS; Heisler, LK (October 2012). "Unraveling the brain regulation of appetite: lessons from genetics". Nature Neuroscience (Review). 15 (10): 1343–9. doi:10.1038/nn.3211. PMID   23007189. S2CID   13927767.
  4. 1 2 3 Horvath, TL; Diano, S; Tschöp, M (June 2004). "Brain circuits regulating energy homeostasis". The Neuroscientist (Review). 10 (3): 235–46. doi:10.1177/1073858403262151. PMC   2605273 . PMID   15155062.
  5. ↑ Sutton, AK; Myers MG, Jr; Olson, DP (2016). "The Role of PVH Circuits in Leptin Action and Energy Balance". Annual Review of Physiology (Review). 78: 207–21. doi:10.1146/annurev-physiol-021115-105347. PMC   5087283 . PMID   26863324.
  6. ↑ Picciotto, MR; Mineur, YS (January 2014). "Molecules and circuits involved in nicotine addiction: The many faces of smoking". Neuropharmacology (Review). 76 Pt B: 545–53. doi:10.1016/j.neuropharm.2013.04.028. PMC   3772953 . PMID   23632083. Rat studies have shown that nicotine administration can decrease food intake and body weight, with greater effects in female animals (Grunberg et al., 1987). A similar nicotine regimen also decreases body weight and fat mass in mice as a result of β4* nAChR-mediated activation of POMC neurons and subsequent activation of MC4 receptors on second order neurons in the paraventricular nucleus of the hypothalamus (Mineur et al., 2011).
  7. ↑ Tecott, LH (November 2007). "Serotonin and the orchestration of energy balance". Cell Metabolism (Review). 6 (5): 352–61. doi: 10.1016/j.cmet.2007.09.012 . PMID   17983581.
  8. ↑ Lam, DD; Garfield, AS; Marston, OJ; Shaw, J; Heisler, LK (November 2010). "Brain serotonin system in the coordination of food intake and body weight". Pharmacology, Biochemistry, and Behavior (Review). 97 (1): 84–91. doi:10.1016/j.pbb.2010.09.003. PMID   20837046. S2CID   21267163.
  9. ↑ Magalhães, CP; de Freitas, MF; Nogueira, MI; Campina, RC; Takase, LF; de Souza, SL; de Castro, RM (December 2010). "Modulatory role of serotonin on feeding behavior". Nutritional Neuroscience (Review). 13 (6): 246–55. doi:10.1179/147683010X12611460764723. PMID   21040622. S2CID   23595293. The activation of the serotonergic neurons leads to the hyperpolarization of NPY/AgRP neurons and to the depolarization of POMC/CART neurons. The combined action of 5-HT in these two groups of neurons produces hypophagia. The inhibitory effects of serotonin on NPY/AgRP neurons are mediated by 5-HT2C receptors whereas its stimulatory action on POMC/CART neurons is the result of the specific stimulation of 5-HT1B receptors. [...] The hypophagia produced by the systemic administration of mCPP is blocked by the injection at the level of the fourth ventricle of a 5-HT2A/2C receptor agonist. Moreover, the analysis of the neuronal activity of the NTS during the phase of feeding using the expression of c-Fos as indicator of cell activity showed that the catecholaminergic neurons of this nucleus are activated in response to the administration of mCPP into the fourth ventricle. Altogether, these observations sustain the idea that the anorexic effects of serotonin are also the result of its direct action in the brain stem.
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  12. ↑ Kirsz, K; Zieba, DA (1 November 2012). "A review on the effect of the photoperiod and melatonin on interactions between ghrelin and serotonin". General and Comparative Endocrinology (Review). 179 (2): 248–53. doi:10.1016/j.ygcen.2012.08.025. PMID   22974511. The administration of exogenous melatonin in rats has been reported to induce the expression of the POMC gene in the ARC. [...] The rhythm of the activity of serotonin neurons is also shown as circadian changes, with a clear downward trend during the dark phase and an increase during the light phase. The changes were revealed in the dorsal raphe nucleus (DRN), hypothalamus and striatum; and these changes are likely the result of interactions between melatonin and serotonin. Anatomic proof of the existence of direct dependence between these two hormones is demonstrated through the proximity of their receptors in the DRN. The inhibitive impact of exogenous melatonin on the immunoreactivity of serotonin neurons in the DRN was observed, and the receptor of melatonin type 1 (MT1) acted as an agent in this effect.
  13. ↑ Gong, T; Torres, DJ; Berry, MJ; Pitts, MW (1 November 2018). "Hypothalamic redox balance and leptin signaling - Emerging role of selenoproteins". Free Radical Biology & Medicine (Review). 127: 172–181. doi:10.1016/j.freeradbiomed.2018.02.038. PMC   6123311 . PMID   29518483.
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  18. 1 2 Burke, LK; Heisler, LK (June 2015). "5-hydroxytryptamine medications for the treatment of obesity". Journal of Neuroendocrinology (Review). 27 (6): 389–98. doi:10.1111/jne.12287. PMID   25925636. S2CID   3407055.
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  21. ↑ Marks, DL; Ling, N; Cone, RD (15 February 2001). "Role of the central melanocortin system in cachexia". Cancer Research. 61 (4): 1432–8. PMID   11245447.
  22. ↑ O'Rahilly, S; Farooqi, IS; Yeo, GS; Challis, BG (September 2003). "Minireview: human obesity-lessons from monogenic disorders". Endocrinology. 144 (9): 3757–64. doi: 10.1210/en.2003-0373 . PMID   12933645. MC4R deficiency represents the most commonly known monogenic disorder presenting as morbid obesity (53).
  23. ↑ Huvenne, H; Dubern, B; Clément, K; Poitou, C (2016). "Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016". Obesity Facts (Review). 9 (3): 158–73. doi:10.1159/000445061. PMC   5644891 . PMID   27241181.
  24. ↑ Cone, RD (March 1999). "The central melanocortin system and its role in energy homeostasis". Annales d'endocrinologie (Review) (in French). 60 (1): 3–9. PMID   10374010.
  25. ↑ Fairbrother, U; Kidd, E; Malagamuwa, T; Walley, A (18 August 2018). "Genetics of Severe Obesity". Current Diabetes Reports (Review). 18 (10): 85. doi:10.1007/s11892-018-1053-x. PMC   6105241 . PMID   30121879. The artificial distinction between rare monogenic obesity and common polygenic obesity is now obsolete with the identification of MC4R variants of strong effect in the general population.

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