Central melanocortin system

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Updated leptin–melanocortin model

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

  • Neurons that express hypothalamic neuropeptide Y and agouti gene-related protein or proopiomelanocortin and that originate in the arcuate nucleus
    .
  • Brainstem 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

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

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.

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]

References

  1. S2CID 28772158
    .
  2. ^
    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. S2CID 13927767
    .
  4. ^
    PMID 15155062
    .
  5. PMID 26863324
    .
  6. 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. PMID 17983581
    .
  8. S2CID 21267163
    .
  9. 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.
  10. S2CID 28219196
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  11. PMID 23543912
    .
  12. 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. PMID 29518483
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  14. PMID 12176114
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  15. PMID 20002079
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  16. PMID 29388462
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  17. S2CID 38418965
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  18. ^
    S2CID 3407055
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  19. S2CID 3523740
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  20. S2CID 21392044
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  21. PMID 11245447
    .
  22. PMID 12933645
    . MC4R deficiency represents the most commonly known monogenic disorder presenting as morbid obesity (53).
  23. PMID 27241181
    .
  24. PMID 10374010
    .
  25. 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.

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
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