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 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.

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]

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.
  10. ↑ Zhou, L; Williams, T; Lachey, JL; Kishi, T; Cowley, MA; Heisler, LK (October 2005). "Serotonergic pathways converge upon central melanocortin systems to regulate energy balance". Peptides. 26 (10): 1728–32. doi:10.1016/j.peptides.2004.12.028. PMID 15993514. S2CID 28219196.
  11. ↑ Donovan, MH; Tecott, LH (2013). "Serotonin and the regulation of mammalian energy balance". Frontiers in Neuroscience. 7: 36. doi:10.3389/fnins.2013.00036. PMC 3608917. PMID 23543912.
  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.
  14. ↑ MacNeil, DJ; Howard, AD; Guan, X; Fong, TM; Nargund, RP; Bednarek, MA; Goulet, MT; Weinberg, DH; Strack, AM; Marsh, DJ; Chen, HY; Shen, CP; Chen, AS; Rosenblum, CI; MacNeil, T; Tota, M; MacIntyre, ED; Van der Ploeg, LH (16 August 2002). "The role of melanocortins in body weight regulation: opportunities for the treatment of obesity". European Journal of Pharmacology (Review). 450 (1): 93–109. doi:10.1016/s0014-2999(02)01989-1. PMID 12176114.
  15. ↑ Sargent, BJ; Moore, NA (December 2009). "New central targets for the treatment of obesity". British Journal of Clinical Pharmacology (Review). 68 (6): 852–60. doi:10.1111/j.1365-2125.2009.03550.x. PMC 2810796. PMID 20002079.
  16. ↑ Patel, DK; Stanford, FC (March 2018). "Safety and tolerability of new-generation anti-obesity medications: a narrative review". Postgraduate Medicine (Narrative review). 130 (2): 173–182. doi:10.1080/00325481.2018.1435129. PMC 6261426. PMID 29388462.
  17. ↑ Greenway, FL; Shanahan, W; Fain, R; Ma, T; Rubino, D (October 2016). "Safety and tolerability review of lorcaserin in clinical trials". Clinical Obesity (Review). 6 (5): 285–95. doi:10.1111/cob.12159. PMID 27627785. S2CID 38418965.
  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.
  19. ↑ Molfino, A; Laviano, A; Rossi Fanelli, F (December 2010). "Contribution of anorexia to tissue wasting in cachexia". Current Opinion in Supportive and Palliative Care (Review). 4 (4): 249–53. doi:10.1097/SPC.0b013e32833e4aa5. PMID 20693907. S2CID 3523740.
  20. ↑ Halford, Jason C. G.; Boyland, Emma J.; Lawton, Clare L.; Blundell, John E.; Harrold, Joanne A. (2011). "Serotonergic Anti-Obesity Agents". Drugs. 71 (17): 2247–2255. doi:10.2165/11596680-000000000-00000. ISSN 1179-1950. PMID 22085383. S2CID 21392044.
  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.

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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