Central melanocortin system: Difference between revisions

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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]]s development,<ref>{{cite journal |last1=MacNeil |first1=DJ |last2=Howard |first2=AD |last3=Guan |first3=X |last4=Fong |first4=TM |last5=Nargund |first5=RP |last6=Bednarek |first6=MA |last7=Goulet |first7=MT |last8=Weinberg |first8=DH |last9=Strack |first9=AM |last10=Marsh |first10=DJ |last11=Chen |first11=HY |last12=Shen |first12=CP |last13=Chen |first13=AS |last14=Rosenblum |first14=CI |last15=MacNeil |first15=T |last16=Tota |first16=M |last17=MacIntyre |first17=ED |last18=Van der Ploeg |first18=LH |title=The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. |journal=European journal of pharmacology |date=16 August 2002 |volume=450 |issue=1 |pages=93-109 |doi=10.1016/s0014-2999(02)01989-1 |pmid=12176114 |type=Review}}</ref> such as [[setmelanotide]] and [[lorcaserin]].<ref>{{cite journal |last1=Patel |first1=DK |last2=Stanford |first2=FC |title=Safety and tolerability of new-generation anti-obesity medications: a narrative review. |journal=Postgraduate medicine |date=March 2018 |volume=130 |issue=2 |pages=173-182 |doi=10.1080/00325481.2018.1435129 |pmid=29388462 |type=Narrative review}}</ref><ref>{{cite journal |last1=Greenway |first1=FL |last2=Shanahan |first2=W |last3=Fain |first3=R |last4=Ma |first4=T |last5=Rubino |first5=D |title=Safety and tolerability review of lorcaserin in clinical trials. |journal=Clinical obesity |date=October 2016 |volume=6 |issue=5 |pages=285-95 |doi=10.1111/cob.12159 |pmid=27627785 |type=Review}}</ref> However, it is important to note that this system also elicits effects on cardiovascular and sexual function.{{citationneeded}}
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]]s development,<ref>{{cite journal |last1=MacNeil |first1=DJ |last2=Howard |first2=AD |last3=Guan |first3=X |last4=Fong |first4=TM |last5=Nargund |first5=RP |last6=Bednarek |first6=MA |last7=Goulet |first7=MT |last8=Weinberg |first8=DH |last9=Strack |first9=AM |last10=Marsh |first10=DJ |last11=Chen |first11=HY |last12=Shen |first12=CP |last13=Chen |first13=AS |last14=Rosenblum |first14=CI |last15=MacNeil |first15=T |last16=Tota |first16=M |last17=MacIntyre |first17=ED |last18=Van der Ploeg |first18=LH |title=The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. |journal=European journal of pharmacology |date=16 August 2002 |volume=450 |issue=1 |pages=93-109 |doi=10.1016/s0014-2999(02)01989-1 |pmid=12176114 |type=Review}}</ref> such as [[setmelanotide]] and [[lorcaserin]].<ref>{{cite journal |last1=Patel |first1=DK |last2=Stanford |first2=FC |title=Safety and tolerability of new-generation anti-obesity medications: a narrative review. |journal=Postgraduate medicine |date=March 2018 |volume=130 |issue=2 |pages=173-182 |doi=10.1080/00325481.2018.1435129 |pmid=29388462 |type=Narrative review}}</ref><ref>{{cite journal |last1=Greenway |first1=FL |last2=Shanahan |first2=W |last3=Fain |first3=R |last4=Ma |first4=T |last5=Rubino |first5=D |title=Safety and tolerability review of lorcaserin in clinical trials. |journal=Clinical obesity |date=October 2016 |volume=6 |issue=5 |pages=285-95 |doi=10.1111/cob.12159 |pmid=27627785 |type=Review}}</ref> However, it is important to note that this system also elicits effects on cardiovascular and sexual function.{{citationneeded}}


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 [[Proopiomelanocortin|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.<ref name=HuYang2018 /><ref name="Picciotto2014">{{cite journal |last1=Picciotto |first1=MR |last2=Mineur |first2=YS |title=Molecules and circuits involved in nicotine addiction: The many faces of smoking. |journal=Neuropharmacology |date=January 2014 |volume=76 Pt B |pages=545-53 |doi=10.1016/j.neuropharm.2013.04.028 |pmid=23632083 |type=Review |quote=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).}}</ref> [[Serotonin]] also has an appetite-suppressant effect, by stimulation of the melanocortin-4 receptors,<ref>{{cite journal |last1=Magalhães |first1=CP |last2=de Freitas |first2=MF |last3=Nogueira |first3=MI |last4=Campina |first4=RC |last5=Takase |first5=LF |last6=de Souza |first6=SL |last7=de Castro |first7=RM |title=Modulatory role of serotonin on feeding behavior. |journal=Nutritional neuroscience |date=December 2010 |volume=13 |issue=6 |pages=246-55 |doi=10.1179/147683010X12611460764723 |pmid=21040622 |type=Review |quote=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.}}</ref> as was previously hypothesized.<ref>{{cite journal |last1=Zhou |first1=L |last2=Williams |first2=T |last3=Lachey |first3=JL |last4=Kishi |first4=T |last5=Cowley |first5=MA |last6=Heisler |first6=LK |title=Serotonergic pathways converge upon central melanocortin systems to regulate energy balance. |journal=Peptides |date=October 2005 |volume=26 |issue=10 |pages=1728-32 |doi=10.1016/j.peptides.2004.12.028 |pmid=15993514}}</ref>
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 [[Proopiomelanocortin|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.<ref name=HuYang2018 /><ref name="Picciotto2014">{{cite journal |last1=Picciotto |first1=MR |last2=Mineur |first2=YS |title=Molecules and circuits involved in nicotine addiction: The many faces of smoking. |journal=Neuropharmacology |date=January 2014 |volume=76 Pt B |pages=545-53 |doi=10.1016/j.neuropharm.2013.04.028 |pmid=23632083 |type=Review |quote=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).}}</ref> [[Serotonin]] also has an appetite-suppressant effect, by stimulation of the melanocortin-4 receptors,<ref>{{cite journal |last1=Magalhães |first1=CP |last2=de Freitas |first2=MF |last3=Nogueira |first3=MI |last4=Campina |first4=RC |last5=Takase |first5=LF |last6=de Souza |first6=SL |last7=de Castro |first7=RM |title=Modulatory role of serotonin on feeding behavior. |journal=Nutritional neuroscience |date=December 2010 |volume=13 |issue=6 |pages=246-55 |doi=10.1179/147683010X12611460764723 |pmid=21040622 |type=Review |quote=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.}}</ref> as was previously hypothesized,<ref>{{cite journal |last1=Zhou |first1=L |last2=Williams |first2=T |last3=Lachey |first3=JL |last4=Kishi |first4=T |last5=Cowley |first5=MA |last6=Heisler |first6=LK |title=Serotonergic pathways converge upon central melanocortin systems to regulate energy balance. |journal=Peptides |date=October 2005 |volume=26 |issue=10 |pages=1728-32 |doi=10.1016/j.peptides.2004.12.028 |pmid=15993514}}</ref> by a pathway to the brain stem via the hypothalamus, even though there are also peripheral pathways.<ref>{{cite journal |last1=Donovan |first1=MH |last2=Tecott |first2=LH |title=Serotonin and the regulation of mammalian energy balance. |journal=Frontiers in neuroscience |date=2013 |volume=7 |pages=36 |doi=10.3389/fnins.2013.00036 |pmid=23543912}}</ref>


== Therapeutic Implications ==
== Therapeutic Implications ==

Revision as of 06:41, 5 November 2019

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 body weight and peripheral tissue such as skin and hair.[1] This system is essential in body weight regulation through its role in appetite and energy expenditure via Leptin, Ghrelin and Agouti-related protein.[2] 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.[2]

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,[3] such as setmelanotide and lorcaserin.[4][5] However, it is important to note that this system also elicits effects on cardiovascular and sexual function.[citation needed]

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 melatocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus.[1][6] Serotonin also has an appetite-suppressant effect, by stimulation of the melanocortin-4 receptors,[7] as was previously hypothesized,[8] by a pathway to the brain stem via the hypothalamus, even though there are also peripheral pathways.[9]

Therapeutic Implications

This system is a target for drugs which treat obesity, diabetes and cachexia. 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.[10] Conversely, damage to this receptor has been shown to result in morbid obesity, and is the most commonly known cause of monogenic morbid obesity.[11] Mutation in an allele of the melanocortin-4 receptor causes 2-3% of childhood and adult obesity.[2][12][13] 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.[14]

References

  1. ^ a b 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. 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.
  2. ^ a b c Horvath, TL; Diano, S; Tschöp, M (June 2004). "Brain circuits regulating energy homeostasis". The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry (Review). 10 (3): 235–46. doi:10.1177/1073858403262151. PMID 15155062.
  3. ^ 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.
  4. ^ 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. PMID 29388462.
  5. ^ 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.
  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. 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. ^ 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. 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.
  8. ^ 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.
  9. ^ Donovan, MH; Tecott, LH (2013). "Serotonin and the regulation of mammalian energy balance". Frontiers in neuroscience. 7: 36. doi:10.3389/fnins.2013.00036. PMID 23543912.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ 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.
  11. ^ 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).
  12. ^ 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. PMID 27241181.
  13. ^ 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.
  14. ^ 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. 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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