Zheng-Yong Wen*, Yuan-Chao Zou, Chuan-Jie Qin*, Deng-Yue Yuan and Rui Li
College of Life Sciences, Conservation and Utilization of Fishes resources in the Upper Reaches of the Yangtze River Key Laboratory of Sichuan Province, Neijiang Normal University, Neijiang, Sichuan 641100, China
Received: 23 December, 2016; Accepted: 16 January, 2017; Published: 20 January, 2017
*Corresponding author:
Zheng-Yong Wen, College of Life Sciences, Neijiang Normal University, Neijiang, Sichuan 641100, China, Tel: + 86 18582681220; Fax: + 86 18582681220; E-mail: @;
*Corresponding author:
Chuan-Jie Qin, College of Life Sciences, Neijiang Normal University, Neijiang, Sichuan 641100, China, Tel: + 86 18582681220; Fax: + 86 18582681220; E-mail: @;
Wen ZY, Zou YC, Qin CJ, Yuan DY, Li R (2017) Melanocortin-4 Receptor in Fish: A Review. Int J Agric Sc Food Technol 3(1): 001-004. DOI: 10.17352/2455-815X.000014
© 2017 Wen ZY, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The melanocortin-4 receptor (MC4R) belongs to the melanocortin system, has been well investigated in mammals. Which plays important roles in several physiological processes, such as regulating energy homeostasis, cachexia, cardiovascular function, glucose and lipid homeostasis, reproduction and sexual function, drug abuse, pain perception, brain inflammation, and anxiety. Although there are some studies have performed, its role still remain mystery in fish. This review will summarize the studies on the fish MC4R from its cloning and tissue distribution to its physiological roles. Which should be useful for further studies in fish and might provide a new insight in aquaculture industry


The melanocortin system is an ancient system conserved from teleosts to mammals. It consists of four agonists, two antagonists, and five receptors. The four agonists including α, β, and γ melanocyte-stimulating hormone (MSH), and adrenocorticotropin (ACTH), are derived from tissue-specific posttranslational processing of the prohormone proopiomelanocortin (POMC) [1-3]. The two endogenous antagonists are consist of agouti and agouti related peptide (AgRP), Agouti is an antagonist for MC1R whereas AgRP for MC3R and MC4R [2,4]. The five melanocortin receptors are called melanocortin receptors 1-5 (MC1R-MC5R) based on the sequence of their cloning. They are all members of Family A G protein coupled receptors (GPCRs) consisting of seven transmembrane domains (TMs) connected by alternating intracellular and extracellular loops, with the N-terminus extracellular, and the C-terminus intracellular [5-7].

MC4R is a member of family A GPCRs with seven TMs connected by alternating extracellular loops (ELs) and intracellular loops. The molecular processes involved in the binding of the MSH peptides to the MC4R were extensively studied. Most notably, the acidic residues Asp122/126 (TM3) and the basic residue His264 (TM4) are essential for ligand binding [8].

The human MC4R is an intron less gene with an open reading frame of 999 bp that encodes a protein of 332 amino acids. Alignment of MC4R with other MCRs showed that it has the highest homology with the MC3R, with 58% identity and 76% similarity. By fluorescent in situ hybridization, the MC4R gene was localized to chromosome 18q21.3 [9,10].

Since the cloning of hMC4R, the MC4R has been cloned from mouse, rat, hamster, guinea pig, dog, cat, fox, pig, sheep, cow, and several primates including marmoset, cynomolgus macaque, vervet monkey, and orangutan. It has also been cloned from several nonmammalian species including fish, chicken, and pigeon. The amino acid sequences between the different species are highly conserved [11,12].

It has been proved that MC4R is involved in regulating energy homeostasis in mammals [7]. Knockout of the MC4R resulted in increased food intake and decreased energy expenditure therefore obesity in mouse [13]. A similar phenotype is also observed in mice ubiquitously overexpressing Agouti or AgRP genes [14,15]. The frameshift mutations found in MC4R lead to a dominant form of obesity in human [16,17]. Furthermore, central administration of the MC4R agonist α-MSH has been shown to inhibit appetite and increase basal metabolic rate [18]. Conversely, MC4R antagonism by AgRP results in hyperphagia and decreased metabolic activity.

Recent years, despite the MC4R has been cloned from several fishes, the physiological functions are still very limited to us. Herein we summarize the studies of MC4R in fish, including the molecular cloning, tissue distribution and physiology, which should be useful for us to understand the MC4R evolutionary history in vertebrate, as well as improving the aquaculture industry.

Molecular cloning of the fish MC4R

The MC4R was first cloned from zebrafish in 2002 [19], since then, more and more MC4R were cloned from different fishes. To date, there are more than twenty fish MC4R can be found in the National Center for Biotechnology Information database (NCBI:, including Osteichyes fishes, Chondrichthyes fishes and Cyclostomata fishes (Table 1). The Osteichyes fishes are the primary investigated object involved in five orders inculding Perciformes (Dicentrarchus labrax, Scatophagus argus, Astatotilapia burtoni and Channa argus), Pleuronectiformes (Verasper moseri and Paralichthys olivaceus), Tetraodontiforms (Takifugu rubripes, Takifugu chinensis and Tetraodon nigroviridis), Salmoniforms (Oncorhynchus mykiss) and Cypriniforms (Danio rerio, Cyprinus carpio, Carassius auratus, Ctenopharyngodon idella, Luciobrama microcephalus, Schizothorax prenanti and Xiphophorus maculatus). The Chondrichthyes fishes involved in three Orders including Squaliformes (Squalus acanthias), Heterodontiformes (Heterondotus francisci) and Myliobatiformes (Dasyatis akajei). The Cyclostomata fish only including one kind of Petromyzoniformes fish (Lampetra fluviatilis).

  1. avatar

    Table 1:

    Melanocortin-4 receptor identified from the main fish species.

Tissue distribution of the fish MC4R

In mammals, over the past two decades, since the initial cloning [9,36], significant attention has been paid to the melanocortin-4 receptor (MC4R), due to its central expression and roles in regulation of energy homeostasis and body weight. Simultaneously, it also expressed in some peripheral tissues such as heart, lung, kidney medulla, renal nerve, ureter, intercostal muscle and skull bone [37]. The extensive expression of mammalian MC4R suggested it could be involved in many physiological processes.

In tetrapods, five MCRs (MC1R-MC5R) have been identified. Of the five MCRs, only MC3R and MC4R are significantly expressed within the central nervous system, hence these two MCRs are also called neural MCRs [38,39]. MC4R is also expressed in some peripheral tissues such as enteroendocrine L cells [40].

In fish, the MC4R is extensively expressed in a variety of tissues. Cerda-Reverter et al. reported that MC4R was expressed in gill, spleen, retina, and ovaries in goldfish [27], Kobayashi et al. and Ringholm et al. reported that the flounder MC4R was mainly expressed in liver, ovary, and testis [19,22]. Li et al., reported that the spotted scats MC4R was found to be expressed in the brain, pituitary, and gonads in both male and female [21]. Further research showed that common carp MC4R was highly expressed in brain, testis, and eye, followed by expression in the pituitary and heart [26]. Recent study on grass carp showed that MC4R was found to be highly expressed in the brain and eye, but expressed at low levels in the muscle, heart, intestine, liver, gill, spleen, and kidney [28]. The extensive expression pattern of MC4R in fish suggested it might act as different physiological functions in different tissues.

Physiology of the fish MC4R

Regulating food intake and energy homeostasis: The roles of mammalian MC4R in regulating energy homeostasis were well studied [7]. MC4R knockout mice exhibit maturity-onset obesity, hyperphagia, increased linear growth, hyperinsulinemia, hyperglycemia, and delayed meal termination and reduced sensitivity to cholecystokinin [13]. Conversely, MC4R over expressed mice found to be obese, similar to mice over-expressing AgRP [41]. In addition, Human genetic studies demonstrated that mutations in MC4R are the most common form of monogenic obesity, characterized by its early-onset and severity [2,16,17,39]. These studies suggest that MC4R plays a key role in regulating energy homeostasis and body weight in mammals including human.

Recent studies showed that the mechanism of regulation of energy homeostasis by the MC4R is also operational in lower vertebrates including fish. In goldfish, ICV injection of NDP-MSH or MTII inhibits food intake, whereas the MC4R-specific antagonist HS024 increases food intake [27,42]. These experiments suggested that the MC4R is exerting a tonic inhibitory effect on food intake. Similar results were obtained in rainbow trout, ICV injection of MTII decreases food intake, whereas ICV injection of HS024 and the MC3/4R antagonist SHU9119 increases food intake in rainbow trout [43]. Moreover, nonsynonymous mutations in cavefish MC4R are identified to contribute to enhanced appetite, growth, and starvation resistance [44]. Taking together, these studies indicating the piscine also involved in regulating food intake and energy homeostasis.

Modulating reproductive founction:
Several recent studies suggested that the MC4R is also involved in modulating reproductive function through affecting the secretion of reproductive hormones, and consequent sexual maturation in fish [7]. Moreover, the MC4R was found to be highly expressed in gonads of several fish, such as goldfish [42], Ya-fish [30], and snakeskin gourami [45]. In addition, some previous studies revealed that MC4R copies located on the sex chromosomes participate in the functional modulation of onset of sexual maturity in both male and female swordtails and platyfish, suggesting the potential participation of MC4R in the regulation of reproduction [31,46]. Hence, understanding how MC4R mediates the reproductive function in economically important species is important for artificial breeding.

Other functions of the MC4R:
The functions of fish MC4R are very limited, it might be involved in some physiological functions such as mediating body color, modulating blood glucose homeostasis and other miscellaneous functions. However, these hypothesizes have not yet established, and it need to be further studied.

Conclusions and Future Directions

Tremendous progress has been made on the MC4R since 1993 when it was cloned. As an important transmembrane protein, it’s involved in many physiological processes not only in higher vertebrate but also in lower vertebrate. Although it has well studied in mammals, there are still exsit many mysteries need to be resolved especially in fish. In future, the MC4R should be well known by people following extensive research carrying out, and it might be as a useful tool for improving aquaculture industry.


This work was supported by the National Natural Science Funds (No. 31402305), the Educational Commission of Sichuan Province of China (No. KYTD201009; No. 15ZA0285) and the department of science and technology of Sichuan Province of China (No. 2015JY0262).

  1. Fan ZC, Sartin JL, Tao YX (2008) Molecular cloning and pharmacological characterization of porcine melanocortin-3 receptor. J Endocrinol 196: 139-148. Link:
  2. Tao YX (2009) Mutations in Melanocortin‐4 Receptor and Human Obesity. Progress in molecular biology and translational science 88: 173-204. Link:
  3. Takahashi A, Kawauchi H (2006) Evolution of melanocortin systems in fish. Gen Comp Endocrinol 148: 85-94. Link:
  4. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, et al. (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278: 135-138. Link:
  5. Tao YX, Conn PM (2014) Chaperoning G protein-coupled receptors: from cell biology to therapeutics. Endocr Rev 35: 602-647. Link:
  6. Ghamari-Langroudi M, Digby GJ, Sebag JA, Millhauser GL, Palomino R, et al. (2015) G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons. Nature 520: 94-98. Link:
  7. Tao Y-X (2010) The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocrine reviews 31: 506-543. Link:
  8. Metz JR, Peters JJ, Flik G (2006) Molecular biology and physiology of the melanocortin system in fish: a review. Gen Comp Endocrinol 148: 150-162. Link:
  9. Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, et al. (1993) Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem 268: 15174-15179. Link:
  10. Magenis RE, Smith L, Nadeau JH, Johnson KR, Mountjoy KG, et al. (1994) Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mamm Genome 5: 503-508. Link:
  11. Staubert C, Tarnow P, Brumm H, Pitra C, Gudermann T, et al. (2007) Evolutionary aspects in evaluating mutations in the melanocortin 4 receptor. Endocrinology 148: 4642-4648. Link:
  12. Hughes DA, Hinney A, Brumm H, Wermter AK, Biebermann H, et al. (2009) Increased constraints on MC4R during primate and human evolution. Hum Genet 124: 633-647. Link:
  13. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, et al. (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131-141. Link:
  14. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385: 165-168. Link:
  15. Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark KL (1997) Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet 17: 273-274. Link:
  16. Vaisse C, Clement K, Guy-Grand B, Froguel P (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20: 113-114. Link:
  17. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, et al. (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20: 111-112. Link:
  18. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8: 571-578. Link:
  19. Ringholm A, Fredriksson R, Poliakova N, Yan YL, Postlethwait JH, et al. (2002) One melanocortin 4 and two melanocortin 5 receptors from zebrafish show remarkable conservation in structure and pharmacology. J Neurochem 82: 6-18. Link:
  20. Sanchez E, Rubio VC, Thompson D, Metz J, Flik G, et al. (2009) Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax). Am J Physiol Regul Integr Comp Physiol 296: R1293-1306. Link:
  21. Li JT, Yang Z, Chen HP, Zhu C-H, Deng SP, et al. (2016) Molecular cloning, tissue distribution, and pharmacological characterization of melanocortin-4 receptor in spotted scat, Scatophagus argus. Gen Comp Endocrinol 230-231: 143-152. Link:
  22. Kobayashi Y, Tsuchiya K, Yamanome T, Schioth HB, Kawauchi H, et al. (2008) Food deprivation increases the expression of melanocortin-4 receptor in the liver of barfin flounder, Verasper moseri. Gen Comp Endocrinol 155: 280-287. Link:
  23. Lee HJ, Kim JM (2010) Molecular Cloning and Tissue-specific Expression of the Melanocortin 4 Receptor Gene from Olive Flounder, Paralichthys olivaceus. Fisheries and aquatic sciences 13: 263-271. Link:
  24. Klovins J, Haitina T, Fridmanis D, Kilianova Z, Kapa I, et al. (2004) The melanocortin system in Fugu: determination of POMC/AGRP/MCR gene repertoire and synteny, as well as pharmacology and anatomical distribution of the MCRs. Mol Biol Evol 21: 563-579. Link:
  25. Haitina T, Klovins J, Andersson J, Fredriksson R, Lagerstrom MC, et al. (2004) Cloning, tissue distribution, pharmacology and three-dimensional modelling of melanocortin receptors 4 and 5 in rainbow trout suggest close evolutionary relationship of these subtypes. Biochem J 380: 475-486. Link:
  26. Wan Y, Zhang Y, Ji P, Li Y, Xu P, et al. (2012) Molecular characterization of CART, AgRP, and MC4R genes and their expression with fasting and re-feeding in common carp (Cyprinus carpio). Mol Biol Rep 39: 2215-2223. Link:
  27. Cerda-Reverter JM, Ringholm A, Schioth HB, Peter RE (2003) Molecular cloning, pharmacological characterization, and brain mapping of the melanocortin 4 receptor in the goldfish: involvement in the control of food intake. Endocrinology 144: 2336-2349. Link:
  28. Li L, Yang Z, Zhang YP, He S, Liang XF, et al. (2016) Molecular cloning, tissue distribution, and pharmacologic characterization of melanocortin-4 receptor in grass carp (Ctenopharyngodon idella). Domestic Animal Endocrinology. Link:
  29. Tao W, Zou M, Wang X, Gan X, Mayden RL, et al. (2010) Phylogenomic analysis resolves the formerly intractable adaptive diversification of the endemic clade of east Asian Cyprinidae (Cypriniformes). PLoS One 5: e13508. Link:
  30. Wei R, Yuan D, Zhou C, Wang T, Lin F, et al. (2013) Cloning, distribution and effects of fasting status of melanocortin 4 receptor (MC4R) in Schizothorax prenanti. Gene 532: 100-107. Link:
  31. Volff JN, Selz Y, Hoffmann C, Froschauer A, Schultheis C, et al. (2013) Gene amplification and functional diversification of melanocortin 4 receptor at an extremely polymorphic locus controlling sexual maturation in the platyfish. Genetics 195: 1337-1352. Link:
  32. Ringholm A, Klovins J, Fredriksson R, Poliakova N, Larson ET, et al. (2003) Presence of melanocortin (MC4) receptor in spiny dogfish suggests an ancient vertebrate origin of central melanocortin system. Eur J Biochem 270: 213-221. Link:
  33. Baron A, Veo K, Angleson J, Dores RM (2009) Modeling the evolution of the MC2R and MC5R genes: studies on the cartilaginous fish, Heterondotus francisci. Gen Comp Endocrinol 161: 13-19. Link:
  34. Takahashi A, Davis P, Reinick C, Mizusawa K, Sakamoto T, et al. (2016) Characterization of melanocortin receptors from stingray Dasyatis akajei, a cartilaginous fish. Gen Comp Endocrinol 232: 115-124. Link:
  35. Haitina T, Klovins J, Takahashi A, Lowgren M, Ringholm A, et al. (2007) Functional characterization of two melanocortin (MC) receptors in lamprey showing orthology to the MC1 and MC4 receptor subtypes. BMC Evol Biol 7: 101. Link:
  36. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD (1994) Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 8: 1298-1308. Link:
  37. Mountjoy KG, Jenny Wu CS, Dumont LM, Wild JM (2003) Melanocortin-4 receptor messenger ribonucleic acid expression in rat cardiorespiratory, musculoskeletal, and integumentary systems. Endocrinology 144: 5488-5496. Link:
  38. Cone RD (2006) Studies on the physiological functions of the melanocortin system. Endocr Rev 27: 736-749. Link:
  39. Tao YX (2005) Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol 239: 1-14. Link:
  40. Panaro BL, Tough IR, Engelstoft MS, Matthews RT, Digby GJ, et al. (2014) The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. Cell Metab 20: 1018-1029. Link:
  41. Reizes O, Lincecum J, Wang Z, Goldberger O, Huang L, et al. (2001) Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell 106: 105-116. Link:
  42. Cerda-Reverter JM, Schioth HB, Peter RE (2003) The central melanocortin system regulates food intake in goldfish. Regul Pept 115: 101-113. Link:
  43. Schjolden J, Schioth HB, Larhammar D, Winberg S, Larson ET (2009) Melanocortin peptides affect the motivation to feed in rainbow trout (Oncorhynchus mykiss). Gen Comp Endocrinol 160: 134-138. Link:
  44. Aspiras AC, Rohner N, Martineau B, Borowsky RL, Tabin CJ (2015) Melanocortin 4 receptor mutations contribute to the adaptation of cavefish to nutrient-poor conditions. Proc Natl Acad Sci U S A 112: 9668-9673. Link:
  45. Jangprai A, Boonanuntanasarn S, Yoshizaki G (2011) Characterization of melanocortin 4 receptor in Snakeskin Gourami and its expression in relation to daily feed intake and short-term fasting. Gen Comp Endocrinol 173: 27-37. Link:
  46. Lampert KP, Schmidt C, Fischer P, Volff JN, Hoffmann C, et al. (2010) Determination of onset of sexual maturation and mating behavior by melanocortin receptor 4 polymorphisms. Curr Biol 20: 1729-1734 . Link:

Follow us on