+Advanced Search
Volume 4 Issue 1
Feb.  2022
Article Contents

Citation:

Neuropeptide Y and melanocortin receptors in fish: regulators of energy homeostasis

  • Corresponding author: Hai-Shen Wen, wenhaishen@ouc.edu.cn
  • Received Date: 2020-06-28
    Accepted Date: 2021-04-19
    Published online: 2021-09-13
  • Edited by Xin Yu.
  • Energy homeostasis, which refers to the physiological processes that the energy intake is exquisitely coordinated with energy expenditure, is critical for survival. Therefore, multiple and complex mechanisms have been involved in the regulation of energy homeostasis. The central melanocortin system plays an important role in modulating energy homeostasis. This system includes the orexigenic neurons, expressing neuropeptide Y/Agouti-related protein (NPY/AgRP), and the anorexigenic neurons expressing proopiomelanocortin (POMC). The downstream receptors of NPY, AgRP and post-translational products of POMC are G protein-coupled receptors (GPCRs). This review summarizes the compelling evidence demonstrating that NPY and melanocortin receptors are involved in energy homeostasis. Subsequently, the comparative studies on physiology and pharmacology of NPY and melanocortin receptors in humans, rodents and teleosts are summarized. Also, we provide a strategy demonstrating the potential application of the new ligands and/or specific variants of melanocortin system in aquaculture.
  • 加载中
  • Arends RJ, Vermeer H, Martens GJM, Leunissen JAM, Bonga SEW, Flik G (1998) Cloning and expression of two proopiomelanocortin mRNAs in the common carp (Cyprinus carpio). Mol Cell Endocrinol 143: 23–31 doi: 10.1016/S0303-7207(98)00139-7
    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 USA 112: 9668–9673 doi: 10.1073/pnas.1510802112
    Bjarnadottir TK, Gloriam DE, Hellstrand SH, Kristiansson H, Fredriksson R, Schioth HB (2006) Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Genomics 88: 263–273 doi: 10.1016/j.ygeno.2006.04.001
    Blomqvist AG, Söderberg C, Lundell I, Milner RJ, Larhammar D (1992) Strong evolutionary conservation of neuropeptide Y: sequences of chicken, goldfish, and Torpedo marmorata DNA clones. Proc Natl Acad Sci USA 89: 2350–2354 doi: 10.1073/pnas.89.6.2350
    Bockaert J, Pin JP (1999) Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 18: 1723–1729 doi: 10.1093/emboj/18.7.1723
    Boyce-Derricott J, Nagler JJ, Cloud JG (2009) Regulation of hepatic estrogen receptor isoform mRNA expression in rainbow trout (Oncorhynchus mykiss). Gen Comp Endocrinol 161: 73–78 doi: 10.1016/j.ygcen.2008.11.022
    Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, Baetscher M, Cone RD (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141: 3518–3521 doi: 10.1210/endo.141.9.7791
    Butler AA, Girardet C, Mavrikaki M, Trevaskis JL, Macarthur H, Marks DL, Farr SA (2017) A life without hunger: the ups (and downs) to modulating melanocortin-3 receptor signaling. Front Neurosci 11: 128
    Cerda-Reverter JM, Schioth HB, Peter RE (2003) The central melanocortin system regulates food intake in goldfish. Regul Pept 115: 101–113 doi: 10.1016/S0167-0115(03)00144-7
    Cerdá-Reverter JM, Larhammar D (2000) cNeuropeptide Y family of peptides: structure, anatomical expression, function, and molecular evolution. Biochem Cell Biol 78: 371–392
    Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY et al (2000) Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26: 97–102 doi: 10.1038/79254
    Chhajlani V (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem Mol Biol Int 38: 73–80
    Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8: 571–578 doi: 10.1038/nn1455
    Cone RD (2006) Studies on the physiological functions of the melanocortin system. Endocr Rev 27: 736–749 doi: 10.1210/er.2006-0034
    de Pedro N, López-Patino MA, Guijarro AI, Pinillos ML, Delgado MJ, Alonso-Bedate M (2000) NPY receptors and opioidergic system are involved in NPY-induced feeding in goldfish. Peptides 21: 1495–1502 doi: 10.1016/S0196-9781(00)00303-X
    de Pedro N, Martinez-Alvarez R, Delgado MJ (2006) Acute and chronic leptin reduces food intake and body weight in goldfish (Carassius auratus). J Endocrinol 188: 513–520 doi: 10.1677/joe.1.06349
    Demski LS (2012) The neural control of feeding in elasmobranchs: a review and working model. Environ Biol Fishes 95: 169–183 doi: 10.1007/s10641-011-9827-x
    Dores RM, Lecaude S (2005) Trends in the evolution of the proopiomelanocortin gene. Gen Comp Endocrinol 142: 81–93 doi: 10.1016/j.ygcen.2005.02.003
    Dorsam RT, Gutkind JS (2007) G-protein-coupled receptors and cancer. Nat Rev Cancer 7: 79–94 doi: 10.1038/nrc2069
    Duarte-Neves J, de Almeida LP, Cavadas C (2016) Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. Neurobiol Dis 95: 210–224 doi: 10.1016/j.nbd.2016.07.022
    Fällmar H, Sundström G, Lundell I, Mohell N, Larhammar D (2011) Neuropeptide Y/peptide YY receptor Y2 duplicate in zebrafish with unique introns displays distinct peptide binding properties. Comp Biochem Phys B 160: 166–173
    Fan ZC, Sartin JL, Tao YX (2008) Pharmacological analyses of two naturally occurring porcine melanocortin-4 receptor mutations in domestic pigs. Domest Anim Endocrinol 34: 383–390 doi: 10.1016/j.domaniend.2007.05.003
    Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63: 1256–1272 doi: 10.1124/mol.63.6.1256
    Fredriksson R, Larson ET, Yan YL, Postlethwait JH, Larhammar D (2004) Novel neuropeptide Y Y2-like receptor subtype in zebrafish and frogs supports early vertebrate chromosome duplications. J Mol Evol 58: 106–114 doi: 10.1007/s00239-003-2529-z
    Gantz I, Fong TM (2003) The melanocortin system. Am J Physiol 284: E468–E474
    Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T (1993) Molecular cloning of a novel melanocortin receptor. J Biol Chem 268: 8246–8250 doi: 10.1016/S0021-9258(18)53088-X
    Ghamari-Langroudi M, Cakir I, Lippert RN, Sweeney P, Litt MJ, Ellacott KLJ, Cone RD (2018) Regulation of energy rheostasis by the melanocortin-3 receptor. Sci Adv 4: eaat0866 doi: 10.1126/sciadv.aat0866
    Hinney A, Volckmar AL, Knoll N (2013) Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl 114: 147–191
    Hoegg S, Brinkmann H, Taylor JS, Meyer A (2004) Phylogenetic timing of the fish-specific genome duplication correlates with the diversification of teleost fish. J Mol Evol 59: 190–203 doi: 10.1007/s00239-004-2613-z
    Holzer P, Reichmann F, Farzi A (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut–brain axis. Neuropeptides 46: 261–274 doi: 10.1016/j.npep.2012.08.005
    Hoskins LJ, Volkoff H (2012) The comparative endocrinology of feeding in fish: insights and challenges. Gen Comp Endocrinol 176: 327–335 doi: 10.1016/j.ygcen.2011.12.025
    Hughes DA, Hinney A, Brumm H, Wermter AK, Biebermann H, Hebebrand J, Stoneking M (2009) Increased constraints on MC4R during primate and human evolution. Hum Genet 124: 633–647 doi: 10.1007/s00439-008-0591-8
    Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131–141 doi: 10.1016/S0092-8674(00)81865-6
    Jegou S, Boutelet I, Vaudry H (2000) Melanocortin-3 receptor mRNA expression in pro-opiomelanocortin neurones of the rat arcuate nucleus. J Neuroendocrinol 12: 501–505
    Kalananthan T, Lai F, Gomes AS, Murashita K, Handeland S, Rønnestad I (2020) The melanocortin system in Atlantic salmon (Salmo salar L. ) and its role in appetite control. Front Neuroanat 14: 48 doi: 10.3389/fnana.2020.00048
    Kim KS, Larsen N, Short T, Plastow G, Rothschild MF (2000) A missense variant of the porcine melanocortin-4 receptor (MC4R) gene is associated with fatness, growth, and feed intake traits. Mamm Genome 11: 131–135 doi: 10.1007/s003350010025
    Kim KS, Reecy JM, Hsu WH, Anderson LL, Rothschild MF (2004) Functional and phylogenetic analyses of a melanocortin-4 receptor mutation in domestic pigs. Domest Anim Endocrinol 26: 75–86 doi: 10.1016/j.domaniend.2003.12.001
    Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK (2003) Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol 457: 213–235 doi: 10.1002/cne.10454
    Kitahara N, Nishizawa T, Iida K, Okazaki H, Andoh T, Soma GI (1988) Absence of a gamma-melanocyte-stimulating hormone sequence in proopiomelanocortin mRNA of chum salmon Oncorhynchus keta. Comp Biochem Physiol B 91: 365–370 doi: 10.1016/0305-0491(88)90155-1
    Klovins J, Haitina T, Ringholm A, Löwgren M, Fridmanis D, Slaidina M, Stier S, Schiöth HB (2004) Cloning of two melanocortin (MC) receptors in spiny dogfish: MC3 receptor in cartilaginous fish shows high affinity to ACTH-derived peptides while it has lower preference to γ-MSH. Eur J Biochem 271: 4320–4331 doi: 10.1111/j.1432-1033.2004.04374.x
    Larhammar D (1996) Evolution of neuropeptide Y, peptide YY and pancreatic polypeptide. Regul Pept 62: 1–11 doi: 10.1016/0167-0115(95)00169-7
    Larhammar D, Wraith A, Berglund MM, Holmberg SKS, Lundell I (2001) Origins of the many NPY-family receptors in mammals. Peptides 22: 295–307 doi: 10.1016/S0196-9781(01)00331-X
    Larson ET, Fredriksson R, Johansson SRT, Larhammar D (2003) Cloning, pharmacology, and distribution of the neuropeptide Y-receptor Yb in rainbow trout. Peptides 24: 385–395 doi: 10.1016/S0196-9781(03)00053-6
    Larsson TA, Olsson F, SundstrÖm G, Brenner S, Venkatesh B, Larhammar D (2005) Pufferfish and zebrafish have five distinct NPY receptor subtypes, but have lost appetite receptors Y1 and Y5. Ann NY Acad Sci 1040: 375–377 doi: 10.1196/annals.1327.066
    Larsson A, Larson ET, Fredriksson R, Conlon JM, Larhammar D (2006) Characterization of NPY receptor subtypes Y2 and Y7 in rainbow trout Oncorhynchus mykiss. Peptides 27: 1320–1327 doi: 10.1016/j.peptides.2005.10.008
    Lee YS, Poh LK, Loke KY (2002) A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. J Clin Endocrinol Metab 87: 1423–1426 doi: 10.1210/jcem.87.3.8461
    Li JT, Yang Z, Chen HP, Zhu CH, Deng SP, Li GL, Tao YX (2016) Molecular cloning, tissue distribution, and pharmacological characterization of melanocortin-4 receptor in spotted scat, Scatophagus argus. Gen Comp Endocrinol 230–231: 143–152 doi: 10.1016/j.ygcen.2016.04.010
    Li L, Yang Z, Zhang YP, He S, Liang XF, Tao YX (2017) Molecular cloning, tissue distribution, and pharmacological characterization of melanocortin-4 receptor in grass carp (Ctenopharyngodon idella). Domest Anim Endocrinol 59: 140–151 doi: 10.1016/j.domaniend.2016.11.004
    Logan DW, Bryson-Richardson RJ, Taylor MS, Currie P, Jackson IJ (2003a) Sequence characterization of teleost fish melanocortin receptors. Ann NY Acad Sci 994: 319–330 doi: 10.1111/j.1749-6632.2003.tb03196.x
    Logan DW, Bryson-Richardson RJ, Pagan KE, Taylor MS, Currie PD, Jackson IJ (2003b) The structure and evolution of the melanocortin and MCH receptors in fish and mammals. Genomics 81: 184–191 doi: 10.1016/S0888-7543(02)00037-X
    Lotta LA, Mokrosiński J, de Oliveira EM, Li C, Sharp SJ, Luan J, Brouwers B, Ayinampudi V, Bowker N, Kerrison N (2019) Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell 177(597–607): e599
    Lundell I, Blomqvist AG, Berglund MM, Schober DA, Johnson DG, Statnick MA, Gadski RA, Gehlert DR, Larhammar D (1995) Cloning of a human receptor of the NPY receptor family with high affinity for pancreatic polypeptide and peptide YY. J Biol Chem 270: 29123–29128 doi: 10.1074/jbc.270.49.29123
    Lundell I, Berglund MM, Starbäck P, Salaneck E, Gehlert DR, Larhammar D (1997) Cloning and characterization of a novel neuropeptide Y receptor subtype in the zebrafish. DNA Cell Biol 16: 1357–1363 doi: 10.1089/dna.1997.16.1357
    Martemyanov KA, Garcia-Marcos M (2018) Making useful gadgets with miniaturized G proteins. J Biol Chem 293: 7474–7475 doi: 10.1074/jbc.H118.002879
    Matsuda K, Kang KS, Sakashita A, Yahashi S, Vaudry H (2011) Behavioral effect of neuropeptides related to feeding regulation in fish. Ann NY Acad Sci 1220: 117–126 doi: 10.1111/j.1749-6632.2010.05884.x
    Metz JR, Peters JJM, Flik G (2006) Molecular biology and physiology of the melanocortin system in fish: a review. Gen Comp Endocrinol 148: 150–162 doi: 10.1016/j.ygcen.2006.03.001
    Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T (1998) ⅩⅥ. International union of pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev 50: 143–150
    Miller WE, Lefkowitz RJ (2001) Expanding roles for β-arrestins as scaffolds and adapters in GPCR signaling and trafficking. Curr Opin Cell Biol 13: 139–145 doi: 10.1016/S0955-0674(00)00190-3
    Morton G, Cummings D, Baskin D, Barsh G, Schwartz M (2006) Central nervous system control of food intake and body weight. Nature 443: 289 doi: 10.1038/nature05026
    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
    Narnaware YK, Peter RE (2001a) Effects of food deprivation and refeeding on neuropeptide Y (NPY) mRNA levels in goldfish. Comp Biochem Physiol B 129: 633–637 doi: 10.1016/S1096-4959(01)00359-1
    Narnaware YK, Peter RE (2001b) Neuropeptide Y stimulates food consumption through multiple receptors in goldfish. Physiol Behav 74: 185–190 doi: 10.1016/S0031-9384(01)00556-X
    Narnaware YK, Peyon PP, Lin X, Peter RE (2000) Regulation of food intake by neuropeptide Y in goldfish. Am J Physiol Regul Integr Comp Physiol 279: R1025–R1034 doi: 10.1152/ajpregu.2000.279.3.R1025
    Ni XP, Butler AA, Cone RD, Humphreys MH (2006) Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones. J Hypertens 24: 2239–2246 doi: 10.1097/01.hjh.0000249702.49854.fa
    Offermanns S (2003) G-proteins as transducers in transmembrane signalling. Prog Biophys Mol Biol 83: 101–130 doi: 10.1016/S0079-6107(03)00052-X
    Oldham WM, Hamm HE (2008) Heterotrimeric G protein activation by G-protein-coupled receptors. Nat Rev Mol Cell Biol 9: 60–71 doi: 10.1038/nrm2299
    Rao YZ, Chen R, Zhang Y, Tao YX (2019) Orange-spotted grouper melanocortin-4 receptor: modulation of signaling by MRAP2. Gen Comp Endocrinol 284: 113234 doi: 10.1016/j.ygcen.2019.113234
    Reichmann F, Holzer P (2016) Neuropeptide Y: a stressful review. Neuropeptides 55: 99–109 doi: 10.1016/j.npep.2015.09.008
    Ritter SL, Hall RA (2009) Fine-tuning of GPCR activity by receptor-interacting proteins. Nat Rev Mol Cell Biol 10: 819–830 doi: 10.1038/nrm2803
    Rodrigues AR, Almeida H, Gouveia AM (2015) Intracellular signaling mechanisms of the melanocortin receptors: current state of the art. Cell Mol Life Sci 72: 1331–1345 doi: 10.1007/s00018-014-1800-3
    Rønnestad I, Gomes AS, Murashita K, Angotzi R, Jönsson E, Volkoff H (2017) Appetite-controlling endocrine systems in teleosts. Front Endocrinol 8: 73
    Salaneck E, Fredriksson R, Larson ET, Conlon JM, Larhammar D (2001) A neuropeptide Y receptor Y1-subfamily gene from an agnathan, the European river lamprey: a potential ancestral gene. Eur J Biochem 268: 6146–6154 doi: 10.1046/j.0014-2956.2001.02561.x
    Salaneck E, Larsson TA, Larson ET, Larhammar D (2008) Birth and death of neuropeptide Y receptor genes in relation to the teleost fish tetraploidization. Gene 409: 61–71 doi: 10.1016/j.gene.2007.11.011
    Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, Hadley ME (1980) 4-Norleucine, 7-D-phenylalanine-a-melanocyte-stimulating hormone: a highly potent a-melanotropin with ultralong biological activity. Proc Natl Acad Sci USA 77: 5754–5758 doi: 10.1073/pnas.77.10.5754
    Schjolden J, Schiöth 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 doi: 10.1016/j.ygcen.2008.11.003
    Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404: 661–671 doi: 10.1038/35007534
    Sebhat IK, Martin WJ, Ye Z, Barakat K, Mosley RT, Johnston DB, Bakshi R, Palucki B, Weinberg DH, MacNeil T, Kalyani RN, Tang R, Stearns RA, Miller RR, Tamvakopoulos C, Strack AM, McGowan E, Cashen DE, Drisko JE, Hom GJ et al (2002) Design and pharmacology of N-[(3R)-1, 2, 3, 4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H–1, 2, 4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist. J Med Chem 45: 4589–4593 doi: 10.1021/jm025539h
    Sharma P, Arvidsson AK, Wraith A, Beck-Sickinger AG, Jönsson-Rylander AC, Larhammar D (1999) Characterization of the cloned Atlantic cod neuropeptide Y-Yb receptor: peptide-binding requirements distinct from known mammalian Y receptors. Gen Comp Endocrinol 115: 422–428 doi: 10.1006/gcen.1999.7332
    Silva AP, Xapelli S, Grouzmann E, Cavadas C (2005) The putative neuroprotective role of neuropeptide Y in the central nervous system. Curr Drug Targets CNS Neurol Disord 4: 331–347 doi: 10.2174/1568007054546153
    Silverstein JT, Plisetskaya EM (2000) The effects of NPY and insulin on food intake regulation in fish. Am Zool 40: 296–308
    Silverstein JT, Breininger J, Baskin DG, Plisetskaya EM (1998) Neuropeptide Y-like gene expression in the salmon brain increases with fasting. Gen Comp Endocrinol 110: 157–165 doi: 10.1006/gcen.1998.7058
    Smith AI, Funder JW (1988) Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues. Endocr Rev 9: 159–179 doi: 10.1210/edrv-9-1-159
    Srinivasan S, Lubrano-Berthelier C, Govaerts C, Picard F, Santiago P, Conklin BR, Vaisse C (2004) Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. J Clin Invest 114: 1158–1164 doi: 10.1172/JCI200421927
    Staubert C, Tarnow P, Brumm H, Pitra C, Gudermann T, Gruters A, Schoneberg T, Biebermann H, Rompler H (2007) Evolutionary aspects in evaluating mutations in the melanocortin 4 receptor. Endocrinology 148: 4642–4648 doi: 10.1210/en.2007-0138
    Sundström G, Larsson TA, Xu B, Heldin J, Larhammar D (2013) Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a, and Y8b. Front Neurosci 7: 29
    Tao YX (2005) Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol 239: 1–14 doi: 10.1016/j.mce.2005.04.012
    Tao YX (2007) Functional characterization of novel melanocortin-3 receptor mutations identified from obese subjects. Biochim Biophys Acta 1772: 1167–1174 doi: 10.1016/j.bbadis.2007.09.002
    Tao YX (2008) Constitutive activation of G protein-coupled receptors and diseases: insights into mechanism of activation and therapeutics. Pharmacol Ther 120: 129–148 doi: 10.1016/j.pharmthera.2008.07.005
    Tao YX (2009) Mutations in melanocortin-4 receptor and human obesity. Prog Mol Biol Transl Sci 88: 173–204
    Tao Y-X (2010) The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 31: 506–543 doi: 10.1210/er.2009-0037
    Tao YX (2020) Molecular chaperones and G protein-coupled receptor maturation and pharmacology. Mol Cell Endocrinol 511: 110862 doi: 10.1016/j.mce.2020.110862
    Tao YX, Segaloff DL (2004) Functional characterization of melanocortin-3 receptor variants identify a loss-of-function mutation involving an amino acid critical for G protein-coupled receptor activation. J Clin Endocrinol Metab 89: 3936–3942 doi: 10.1210/jc.2004-0367
    Tao YX, Yuan ZH, Xie J (2013) G protein-coupled receptors as regulators of energy homeostasis. Prog Mol Biol Transl Sci 114: 1–43
    Tao M, Ji RL, Huang L, Fan SY, Liu T, Liu SJ, Tao YX (2020) Regulation of melanocortin-4 receptor pharmacology by two isoforms of melanocortin receptor accessory protein 2 in topmouth culter (Culter alburnus). Front Endocrinol 11: 538 doi: 10.3389/fendo.2020.00538
    Tatemoto K (1982) Neuropeptide Y: complete amino acid sequence of the brain peptide. Proc Natl Acad Sci USA 79: 5485–5489 doi: 10.1073/pnas.79.18.5485
    Thomsen ARB, Plouffe B, Cahill TJ Ⅲ, Shukla AK, Tarrasch JT, Dosey AM, Kahsai AW, Strachan RT, Pani B, Mahoney JP (2016) GPCR-G protein-β-arrestin super-complex mediates sustained G protein signaling. Cell 166: 907–919 doi: 10.1016/j.cell.2016.07.004
    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 doi: 10.1038/2407
    van der Kraan M, Tatro JB, Entwistle ML, Brakkee JH, Burbach JP, Adan RA, Gispen WH (1999) Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins. Mol Brain Res 63: 276–286 doi: 10.1016/S0169-328X(98)00291-5
    Volkoff H (2016) The neuroendocrine regulation of food intake in fish: a review of current knowledge. Front Neurosci 10: 540
    Volkoff H, Canosa LF, Unniappan S, Cerda-Reverter JM, Bernier NJ, Kelly SP, Peter RE (2005) Neuropeptides and the control of food intake in fish. Gen Comp Endocrinol 142: 3–19 doi: 10.1016/j.ygcen.2004.11.001
    Wang F, Chen W, Lin H, Li WJ (2014) Cloning, expression, and ligand-binding characterization of two neuropeptide Y receptor subtypes in orange-spotted grouper, Epinephelus coioides. Fish Physiol Biochem 40: 1693–1707 doi: 10.1007/s10695-014-9960-5
    Wang T, Liang J, Xiang X, Chen X, Zhang B, Zhou N, Huang W, Yang J (2019) Pharmacological characterization, cellular localization and expression profile of NPY receptor subtypes Y2 and Y7 in large yellow croaker, Larimichthys crocea. Comp Biochem Physiol B 238: 110347 doi: 10.1016/j.cbpb.2019.110347
    Wei R, Yuan D, Zhou C, Wang T, Lin F, Chen H, Wu H, Xin Z, Yang S, Chen D, Wang Y, Liu J, Gao Y, Li Z (2013) Cloning, distribution and effects of fasting status of melanocortin 4 receptor (MC4R) in Schizothorax prenanti. Gene 532: 100–107 doi: 10.1016/j.gene.2013.09.068
    Won ET, Borski RJ (2013) Endocrine regulation of compensatory growth in fish. Front Endocrinol 4: 74
    Yang H, Yang L (2016) Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy. J Mol Endocrinol 57: R93–R108 doi: 10.1530/JME-15-0316
    Yang LK, Zhang ZR, Wen HS, Tao YX (2019) Characterization of channel catfish (Ictalurus punctatus) melanocortin-3 receptor reveals a potential network in regulation of energy homeostasis. Gen Comp Endocrinol 277: 90–103 doi: 10.1016/j.ygcen.2019.03.011
    Yang Z, Liang XF, Li GL, Tao YX (2020) Biased signaling in fish melanocortin-4 receptors (MC4Rs): Divergent pharmacology of four ligands on spotted scat (Scatophagus argus) and grass carp (Ctenopharyngodon idella) MC4Rs. Mol Cell Endocrinol 515: 110929 doi: 10.1016/j.mce.2020.110929
    Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20: 111–112 doi: 10.1038/2404
    Yi TL, Yang LK, Ruan GL, Yang DQ, Tao YX (2018) Melanocortin-4 receptor in swamp eel (Monopterus albus): Cloning, tissue distribution, and pharmacology. Gene 678: 79–89 doi: 10.1016/j.gene.2018.07.056
    Zhang KQ, Hou ZS, Wen HS, Li Y, Qi X, Li WJ, Tao YX (2019) Melanocortin-4 receptor in spotted sea bass, Lateolabrax maculatus: cloning, tissue distribution, physiology, and pharmacology. Front Endocrinol 10: 705 doi: 10.3389/fendo.2019.00705
    Zhang Y, Wen HS, Li Y, Lyu LK, Zhang ZX, Wang XJ, Li JS, Tao YX, Qi X (2020) Melanocortin-4 receptor regulation of reproductive function in black rockfish (Sebastes schlegelii). Gene 741: 144541 doi: 10.1016/j.gene.2020.144541
  • 加载中
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Figures(2) / Tables(1)

Article Metrics

Article views(1031) PDF downloads(7) Cited by()

Related
Proportional views

Neuropeptide Y and melanocortin receptors in fish: regulators of energy homeostasis

    Corresponding author: Hai-Shen Wen, wenhaishen@ouc.edu.cn
  • 1. Key Laboratory of Mariculture (Ocean University of China), Ministry of Education (KLMME), Fisheries College, Ocean University of China, Qingdao 266003, China

Abstract: Energy homeostasis, which refers to the physiological processes that the energy intake is exquisitely coordinated with energy expenditure, is critical for survival. Therefore, multiple and complex mechanisms have been involved in the regulation of energy homeostasis. The central melanocortin system plays an important role in modulating energy homeostasis. This system includes the orexigenic neurons, expressing neuropeptide Y/Agouti-related protein (NPY/AgRP), and the anorexigenic neurons expressing proopiomelanocortin (POMC). The downstream receptors of NPY, AgRP and post-translational products of POMC are G protein-coupled receptors (GPCRs). This review summarizes the compelling evidence demonstrating that NPY and melanocortin receptors are involved in energy homeostasis. Subsequently, the comparative studies on physiology and pharmacology of NPY and melanocortin receptors in humans, rodents and teleosts are summarized. Also, we provide a strategy demonstrating the potential application of the new ligands and/or specific variants of melanocortin system in aquaculture.

    HTML

Introduction
  • G protein-coupled receptors (GPCRs) are ancient membrane proteins that exert highly conserved versatile signaling, with more than 1000 members identified with functional diversity (Bjarnadottir et al. 2006; Fredriksson et al. 2003; Tao 2020). Diverse extracellular signals, including light, odorants, ions, steroids, fatty acids, peptides and neurotransmitters, could act as the ligands of GPCRs (Bockaert and Pin 1999). After receptor activation by the ligands, the membrane-associated heterotrimeric G proteins serve as the molecular switches in GPCRs-regulated intracellular signal transduction pathways (Oldham and Hamm 2008). The heterotrimeric G proteins are composed of two functional units: an α subunit and a βγ dimer. In the absence of the ligands, the heterotrimeric G protein is inactivated, and the GDP-attached α subunit is tightly associated with the βγ dimer (Oldham and Hamm 2008). Binding of a signaling molecule to the receptor could activate the G protein with conformational changes, thus triggering the substitution of GTP for GDP on the α-subunit and the dissociation of α-subunit from βγ dimer (Tao et al. 2013).

    The GTP-bound α-subunit could activate multiple signaling proteins, thereby regulating the intracellular signal transduction pathways via second messengers of cyclic AMP (cAMP), inositol 1, 4, 5-trisphosphate (IP3), diacylglycerol (DAG) and calcium (Ca2+). Based on structural and functional similarity, the α-subunits could be broadly divided into four subtypes of stimulatory G protein (Gαs), inhibitory G protein (Gαi), Gαq and Gα12/13 (Martemyanov and Garcia-Marcos 2018; Offermanns 2003). The Gαs protein could activate the adenylyl cyclase, resulting in increased cAMP concentrations, and subsequently activation of protein kinase A (PKA). Gαi inhibits the production of the cAMP. PKA could activate the functional proteins targeted in cytoplasm and the membrane, thus regulating the cellular functions via a faster non-genomic signaling. Also, PKA activates the proteins targeted in the nucleus [such as the cAMP response element-binding protein (CREB)] and modulates the cellular functions, via a slower genomic signaling (Yang and Yang 2016). For example, the phosphorylated CREB could transfer to the nucleus and then bind to the cAMP response element (CRE) in target genes, regulating gene expressions. Activation of Gαq could increase the intracellular IP3 and DAG via activating phospholipase C (PLC). IP3 activates the release of Ca2+ from the endoplasmic reticulum (ER). DAG and Ca2+ can activate protein kinase C (PKC), thus regulating enzyme activities, metabolic pathways and gene expressions. The Gα12/13 subtype specifically target Rho guanine nucleotide exchange factors (RhoGEFs) and activates the RhoA kinase. In addition to the α-subunit-regulated second messengers signaling pathway, the βγ dimer and other proteins (such as β-arrestin) could also trigger the downstream signaling pathway and modulate cellular functions (Dorsam and Gutkind 2007; Miller and Lefkowitz 2001; Ritter and Hall 2009; Thomsen et al. 2016).

    Energy homeostasis, which refers to biological processes that coordinate the energy intake and energy expenditure over a prolonged time, is important to maintain the longterm stability of the energy storage in organisms (Schwartz et al. 2000). Energy homeostasis not only regulates the normal energy expenditure, which is consumed by daily behavior and regular physiology, but also monitors the energy storage, which is essential for survival, development, growth and reproduction with low food availability (Schwartz et al. 2000). Despite daily energy intake may be variable, energy homeostasis enable animals to adjust cumulative energy intake in response to energy requirement changes (Morton et al. 2006).

    Energy homeostasis is regulated by external factors, such as temperature, stress and food availability, as well as multiple internal factors, including genetic information, development stages, metabolite and hormone levels (Morton et al. 2006; Rønnestad et al. 2017). The hypothalamus is the hub that integrates these external and internal signals, thus regulating energy homeostasis (de Pedro et al. 2006). In the hypothalamus, the central melanocortin system plays an important role in regulating energy homeostasis (Tao 2010). This system includes the orexigenic neuropeptide Y/ Agouti-related peptide (NPY/AgRP) expressing neurons and the anorexigenic neurons expressing proopiomelanocortin (POMC) in the arcuate nucleus, and the downstream receptors of melanocortin-3 and -4 receptors (MC3R and MC4R, Cone 2005). The post-translational products of POMC serve as agonists whereas the AgRP serves as an antagonist (or inverse agonist) to MC3R and MC4R (Tao 2010; Tao et al. 2013) (Fig. 1).

    Figure 1.  Leptin-Melanocortin System. A Neurons expressing NPY/AgRP promote appetitestimulating process whereas neurons expressing POMC lead to an appetite-suppressing process. In the hypothalamus, leptin activates the leptin receptors located in NPY/AgRP expressing neurons, and subsequently decreases appetite by suppressing AgRP/NPY. Leptin binds to the receptors on neurons expressing POMC, resulting in increased α-MSH. Energy homeostasis is regulated by neurons expressing POMC and AgRP/NPY and their cognate GPCRs. B In spotted sea bass, activation of MC4R signaling caused down-regulated npy, agrp and growth hormone gene (gh), suggesting that MC4R signaling activation could further inhibit the NPY/AgRP associated appetite-stimulating process and suppress growth

    With more than 33, 000 identified species, teleosts are the most diversified vertebrates. The large variations in genetics, ecology, morphology, anatomy and physiology of teleost species result in complex species-specific energy homeostasis regulatory mechanisms (Rønnestad et al. 2017). For example, a large proportion of teleosts continue to grow during the whole life span, which is in contrast with the determinate growth in mammals and model animals, such as zebrafish (Danio rerio) (Rønnestad et al. 2017). Moreover, the fish-specific genome duplication hypothesis, which hypothesizes that the duplication(s) of the whole genome occurred in fish, indicates that fish genes/proteins have diverged significantly faster than mammalian homologues (Hoegg et al. 2004). In the context of the endocrine system, a larger number of endocrine receptor paralogs have been identified in fish (Boyce-Derricott et al. 2009). Therefore, neuroendocrine-regulated energy homeostasis need to be reviewed in comparison with mammals.

    In recent decades, several studies have reported and/or reviewed the advances on the field of fish energy balance regulation. Some of these articles are general and represent comparative studies (Hoskins and Volkoff 2012), whereas some are focused particularly on a specific trait (Won and Borski 2013), a group of fish species (Demski 2012), or a single species (Matsuda et al. 2011). Volkoff (2016) and Rønnestad et al. (2017) published two outstanding review papers, and summarized systematically neuroendocrine and endocrine-regulated food intake (Rønnestad et al. 2017; Volkoff 2016). The purpose of this article is to provide a brief review of the physiology and pharmacology of the GPCRs in NPYand melanocortin-regulated energy homeostasis in fish.

GPCRs in NPY- and melanocortin-regulated energy homeostasis

    NPY receptor

  • The NPY family contains NPY, peptide YY (PYY) and pancreatic polypeptide (PP) (Holzer et al. 2012). The NPY is first isolated from porcine brain, and reported to be widely expressed in the central nervous system (CNS) with highly conserved protein sequences among mammals (Duarte-Neves et al. 2016; Larhammar et al. 2001; Tatemoto 1982). NPY plays a pivotal role in regulating food intake and energy homeostasis via activating their cognate GPCRs (reviewed in Lundell et al. 1995; Reichmann and Holzer 2016). In mammals, five functional NPY receptors (Y1, Y2, Y4, Y5 and y6) have been identified and these receptors are coupled with Gαi signaling (reviewed in Michel et al. 1998; Silva et al. 2005). The y6 receptor subtype is written with a small "y" because its physiological function has not been demonstrated. The mammalian Y1 subfamily contains Y1, Y4 and y6 subtypes, and these receptors share ~ 50% identities in amino acid sequences. The Y2 and Y5 subtypes are less conserved, showing only 30% homology to each other (Salaneck et al. 2001).

    The fish NPY receptors were first identified from goldfish (Carassius auratus) and electric ray (Torpedo marmorata) (Blomqvist et al. 1992). Teleost NPY receptors are primarily expressed in brain and peripheral tissues, including eye and the gastrointestinal tract (Fredriksson et al. 2004; Lundell et al. 1997). The teleost NPY receptors could be further divided into six subtypes, including Y1 (zebrafish), Y2, Y4 (Ya), Y7, Y8a (Yc), and Y8b (Yb) receptors (Salaneck et al. 2008; Sundström et al. 2013). Previous studies in river lamprey (Lampetra fluviatilis) suggest that the Ya receptor is the fish ortholog of the mammalian Y4 receptor, whereas Yb and Yc seem to constitute a subtype not identified in mammals (Salaneck et al. 2001). Receptors of Y1 (zebrafish), Y4 (Ya), Y8a (Yc) and Y8b (Yb) are identified as the Y1 receptor subfamily; receptors of Y2 and Y7 belong to Y2 receptor subfamily (Larsson et al. 2005). The Y1 subtypes are identified widely in teleost species whereas the Y2 subtypes are found only in limited teleost species, such as zebrafish, rainbow trout (Oncochynchus mykiss), grouper and large yellow croaker (Larimichthys crocea) (Fredriksson et al. 2004; Larsson et al. 2006; Wang et al. 2014, 2019). With zebrafish, in addition to Y2 and Y7 receptors, the Y2 subfamily contains Y2-2 receptor, which is obtained by the local duplication of the Y2 receptor (Fällmar et al. 2011; Sundström et al. 2013).

    Almost all teleosts produce NPY and PYY, whereas some teleost species further release PY (Cerdá-Reverter and Larhammar 2000). Consistent with previous results in mammals, NPY regulates food intake by mediating Y1 and Y5 receptors in teleosts (Larsson et al. 2005). In goldfish, food deprivation induces an up-regulated npy mRNA expression in the hypothalamus, and refeeding reverses the effects of food deprivation on hypothalamus npy mRNA expression (Narnaware and Peter 2001a; Narnaware et al. 2000). Intracerebroventricular (ICV) injection of Y1 or Y5 receptor agonists causes a dose-dependent effects on food intake in goldfish, and the increased food intake could be abrogated by NPY antagonists (de Pedro et al. 2000). Interestingly, the lower dosages of Y1 or Y5 receptor agonist could increase food intake, whereas higher dosages showed the opposite (de Pedro et al. 2000). The following studies showed coadministration of Y1 and Y5 receptor agonists resulted in an increased effect on food intake when compared with the individual administration of Y1 or Y5 receptor agonist (Narnaware and Peter 2001b). Moreover, suppression of one receptor failed to affect the responsiveness of the other one (Narnaware and Peter 2001b). These results probably indicate that Y1 and Y5 receptors independently regulate food intake in goldfish (Volkoff et al. 2005).

    Physiology and pharmacology studies on NPY receptors are also reported in economically important teleost species. Food deprivation results in up-regulated hypothalamus npy mRNA expressions, and the ICV injection of NPY exhibits a dose-dependent increase in food intake in coho salmon (Oncorhynchus kisutch) and channel catfish (Ictalurus punctatus) (Silverstein and Plisetskaya 2000; Silverstein et al. 1998; Volkoff et al. 2005). The Yb receptor of rainbow trout has high affinity to human PP (Larhammar 1996), and the N-terminally truncated porcine NPY could bind to Yb receptors in Atlantic cod and rainbow trout (Larson et al. 2003; Sharma et al. 1999). Because Y1 receptor subtypes exhibit conserved pharmacological characteristics in mammals and teleosts, some exogenous ligands, which are identified in human and mice studies, are probably involved in fish appetite regulation. These exogenous ligands, especially the small molecular agonist(s), should be tested further in aquaculture.

    Functional studies of the teleost Y2 subfamily are limited. In goldfish, a previous study showed ICV injection of Y2 receptor agonist led to no effects on food intake (Narnaware and Peter 2001b). Despite zebrafish Y2-2 and Y2 receptor showing high sequence similarity, the Y2-2 receptor revealed reversed pharmacological characteristics with the Y2 receptor (Fällmar et al. 2011). Recently, two Y2 subfamily members (Y2 and Y7 receptor) were identified in large yellow croaker with different pharmacological characteristics. The endogenous NPY could activate both Y2 and Y7 receptors, whereas the truncated NPY activated only the Y2 receptor (Wang et al. 2019). Future studies should investigate the physiological functions of Y2 and Y7 receptors in regulating appetite of large yellow croaker via in vivo studies.

  • Melanocortin receptor

  • Melanocortins, including α-, β-, and γ-melanocyte stimulating hormones (α-, β-, and γ-MSH) and adrenocorticotropic hormone (ACTH), are produced by post-translational processing of POMC (reviewed in Dores and Lecaude 2005; Smith and Funder 1988). Melanocortins activate the melanocortin receptors (MCRs), thus regulating multiple physiological functions, including skin color, immunomodulation, steroidogenesis, energy balance and lipid metabolism (reviewed in Tao 2010). MCRs belong to family A rhodopsin-like GPCRs; five MCRs, named MC1R to MC5R, have been identified in mammals (Cone 2006). In these MCRs, the MC3R and MC4R are highly expressed in CNS with non-redundant roles in the regulation of energy homeostasis (Chen et al. 2000; Tao 2010). Activation of the MC3R and/ or MC4R stimulates Gαs signaling, and enhances the intracellular cAMP accumulation (Rodrigues et al. 2015; Tao 2010). Melanocortins and other POMC-derived peptides are endogenous agonists; AgRP is the endogenous antagonist of MC3R and MC4R (Butler et al. 2017; Gantz and Fong 2003). In addition, analogs of α-MSH and some small molecules have also been identified as MC3R and/or MC4R ligands (Sawyer et al. 1980; Sebhat et al. 2002).

  • Melanocortin-3 receptor

  • In mammals, MC3R is widely expressed in brain regions and peripheral tissues, including the placenta, gut and immune cells of macrophages (Chhajlani 1996; Gantz et al. 1993; Jegou et al. 2000; Ni et al. 2006). The mc3r has been identified also in several teleost species, including zebrafish, spiny dogfish (Squalus acanthias) and channel catfish (Klovins et al. 2004; Logan et al. 2003b; Yang et al. 2019). However, based on genomic databases, the existences of mc3r orthologues in pufferfish species (Tetraodon nigroviridis and Fugu rubripes) and spotted sea bass (Lateolabrax maculatus, unpublished data) have not been demonstrated (Logan et al. 2003a, b; Metz et al. 2006). The result that mc3r is absent in several teleost species is consistent with previous considerations that MC3R may serve as the receptor of γ-MSH, which is absent in teleosts (Arends et al. 1998; Kitahara et al. 1988).

    Mouse genetic studies showed MC3R regulates feeding efficiency and fat storage, but does not regulate food intake (Butler et al. 2000; Chen et al. 2000). For example, Mc3r knockout mice did not exhibit hyperphagia and obesity when compared to the wild-type litter mates; these Mc3r knockout mice showed normal energy expenditure and even decreased food intake (Butler et al. 2000; Chen et al. 2000). However, the Mc3r knockout mice showed increased fat mass and reduced lean mass (Butler et al. 2000; Chen et al. 2000). Mice lacking both MC3R and MC4R exhibited exacerbated obesity when compared with MC3R or MC4R single gene knockout mice. This was further evidence that MC3R and MC4R have non-redundant functions in regulating energy homeostasis (Chen et al. 2000). In 2002, a potential loss-offunction MC3R mutation was identified from obese patients (Lee et al. 2002). The following study was convincing evidence that this mutant failed to convey ligand binding to Gαs signaling activation (Tao and Segaloff 2004). After that, several novel MC3R variants were identified from subjects, who had increased fat mass and decreased lean mass (Tao 2007). A recent study showed AgRP neurons expressing MC3R could exert inhibitory signaling to MC4R by modulating γ-aminobutyric acid (GABA) release onto anorexigenic MC4R neurons, thus regulating upper and lower boundaries of energy homeostasis (Ghamari-Langroudi et al. 2018).

    Although MC3R is well studied in mammals, the studies on physiology and pharmacology of teleost MC3Rs are still limited. In rainbow trout, ICV injection of MC4R specific antagonist (HS024) is more potent than MC3R/MC4R antagonist (SHU9119) in increasing food intake (Schjolden et al. 2009). Based on previous studies in mammals, we may propose two hypotheses. First, rainbow trout MC3R plays a less important role in regulating appetite when compared to MC4R (Schjolden et al. 2009). Second, considering that MC3R modulates the anorexigenic MC4R signaling, MC3R antagonism probably alleviates the inhibitory signaling to MC4R (Ghamari-Langroudi et al. 2018). A recent study reported MC3R regulates the upper and lower boundaries of set point, or rheostasis during energy dyshomeostasis, further supporting the second hypothesis (Ghamari-Langroudi et al. 2018). In channel catfish, MC3R exerts high constitutive activities in both cAMP and ERK1/2 signaling. The constitutive cAMP signaling could be suppressed by AgRP (Yang et al. 2019). Moreover, the melanocortin receptor accessory protein 2 (MRAP2) preferentially inhibited both the constitutive and agonist-triggered cAMP signaling rather than ERK1/2 signaling in channel catfish MC3R. It is likely that these results reveal a MC3R-regulated energy homeostasis network in teleosts (Yang et al. 2019).

  • Melanocortin-4 receptor

  • MC4R has been identified in several mammalian and nonmammalian species (reviewed in Tao 2010) with highly conserved amino acids sequences (Hughes et al. 2009; Staubert et al. 2007). In mammals, MC4R is primarily expressed in brain regions (Kishi et al. 2003; Mountjoy et al. 1994; van der Kraan et al. 1999), whereas teleost mc4r is expressed widely in both CNS and peripheral tissues, including gill, liver, intestine, and gonads (Zhang et al. 2019, 2020 and reviewed in Tao 2010). Due to teleostor salmonid-specific whole genome duplication, teleosts exert increased mc4r paralogs. For example, four mc4r paralogs were identified in Atlantic salmon (Salmo salar) (Kalananthan et al. 2020).

    Mice lacking Mc4r expression showed obesity and hyperinsulinemia with increased food intake and decreased energy expenditure (Huszar et al. 1997). Moreover, human genetic studies support the results observed in animal studies. In 1998, two groups independently identified frameshift MC4R mutations from patients with early-onset obesity showing that MC4R is important in regulating energy homeostasis (Vaisse et al. 1998; Yeo et al. 1998). After that, more than 175 distinct MC4R mutations associated with obesity and other diseases have been identified from patients (reviewed in Hinney et al. 2013; Tao 2009).

    Also, MC4R plays an important role in regulating energy homeostasis in teleosts. Previous in vitro studies with MC4R ligands showed ICV injection of MC4R agonist (MTII, a superpotent analog of a-MSH) suppresses food intake whereas the MC4R antagonist (SHU9119) increases the food intake in rainbow trout and goldfish (Cerda-Reverter et al. 2003; Schjolden et al. 2009). In Mexican cavefish (Astyanax mexicanus), mc4r mutations contributed to physiological adaptations to nutrient-poor conditions by increasing appetite, growth, and starvation resistance (Aspiras et al. 2015). The short-term fasting resulted in down-regulation of mc4r with fluctuated changes in agrp and npy gene expressions in spotted sea bass. Conversely, down-regulated mc4r and agrp were observed in long-term fasting, showing that MC4R probably played a more important role in regulating long-term energy balance (Zhang et al. 2019). Likewise, the ya-fish (Schizothorax prenanti) showed up-regulated brain mc4r after short-term fasting (Wei et al. 2013).

    Teleost MC4Rs show different pharmacological characteristics when compared to mammalian MC4Rs. [Nle4, D-Phe7]-α-MSH (NDP-MSH), which is a superpotent analog of α-MSH, is widely used in pharmacological studies of MCRs (Sawyer et al. 1980). Despite both human MC4R and teleost MC4Rs binding to NDP-MSH with high affinity, studies in spotted scat (Scatophagus argus) and several other teleost species consistently showed the maximal binding values of teleost MC4Rs were around 20–40% of that of the human MC4R (Li et al. 2017; Rao et al. 2019; Tao et al. 2020; Yi et al. 2018; Zhang et al. 2019). THIQ is a small molecule agonist in human MC4R. In teleosts, including spotted sea bass, swamp eel and spotted scat (Scatophagus argus), THIQ fails to displace NDP-MSH but stimulates intracellular cAMP accumulation, suggesting that THIQ acts as an allosteric agonist in teleost MC4Rs (Li et al. 2016; Yi et al. 2018; Zhang et al. 2019). A recent study with teleost MC4Rs showed that Ipsen 5i and ML00253764, which are two small molecule hMC4R antagonists (or inverse agonists), served as neutral allosteric modulators at cAMP signaling pathway but allosteric agonists at the ERK1/2 signaling pathway (Yang et al. 2020). Furthermore, this study showed that MCL0020, which is a peptidomimetic compound hMC4R blocker, exhibited divergent pharmacology on spotted scat (Scatophagus argus) and grass carp (Ctenopharyngodon idella) MC4Rs (Yang et al. 2020). The MCL0020 served as an inverse agonist for grass carp MC4R but a neutral antagonist for spotted scat MC4R (Yang et al. 2020).

    Teleost MC4Rs show high constitutive activities in Gαs signaling (Li et al. 2017; Rao et al. 2019; Tao et al. 2020; Yang et al. 2020; Yi et al. 2018; Zhang et al. 2019). Human MC4R mutants with decreased constitutive activity are believed to be associated with obesity pathogenesis (Srinivasan et al. 2004; Tao 2005, 2008). However, in aquaculture, the fish with lower MC4R constitutive activity may exhibit a higher food efficiency, lower basal metabolism and faster weight gain. Development of molecular markers linked to MC4R genotypes with decreased constitutive activity probably contribute to selective breeding in aquaculture. In addition, inverse agonists, especially the small molecule compounds that suppress constitutive activity in teleost MC4Rs, may provide benefits for food intake promotion in aquaculture. For example, a recent study showed that MCL0020 acts as an inverse agonist for grass carp MC4R (Yang et al. 2020).

Future studies in aquaculture
  • Although it is controversial whether mutation in the MC3R is a cause for monogenic obesity, a large number of studies confirmed that MC4R is the most common monogenic form of obesity (Tao 2007). Therefore, variants of MC3R and MC4R are important targets for precision medicine and selective breeding (Kim et al. 2000; Lotta et al. 2019). For example, a recent study which was based on functional characterization over sixty MC4R variants identified in 500, 000 people from UK Biobank, showed human gain-of-function MC4R variants with biased signaling could protect against obesity (Lotta et al. 2019). The relevance of the melanocortin system in the regulation of tenergy homeostasis has also been studied in agriculturally important species. In pigs, a MC4R mutation (D298N) was identified in certain strains with increased feed intake and growth rate (Kim et al. 2000). However, the subsequent pharmacological studies with this mutant showed divergent conclusions. One study showed this mutant failed to activate Gαs signaling (Kim et al. 2004), whereas another study indicated that D298N is functional (Fan et al. 2008). Studies of the melanocortin system in energy balance of economically important aquaculture species are still very limited.

    Based on previous studies, we proposed a potential model for the application of the melanocortin system in aquaculture, with rainbow trout as an example (Fig. 2). The genome-wide (or genetic) association study may be used to investigate whether the MC3R and/or MC4R variant(s) are associated with economic traits, such as higher food intake, growth rate and/or weight gain. The three "P" protocols could be used to investigate the phenotype, physiology and pharmacology of trout carrying the variant. Subsequently, the "Key & Lock Strategy" could be used because the hormone and receptor interact with each other, like the key and lock. For Key Strategy, studies should be focused on identifying the exogenously low-cost ligands that decrease the high constitutive activities of trout MC4R. The potential targets include ligands that may serve as inverse agonists, (negative) allosteric modulator or bitopic ligands (ligands that concomitantly interact with the orthosteric and allosteric binding sites). The preferred ligands are non-peptide or small molecule compounds because they can be given by food rather than injection. In the Lock Strategy, the targets are the variants that exert lower constitutive activities and defects in binding and signaling. The purpose of the Key & Lock Strategy is to suppress the anorectic signaling of MC4R, thus increasing the food intake and decreasing the energy expenditure of cultured trout (Table 1).

    Figure 2.  A potential model for the application of the melanocortin system in aquaculture

    Abbreviations Full name Abbreviations Full name
    ACTH Adrenocorticotropic hormone ICV Intracerebroventricular
    AgRP Agouti-related peptide MCRs Melanocortin receptors
    Ca2+ calcium MC3R and MC4R Melanocortin-3 and melanocortin-4 receptors
    CRE cAMP response element NPY Neuropeptide Y
    CREB cAMP response element-binding protein PYY Peptide YY
    CNS Central nervous system PY Pancreatic polypeptide
    cAMP Cyclic AMP PLC Phospholipase C
    DAG Diacylglycerol
    ER Endoplasmic reticulum POMC Proopiomelanocortin
    Y1, Y2, Y4, Y5 Five functional NPY receptors, Y4 receptor (Ya PKA Protein kinase A
    or y6 receptor receptor), Y8a receptor (Yc receptor), Y8b receptor
    (Yb receptor)
    Ya receptor Y4 receptor PKC Protein kinase C
    Yc receptor Y8a receptor RhoGEFs Rho guanine nucleotide exchange factors
    Yb receptor GPCRs Y8b receptor G protein-coupled receptors s NDP-MSH Stimulatory G protein [Nle4, D-Phe7]-α-MSH, a superpotent analog of α-MSH
    i Inhibitory G protein α-, β-, and γ-MSH α-, β-, And γ-melanocyte stimulating hormones
    IP3 Inositol 1, 4, 5-trisphosphate GABA γ-Aminobutyric acid

    Table 1.  Comparison of selected parameters for tendons shortening scenarios Step-5a to Step-5c

Acknowledgements
  • Research in the authors' laboratories was supported by grants from Blue Granary Science and Technology Innovation [2019YFD0901000].

Author contributions
  • Conceptualization: HW and ZH; visualization: HW and ZH; writing-original draft: HW and ZH; writing-review and editing: HW and ZH.

Declarations

    Conflict of interest

  • The authors declare that they have no conflict of interest.

  • Animal and human rights statement

  • Animal and human studies are not involved in this review paper.

Reference (111)

Catalog

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return