The role of melanocortin signalling in the control of body weight: Evidence from human and murine genetic models

QJM: An International Journal of Medicine

Volumn 93, Issue 1, 2000, Pages 7-14

  Yeo, G S H ^a   Farooqi, I S ^a   Challis, B G ^a   Jackson, R S ^b   O'Rahilly, S ^a,b  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b ADDENBROOKE S HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

MELANOCORTIN; MELANOCORTIN RECEPTOR; NEUROPEPTIDE; PROOPIOMELANOCORTIN;

APPETITE; BODY WEIGHT; GENE EXPRESSION; GENETIC MODEL; HUMAN; NERVE CELL; NONHUMAN; OBESITY; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

EID: 0038141363     PISSN: 00335622     EISSN: None     Source Type: Journal    
DOI: 10.1093/qjmed/93.1.7     Document Type: Review

References (67)

1. Bertagna X. Proopiomelanocortin-derived peptides. Endocrinol Metab Clin North Am 1994; 23:467-85.
2. Castro MG, Morrison E. Post-translational processing of proopiomelanocortin in the pituitary and in the brain. Crit Rev Neurobiol 1997; 11:35-57.
3. Smith EM, Blalock JE. Human lymphocyte production of corticotropin and endorphin-like substances: association with leukocyte interferon. Proc Natl Acad Sci USA 1981; 78:7530-4.
4. Bloomquist BT, Eipper BA, Mains RE. Prohormone-converting enzymes: regulation and evaluation of function using antisense RNA. Mol Endocrinol 1991; 5:2014-24.
5. Zhou A, Bloomquist BT, Mains RE. The prohormone convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a strict temporal order during proopiomelanocortin biosynthetic processing. J Biol Chem 1993; 268:1763-9.
6. Axelrod J, Reisine TD. Stress hormones: their interaction and regulation. Science 1984; 224:452-9.
7. Wintzen M, Yaar M, Burbach JP, Gilchrest BA. Proopiomelanocortin gene product regulation in keratinocytes. J Invest Dermatol 1996; 106:673-8.
8. Wakamatsu K, Graham A, Cook D, Thody AJ. Characterisation of ACTH peptides in human skin and their activation of the melanocortin-1 receptor. Pigment Cell Res 1997; 10:288-97.
9. Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 1995; 11:328-30.
10. Cone RD, Lu D, Koppula S, Vage DI, Klungland H, Boston B, Chen W, Orth DN, Pouton C, Kesterson RA. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res 1996; 51:287-317.
11. Frandberg PA, Doufexis M, Kapas S, Chhajlani V. Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor. Biochem Biophys Res Commun 1998; 245:490-2.
12. Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T. Molecular cloning of a novel melanocortin receptor. J Biol Chem 1993; 268:8246-50.
13. Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, Entwistle ML, Simerly RB, Cone RD. Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci USA 1993; 90:8856-60.
14. Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson SJ, DelValle J, Yamada T. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem 1993; 268:15174-9.
15. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 1994; 8:1298-308.
16. Panskepp J, Reilly P, Bishop P, Meeker RB, Vilberg TR, Kastin AJ. Effects of alpha-MSH on motivation, vigilance and brain respiration. Pharmacol Biochem Behav 1976; 5:59-64.
17. Poggioli R, Vergoni AV, Bertolini A. ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa opiate agonists. Peptides 1986; 7:843-8.
18. Hruby VJ, Lu D, Sharma SD, Castrucci AL, Kesterson RA, al-Obeidi FA, Hadley ME, Cone RD. Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995; 38:3454-61.
19. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385:165-8.
20. Cheung CC, Clifton DK, Steiner RA. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997; 138:4489-92.
21. Thornton JE, Cheung CC, Clifton DK, Steiner RA. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 1997; 138:5063-6.
22. Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG. Leptin increases hypothalamic proopiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 1997; 46:2119-23.
23. Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR, Kuhar MJ, Saper CB, Elmquist JK. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 1998; 21:1375-85.
24. Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 1998; 393:72-6.
25. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO, et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 1994; 371:799-802.
26. Bultman SJ, Michaud EJ, Woychik RP. Molecular characterization of the mouse agouti locus. Cell 1992; 71:1195-204.
27. Miller MW, Duhl DM, Vrieling H, Cordes SP, Ollmann MM, Winkes BM, Barsh GS. Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. Genes Dev 1993; 7:454-67.
28. Michaud EJ, Bultman SJ, Klebig ML, van Vugt MJ, Stubbs LJ, Russell LB, Woychik RP. A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. Proc Natl Acad Sci USA 1994; 91:2562-6.
29. Michaud EJ, Bultman SJ, Stubbs LJ, Woychik RP. The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. Genes Dev 1993; 7:1203-13.
30. Duhl DM, Stevens ME, Vrieling H, Saxon PJ, Miller MW, Epstein CJ, Barsh GS. Pleiotropic effects of the mouse lethal yellow (Ay) mutation explained by deletion of a maternally expressed gene and the simultaneous production of agouti fusion RNAs. Development 1994; 120:1695-708.
31. Duhl DM, Vrieling H, Miller KA, Wolff GL, Barsh GS. Neomorphic agouti mutations in obese yellow mice. Nat Gene 1994; 8:59-65.
32. Wolff GL, Galbraith DB, Domon OE, Row JM. Phaeomelanin synthesis and obesity in mice. Interaction of the viable yellow (Avy) and sombre (eso) mutations. J Hered 1978; 69:295-8.
33. Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, Mountjoy KG, Cone RD. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 1993; 72:827-34.
34. Yang YK, Ollmann MM, Wilson BD, Dickinson C, Yamada T, Barsh GS, Gantz I. Effects of recombinant agouti-signaling protein on melanocortin action. Mol Endocrinol 1997; 11:274-80.
35. Shutter JR, Graham M, Kinsey AC, Scully S, Luthy R, Stark KL. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 1997; 11:593-602.
36. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997; 278:135-8.
37. Chen P, Li C, Haskell-Luevano C, Cone RD, Smith MS. Altered expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation. Endocrinology 1999; 140:2645-50.
38. Mizuno TM, Mobbs CV. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 1999; 140:814-17.
39. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19:155-7.
40. Leiter EH. Carboxypeptidase E and obesity in the mouse. J Endocrinol 1997; 155:211-14.
41. Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat Genet 1995; 10:135-42.
42. Fricker LD, Berman YL, Leiter EH, Devi LA. Carboxypeptidase E activity is deficient in mice with the fat mutation. Effect on peptide processing. J Biol Chem 1996; 271:30619-24.
43. Rovere C, Viale A, Nahon J, Kitabgi P. Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice. Endocrinology 1996; 137:2954-8.
44. Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999; 20:68-100.
45. Utsunomiya N, Ohagi S, Sanke T, Tatsuta H, Hanabusa T, Nanjo K. Organization of the human carboxypeptidase E gene and molecular scanning for mutations in Japanese subjects with NIDDM or obesity. Diabetologia 1998; 41:701-5.
46. O'Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, White A, Gibson S, Taylor K, Carr C. Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med 1995; 333:1386-90.
47. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997; 16:303-6.
48. Rouille Y, Martin S, Steiner DF. Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. J Biol Chem 1995; 270:26488-96.
49. Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith DM, Ghatei MA, Herbert J, Bloom SR. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996; 379:69-72.
50. Furuta M, Yano H, Zhou A, Rouille Y, Holst JJ, Carroll R, Ravazzola M, Orci L, Furuta H, Steiner DF. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc Natl Acad Sci USA 1997; 94:6646-51.
51. Perone MJ, Ahmed I, Linton EA, Castro MG. Procorticotrophin releasing hormone is endoproteolytically processed by the prohormone convertase PC2 but not by PC1 within stably transfected CHO-K1 cells. Biochem Soc Trans 1996; 24:497S.
52. Rovere C, Barbero P, Kitabgi P. Evidence that PC2 is the endogenous pro-neurotensin convertase in rMTC 6-23 cells and that PC1- and PC2-transfected PC12 cells differentially process pro-neurotensin. J Biol Chem 1996; 271:11368-75.
53. Johanning K, Juliano MA, Juliano L, Lazure C, Lamango NS, Steiner DF, Lindberg I. Specificity of prohormone convertase 2 on proenkephalin and proenkephalin-related substrates. J Biol Chem 1998; 273:22672-80.
54. Jackson RS, O'Rahilly S, Brain C, Nussey SS. Proopiomelanocortin products and human early-onset obesity. J Clin Endocrinol Metab 1999; 84:819-20.
55. Nussey SS, Soo SC, Gibson S, Gout I, White A, Bain M, Johnstone AP. Isolated congenital ACTH deficiency: a cleavage enzyme defect? Clin Endocrinol 1993; 39:381-5.
56. Clark AJ, McLoughlin L, Grossman A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet 1993; 341:461-2.
57. Chen W, Kelly MA, Opitz-Araya X, Thomas RE, Low MJ, Cone RD. Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell 1997; 91:789-98.
58. 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. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88:131-41.
59. Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yagaloff KA, Fisher SL, Burn P, Palmiter RD. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet 1999; 21:119-22.
60. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 1998; 20:111-12.
61. Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998; 20:113-14.
62. Gu W, Tu Z, Kleyn PW, Kissebah A, Duprat L, Lee J, Chin W, Maruti S, Deng N, Fisher SL, Franco LS, Burn P, Yagaloff KA, Nathan J, Heymsfield S, Albu J, Pi-Sunyer FX, Allison DB. Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 1999; 48:635-9.
63. Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, Ziegler A, Gerber G, Sina M, Gorg T, Mayer H, Siegfried W, Fichter M, Remschmidt H, Hebebrand J. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab 1999; 84:1483-6.
64. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, MacCluer JW, Blangero J. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997; 15:273-6.
65. Hager J, Dina C, Francke S, Dubois S, Houari M, Vatin V, Vaillant E, Lorentz N, Basdevant A, Clement K, Guy-Grand B, Froguel P. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat Genet 1998; 20:304-8.
66. Rotimi CN, Comuzzie AG, Lowe WL, Luke A, Blangero J, Cooper RS. The quantitative trait locus on chromosome 2 for serum leptin levels is confirmed in African-Americans. Diabetes 1999; 48:643-4.
67. Tatro JB. Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides. Neuroimmunomodulation 1996; 3:259-84.