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The Melanocortin-4 Receptor

  • Roger D. Cone
Chapter
Part of the The Receptors book series (REC)

Abstract

After cloning of the melanocyte MC1-R (1,2) and adrenocortical MC2-R (2),interest in the possibility of unique neural homologs of these receptors grew from observations of central effects of melanocortins, such as effects on learning and memory (reviewed in ref. 3) and temperature control (4). Furthermore, the in situ ligand binding experiments of Tatro had demonstrated the presence of high-affinity binding sites for (125I-NDP-MSH) in rat brain (5), and these as well as the physiologic experiments suggested these sites were encoded by pharmacologically distinct melanocortin receptors.

Keywords

Inferior Colliculus Arcuate Nucleus POMC Neuron POMC mRNA Melanocortin System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Chhajlani, V. and Wikberg, J. E. S. (1992) Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 309, 417–420.PubMedCrossRefGoogle Scholar
  2. 2.
    Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., and Cone, R. D. (1992) The cloning of a family of genes that encode the melanocortin receptors. Science 257, 543–546.CrossRefGoogle Scholar
  3. 3.
    DeWied, D. and Jolles, J. (1982) Neuropeptides derived from pro-opiocortin: behavioral, phsyiological, and neurochemical effects. Physiol. Rev. 62, 977–1059.Google Scholar
  4. 4.
    Murphy, M. T., Richards, D. B., and Lipton, J. M. (1983) Antipyretic potency of centrally administered a-melanocyte stimulating hormone. Science 221, 192–194.PubMedCrossRefGoogle Scholar
  5. 5.
    Tatro, J. B. (1990) Melanotropn receptors in the brain are differentially distributed and recognize both corticotropin and a-melanocyte stimulating hormone. Brain Res. 536, 124–132.PubMedCrossRefGoogle Scholar
  6. 6.
    Gantz, I., Shimoto, Y., Konda, Y., Miwa, H., Dickinson, C. J., and Yamada, T. (1994) Molecular cloning, expression, and characterization of a fifth melanocortin receptor. Biochem. Biophys. Res. Commun. 200, 1214–1220.PubMedCrossRefGoogle Scholar
  7. 7.
    Labbe, O., Desarnaud, F., Eggerickx, D., Vassart, G., and Parmentier, M. (1994) Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. Biochemistry 33, 4543–4549.PubMedCrossRefGoogle Scholar
  8. 8.
    DeWied, D. and Wolterink, G. (1988) Structure-activity studies on the neuroactive and neurotropic effects related to ACTH. Ann. N.Y. Acad. Sci. 525, 130–140.CrossRefGoogle Scholar
  9. 9.
    Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B., and Cone, R. D. (1994) Localization of the melanocortin-4 receptor (MCR-4) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298–1308.PubMedCrossRefGoogle Scholar
  10. 10.
    Roselli-Rehfuss, L., Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., Low, M. J., Tatro, J. B., Entwistle, M. L., Simerly, R., and Cone, R. D. (1993) Identification of a receptor for y-MSH and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl. Acad. Sci. U. S. A. 90, 8856–8860.PubMedCrossRefGoogle Scholar
  11. 11.
    Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J., and Cone, R. D. (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168.PubMedCrossRefGoogle Scholar
  12. 12.
    Huszar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q., Berkemeir, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D., Smith, F. J., Campfield, L. A., Burn, P., and Lee, F. (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141.PubMedCrossRefGoogle Scholar
  13. 13.
    Gu, W., Tu, Z., Kleyn, P. W., at al. (1999). Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 48, 635–639.PubMedCrossRefGoogle Scholar
  14. 14.
    Lu, D., Vage, D. I., and Cone, R. D. (1998) A ligand-mimetic model for the constitutive activation of the melanocortin-1 receptor. Mol. Endocrinol. 12, 592–604.PubMedCrossRefGoogle Scholar
  15. 15.
    Schioth, H. B., Petersson, S., Muceniece, R., Szardenings, M., and Wikberg, J. E. S. (1997) Deletions of the N-terminal regions of the human melanocortin receptors FEBS Lett. 410, 223–228.PubMedCrossRefGoogle Scholar
  16. 16.
    Lu, D., Willard, D., Patel, I. R.,Kadwell, S., Overton, L., Kost, T., Luther, M., Chen, W., Woychik, R. P. Wilkison, W. O., and Cone, R. D. (1994) Agouti protein is an antagonist of the melanocyte-stimulating hormone receptor Nature 371 799–802.PubMedCrossRefGoogle Scholar
  17. 17.
    Fong, T. M., Mao, C., MacNeil, C., Kalyani, R., Smith, T., Weinberg, D., Tota, M. R., and Van der Ploeg, L. H. (1997) ART (protein product of the agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem. Biophys. Res. Commun. 237, 629–631.PubMedCrossRefGoogle Scholar
  18. 18.
    Mountjoy, K. G., Willlard, D. H., and Wilkison, W. O. (1999) Agouti antagonism of melanocortin-4 receptor: greater effect with desacetyl-cz-MSH. Endocrinology 140, 2167–2172.PubMedCrossRefGoogle Scholar
  19. 19.
    Ollmann, M. M., Wilson, B. D., Yang, Y.-K., Kerns, J. A., Chen, Y., Gantz, I., and Barsh, G. S. (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–137.PubMedCrossRefGoogle Scholar
  20. 20.
    Yang, Y.-K., Thompson, D. A., Dickinson, C. J., Wilken, J., Barsh, G. S., Kent., S. B. H., and Gantz, I. (1999) Characterization of agouti-related protein binding to melanocortin receptors. Mol. Endocrinol. 13, 148–155.PubMedCrossRefGoogle Scholar
  21. 21.
    Yang, Y., Ollmann, M. M., Wilson, B. D., Dickinson, C., Yamada, T., Barsh, G. S., and Gantz, I. (1997) Effects of recombinant agouti-signaling protein on melanocortin action. Mol. Endocrinol. 11, 274–280.PubMedCrossRefGoogle Scholar
  22. 22.
    Gantz, I., Miwa, H., Konda, Y., Shimoto, Y., Tashiro, T., Watson, S. J., DelValle, J., and Yamada, T. (1993) Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 268, 15,174–15, 179.Google Scholar
  23. 23.
    Low, M. J., Simerly, R. B., and Cone, R. D. (1994) Receptors for the melanocortin peptides in the central nervous system. Curr. Opin. Endocrinol. Diab. 1, 79–88.CrossRefGoogle Scholar
  24. 24.
    Chhajlani, V. (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues Biochem. Mol. Biol. Int. 38, 73–80.PubMedGoogle Scholar
  25. 25.
    Kraan, V. D., Tatro, J. B., Entwistle, M. L., Brakkee, J. H., Burbach, J. P. H., Adan, R. A. H., and Gispen, W. H. (1999) Expression of melanocortin and proopiomelanocortin in the rat spinal cord in relation to the neurotrophic effects of melanocortins. Mol. Brain Res. 63, 276–286.PubMedCrossRefGoogle Scholar
  26. 26.
    Chen, W., Kelly, M. A., Opitz-Araya, X., Thomas, R. E. Low, M. J., and Cone, R. D. (1997) Exocrine gland dysfunction in MC5-R deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell 91, 789–798.PubMedCrossRefGoogle Scholar
  27. 27.
    Elkabes, S., Loh, Y. P., Nieburgs, A., and Wray, S. (1989) Prenatal ontogenesis of pro-opiomelanocortin in the mouse central nervous system and pituitary: gland: an in situ hybridization and immunocytochemical study. Brain Res. Del). Brain Res. 46, 85–95.CrossRefGoogle Scholar
  28. 28.
    Schwartzberg, D. G., and Nakane, P. K. (1982) Ontogenesis of adrenocorticotropin-related peptide determinants in the hypothalamus and pituitary gland of rat. Endocrinology 110, 855–864.PubMedCrossRefGoogle Scholar
  29. 29.
    Lichtensteiger, W., Hanimann, B., Schlumph, M., Siegrist, W., and Eberle, A. N. (1993) Pre-and postnatal ontogeny of [1251] Nle4, D-PFE7-a-MSH binding sites in rat brain. Ann. N. Y. Acad. Sci. 680, 652–654.PubMedCrossRefGoogle Scholar
  30. 30.
    Lichtensteiger, W., Hanimann, B., Siegrist, W., and Eberle, A. N. (1996) Region-and stage-specific patterns of melanocortin receptor ontogeny in rat central nervous system, cranial nerve ganglia and sympathetic ganglia. Dey. Brain. Res. 91, 93–110.CrossRefGoogle Scholar
  31. 31.
    Kistler-Heer, V., Lauber, M. E., and Lichtensteiger, W. (1998) Different developmental patterns of melanocortin MC3 and MC4 receptor mRNA: predominance of MC4 in fetal rat nervous system. J. Neuroendocrinol. 10, 133–146.PubMedCrossRefGoogle Scholar
  32. 32.
    Mountjoy, K. G. and Wild, J. M. (1998) Melanocortin-4 receptor mRNA expression in the developing autonomic and central nervous systems. Dey. Brain. Res. 107, 309–314.CrossRefGoogle Scholar
  33. 33.
    Contreras, P. C., and Takemori, A. E. (1984) Antagonism of morphine-induced analgesia, tolerance, and dependence by a-melanocyte-stimulating hormone. J. Pharmacol. Exp. Ther. 229, 21–26.PubMedGoogle Scholar
  34. 34.
    Szekely, J. I., Miglecz, E., Dunai-Kovacs, Z., Tarnawa, I., Ronai, A. Z., Graf, L., and Bajusz, S. (1979) Attenuation of morphine tolerance and dependence by a-melanocyte stimulating hormone (a-MSH). Life Sci. 24, 1931–1938.PubMedCrossRefGoogle Scholar
  35. 35.
    Alvaro, J. D., Tatro, J. B., Quillan, J. M., Fogliano, M., Eisenhard, M., Lerner, M. R., Nestler, E. J., and Duman, R. S. (1996) Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction. Mol. Pharmacol. 50, 583–591.PubMedGoogle Scholar
  36. 36.
    Alvaro, J. D., Tatro, J. B., and Duman, R. S. (1997) Melanocortins and opiate addiction Life Sci. 61, 1–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Harrold, J.A., Widdowson, P.S., and Williams, G. (1999) Altered energy balance causes selective changes in melanocortin-4 (MCR4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions. Diabetes 48, 267–271.PubMedCrossRefGoogle Scholar
  38. 38.
    Adan, R. A H., Oosterom, J., Ludvigsdotter, G., Brakkee, J. H., Burbach, J. P. H., and Gispen, W. H. (1994) Identification of antagonists for melanocortin MC3, MC4 and MC5 receptors. Eur. J. Pharm. 269, 331–337.CrossRefGoogle Scholar
  39. 39.
    Hruby, V. J., Lu, D., Sharma, S. D., Castrucci, A. L., Kesterson, R. A., Al-Obeidi, F. A., Hadley, M. E., and Cone, R. D. (1995) Cyclic lactam a-melanotropin analogues of Ac-Nle4[Asp4, I-Phe’Lys10]a-MSH (4–10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J. Med. Chem. 38, 3454–3461.PubMedCrossRefGoogle Scholar
  40. 40.
    Al-Obeidi, F., Castrucci, A. M. d. L., HAdley, M. E., and Hruby, V. J. (1989) Potent and prolonged acting cycle lactam analogues of a-melanotropin:design based on molecular dynamics. J. Med. Chem. 32, 2555–2561.PubMedCrossRefGoogle Scholar
  41. 41.
    Kask, A., Mutulis, F., Muceniece, R., Pahkla, R., Mutule, I., Wikberg, J. E. S., Rago, L., and Schioth, H. B. (1998) Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024):evaluation in vitro and in vivo. Endocrinology 139, 5006–5014.PubMedCrossRefGoogle Scholar
  42. 42.
    Schioth, H. B., Mutulis, F., Muceniece, R., Prusis, P., and Wilberg, J. E. S. (1998) Discovery of novel melanocortin-4 receptor selective MSH analogues. Br. J. Pharamacol. 124, 75–82.CrossRefGoogle Scholar
  43. 43.
    Skuladottir, G. V., Jonsson, L., Skarphedinsson, J. O., Mutulis, F., Muceniece, R., Raine, A., Mutule, I., Helgason, J., Prusis, P., Wikberg, J. E. S., and Schioth, H. B. (1999) Long term orexigenic ffect of a novel melanocortin 4 receptor selective antagonist. Br. J. Pharm. 126, 27–34.CrossRefGoogle Scholar
  44. 44.
    Lu, D., Chen, W., and Cone, R. D. (1998) Regulation of melanogenesis by the MSH receptor in The Pigmentary System. (Nordlund, J., Boissy, R., Hearing, V., King, R., and Ortonne, J.-P., eds.) Oxford University Press, New York.Google Scholar
  45. 45.
    Wolff, G. L., Roberts, D. W., and Galbraith, D. B. (1986) Prenatal determination of obesity, tumor susceptibility, and coat color pattern in viable yellow (AvY/a) mice. J. Heredity 77, 151–158Google Scholar
  46. 46.
    Frigeri, L. G., Wolff, G. L., and Robel, G. (1983) Impairment of glucose tolerance in yellow (Avy/A) (Balb/c xVY) F-1 hybrid mice by hyperglycemic peptide(s) from human pituitary glands. Endocrinology 113, 2097–2105.PubMedCrossRefGoogle Scholar
  47. 47.
    Wolff, G. L. and Flack, J. D. (1971) Genetic regulation of plasma corticosterone concentration and its response to castration and allogeneic tumor growth in the mouse. Nature 232, 181–182.Google Scholar
  48. 48.
    Wolff, G. L. (1963) Growth of inbred yellow (Ay) and non-yellow (aa) mice in parabiosis. Genetics 48, 1041–1058.PubMedGoogle Scholar
  49. 49.
    Bultman, S. J., Michaud, E. J., and Woychik, R. P. (1992) Molecular characterization of the mouse agouti locus. Cell 71, 1195–1204.PubMedCrossRefGoogle Scholar
  50. 50.
    Miller, M. W., Duhl, D. M. J., Vrieling, H., Cordes, S. P., Ollmann, M. M., Winkes, B. M., and Barsh, G. S. (1993) Cloning of the mouse agouti gene predicts a novel secreted protein ubiquitously expressed in mice carrying the lethal yellow (AY) mutation. Genes Dev. 7, 454–467.PubMedCrossRefGoogle Scholar
  51. 51.
    Manne, J., Argeson, A. C., and Siracusa, L. D. (1995) Mechanisms for the pleiotropic effects of the agouti gene. Proc. NAt1. Acad. Sci. U. S. A. 92, 4721–4724.CrossRefGoogle Scholar
  52. 52.
    Olivera, B. M., Miljanich, G. P., Ramachandran, J., and Adams, M. E. (1994) Calcium channel diversity and neurotransmitter release: the w-Conotoxins and w-Agatoxins. Annu. Rev. Biochem. 63, 823–867.PubMedCrossRefGoogle Scholar
  53. 53.
    Silvers, W. K. (1958) An experimental approach to action of genes at the agouti locus in the mouse. III. Transplants of newborn Aw A and aa hosts. J. Exp. Zool. 137, 189–196.PubMedCrossRefGoogle Scholar
  54. 54.
    Silvers, W. K. and Russel, E. S. (1955) An experimental approach to action of genes at the agouti locus of the mouse. J. Exp. Zool. 130, 199–220.CrossRefGoogle Scholar
  55. 55.
    Vage, D. I., Lu, D., Klungland, H., Lien, S., Adalsteinsson, S., and Cone, R. D. (1997) A non-epistatic interaction of agouti and extension in the fox, Vulpes vulpes. Nat. Genet. 15, 311–315.CrossRefGoogle Scholar
  56. 56.
    Kwon, H. Y., Bultman, S. J., Loftier, C., Chen, W.-J., Furdon, P. J., Powell, J. G., Usala, A.-L., Wilkison, W., Hansmann, I., and Woychik, R. P. (1994) Molecular structure and chromosomal mapping of the human homolog of the agouti gene. Proc. Natl. Acad. Sci. U. S. A. 91, 9760–9764.PubMedCrossRefGoogle Scholar
  57. 57.
    Klebig, M. L., Wilkinson, J. E., Geisler, J. G., and Woychik, R. P. (1995) Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc. Natl. Acad. Sci. U. S. A. 92, 4728–4732.PubMedCrossRefGoogle Scholar
  58. 57a.
    Jones, B. H., Kim, J. H., Zemel, M. B., Woychik, R. P., Michaud, E. J., Wilkison, W. O., and Moustaid, N. (1996) Upregulation of adipocyte metabolism by agouti protein: possible paracrine actions in yellow mouse obesity. Am. J. Physiol. 270, E192–E196.PubMedGoogle Scholar
  59. 58.
    Kim, J. H., Kiefer, L. L., Woychik, R. P., Wilkison, W. O., Truesdale, A., Ittoop, O., Willard, D., Nichols, J., and Zemel, M. B. (1997) Agouti regulation of intracellular calcium: role of melanocortin receptors. Am J. Physiol. 272, E379–384.PubMedGoogle Scholar
  60. 59.
    Zemel, M. B. (1998) Nutritional and endocrine modulation of intracellular calcium: implications in obesity, insulin resistance and hypertension. Mol. Cell. Biochem. 188, 129–136.PubMedCrossRefGoogle Scholar
  61. 60.
    Mynatt, R. L., Miltenberger, R. J., Klebig, M. L., Zemel, M. B., Wilkison, J. E., Wilkison, W. O., and Woychik, R. P. (1997) Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity. Proc. Natl. Acad. Sci. U. S. A. 94, 919–922.PubMedCrossRefGoogle Scholar
  62. 61.
    Zemel, M. B., Kim, J. H., Woychik, R. P., Michaud, E. J., Kadwell, S. H., Patel, I. R., and Wilkison, W. O. (1995) Agouti regulation of intracellular calcium: role in the insulin resistance of viable yellow mice. Proc. Natl. Acad. Sci. U. S. A. 92, 4733–4737.PubMedCrossRefGoogle Scholar
  63. 61a.
    Boston, B. A. and Cone, R. D. (1996) Characterization of melanocortin receptor subtype expression in murine adipose tissues and in the 3T3–L1 cell line. Endocrinology 137, 2043–2050.PubMedCrossRefGoogle Scholar
  64. 62.
    Shutter, J. R., Graham, M., Kinsey, A. C., Scully, S., Luthy, R., and Stark, K. L. (1997) Hypothalamic expression ART, a novel gene related to agouti, is upregulated in oese and diabetic mutant mice. Genes Dev. 11, 593–602.PubMedCrossRefGoogle Scholar
  65. 63.
    Broberger, C., De Lecea, L., Sutcliffe, J. G., and Hokfelt, T. (1998) Hypocretin/ orexin-and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J. Comp. Neurol. 402, 460–474.PubMedCrossRefGoogle Scholar
  66. 64.
    Chen, P., Li, C., Haskell-Luevano, C., Cone, R. D., and Smith, M. S. (1998) Altered expression of agouti-related protein and its colocalization with neuropeptide in the arcuate nucleus of the hypothalamus. Endocrinology 140, 2645–2650.CrossRefGoogle Scholar
  67. 65.
    Hahn, T. M., Breininger, J. F., Baskin, D. G., and Schwartz, M. W. (1999) Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat. Neurosci. 1, 271–272.Google Scholar
  68. 66.
    Haskell-Luevano, C., Chen, P., Li, C., Chang, K., Smith, M. S. Cameron, J. L., and Cone, R. D. (1999) Characterization of the neuroanatomical distribution of agouti-related protein (AGRP) immunoreactivity in the rhesus monkey and the rat. Endocrinology 140, 1408–1415.PubMedCrossRefGoogle Scholar
  69. 67.
    Wilson, B. D., Kaelin, C. B., Ollmann, M. M., Gantz, I., Watson, S. J., and Barsh, G. S. (1999) Physiological and anatomical circuitry between agouti-related protein and leptin signaling. Endocrinology 140, 2387–2397.PubMedCrossRefGoogle Scholar
  70. 68.
    Broberger, C., Johnsen, J., Schalling, M., and Hokfelt, T. (1997) Hypothalamic neurohistochemistry of the murine anorexia (anx/anx) mutation: altered processing of neuropeptide Yin the arcuate nucleus. J. Comp. Neurol. 13, 124–135.CrossRefGoogle Scholar
  71. 69.
    Maltais, L. J., Lane, P. W., and Beamer, W. G. (1984) Anorexia, a recessive mutation causing starvation in preweanling mice. J. Hered. 75, 468–472.PubMedGoogle Scholar
  72. 70.
    Graham, M., Shuttre, J. R., Sarmieto, U., Sarosi, I., and Stark, K. L. (1997) Overexpression of Agrt leads to obesity in transgenic mice. Nat. Genet. 17, 273–274.PubMedCrossRefGoogle Scholar
  73. 71.
    Mizuno, T. M. and Mobbs, C. V. (1999) Hypothalamic agouti-related messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814–817.PubMedCrossRefGoogle Scholar
  74. 72.
    Quillan, J. M., Sadee, W., Wei, E. T., Jimenez, C., Ji, L., and Chang, J. K. (1998) A synthetic human agouti-related protein-(83–132)-NH2 fragment is a potent inhibitor of melanocortin receptor function. FEBS Lett. 428, 59–62.PubMedCrossRefGoogle Scholar
  75. 73.
    Rossi, M., Kim, M. S., Morgan, D. G., Small, C. J., Edwards, C. M., Sunter, D., Abusnana, S., Goldstone, A. P., Russel, S. H., Stanley, S. A., Smith, D. M., Yagaloff, K., Ghatei, M. A., and Bloom, S. R. (1998) A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139, 4428–4431.PubMedCrossRefGoogle Scholar
  76. 74.
    Rosenfeld, R. D., Zeni, L., Welcher, A. A., Narhi, L. O., Hale, C., Marasco, J., Delaney, J., Gleason, T., Philo, J. S., Katta, V., Hui, J., Baumgartner, J., Graham, M., Stark, K. L., and Karbon, W. (1998) Biochemical, biophysical, and pharmacological characterization bacterially expressed human agouti-related protein. Biochemistry 37, 16, 041–16, 052.Google Scholar
  77. 75.
    Bures, E. J., Hui, J. O., Young, Y., Chow, D. T., Katta, V., Rohde, M. F., Zeni, L., Rosenfeld, R. D., Stark, K. L., and Haniu, M. (1998) Determination of disulfide structure in agouti-related protein (AGRP) by stepwise reduction and alkylation. Biochemistry 37, 12, 172–12, 177.CrossRefGoogle Scholar
  78. 76.
    Tota, M. R., Smith, T. S., Mao, C., MacNeil, T., Mosley, R. T., Van der Ploeg, L. H. T., and Fong, T. M. (1999) Molecular interaction of agouti protein and agouti-related protein with human melanocortin receptors. Biochemistry 38, 897–904.PubMedCrossRefGoogle Scholar
  79. 77.
    Michaud, E. J., Bultman, S. J., Stubbs, L. J., and Woychik, R. P. (1993) The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. Genes Dey. 7, 1203–1213.CrossRefGoogle Scholar
  80. 78.
    Al-Obeidi, F., Hadley, M. E., Pettitt, B.-M., and Hruby, V. J. (1989) Design of a new class of superpotent cyclic a-melanotropins based on quenched dynamic simulations. J. Am. Chem. Soc. 111, 3413–3416.CrossRefGoogle Scholar
  81. 79.
    Sugg, E. E., Castrucci, A. M., Hadley, M. E., van Binst, G., and Hruby, V. J., (1988) Cyclic lactam analogues of Ac-[Nle’]alpha-MSH4–11-NH2. Biochemistry 27, 8181–8188.PubMedCrossRefGoogle Scholar
  82. 80.
    Frigeri, L. G., Wolff, G. L., and Teguh, C. (1988) Differential responses of yellow Avy/A agouti A/a (Balb/c x VY) F-1 hybrid mice to the same diets: glucose tolerance, weight gain, and adipocyte cellularity. Int. J. Obesityl 2, 305–320.Google Scholar
  83. 81.
    Yen, T. T., McKee, M. M., and Stamm, N. B. (1984) Thermogenesis and weight control. Int. J. Obesity 8 (Suppl. 1), 65–78.Google Scholar
  84. 82.
    Jegou, S., Blasquez, C., Delbende, C., Bunel, D. T., and Vaudry, H. (1993) Regulation of alpha-melanocyte-stimulating hormone release from hypothalamic neurons. Ann. N. Y. Acad. Sci. 680, 260–278.PubMedCrossRefGoogle Scholar
  85. 83.
    Garcia de Yebenes, E. and Pelletier, G. (1994) Negative regulation of proopiomelanocortin gene expression by GABAA receptor activation in the rat arcuate nucleus. Peptides 15, 615–618.CrossRefGoogle Scholar
  86. 84.
    Bergendahl, M., Wiemann, J. N., Clifton, D. K., Huhtaniemi, I.,and Steiner, R.A., (1992) Short-term starvation decreases POMC mRNA but does not alter GnRH mRNA in the brain of adult male rats. Neuroendocrinology 56, 913–920.PubMedCrossRefGoogle Scholar
  87. 85.
    Brady, L. S., Smith, M. A., Gold, P. W., and Herkenham, M. (1990) Altered expression of hypothalmic neuropeptide mRNAs in food-restricted and food-deprived rats. Neuroendocrinology 52, 441–447.PubMedCrossRefGoogle Scholar
  88. 86.
    Thornton, J. E., Cheung, C. C., Clifton, D. K., and Steiner, R. A., (1997) Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138, 5063–5066.PubMedCrossRefGoogle Scholar
  89. 87.
    Schwartz, M. W., Seeley, R. J., Woods, S.C., Weigle, D. S, Campfield, L. A., Burn, P., and Baskin, D. G. (1997) Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119–2123.PubMedCrossRefGoogle Scholar
  90. 88.
    Beaulieu, S, Gagne, B., and Barden, N. (1988) Glucocorticoid regulation of proopiomelanocortin messenger ribonucleic acid content of rat hypothalamus. Mol. Endocrinol. 2, 727–731.PubMedCrossRefGoogle Scholar
  91. 89.
    Chowen-Breed, J., Fraser, H. M., Vician, L., Damassa, D. A., Clifton, D. K., and Steiner, R. A. (1989) Testosterone regulation of proopiomelanocortin messenger ribonucleic acid in the arcuate nucleus of the male rat. Endocrinology 124, 1697–1702.PubMedCrossRefGoogle Scholar
  92. 90.
    Smith, M. S. (1993) Lactation alters neuropeptide-Y and proopiomelanocortin gene expression in the arcuate nucleus of the rat. Endocrinology 133, 1258–1265.PubMedCrossRefGoogle Scholar
  93. 91.
    Hagan, M. M., Rushing, P. A., Schwartz, M. W., Yagaloff, K. A., Burn, P., Woods, S.C., and Seely, R. J. (1999) Role of the CNS melanocortin system in the response to overfeeing. J. Neurosci. 19, 2362–2367.PubMedGoogle Scholar
  94. 92.
    Cone, R. D., Lu, D., Chen, W., Koppula, S., Vage, D. I., Klungland, H., Boston, B., Orth, D. N., Pouton, C., and Kesterson, R. A. (1996) The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog. Horm. Res. 51, 287–318.PubMedGoogle Scholar
  95. 93.
    Ahima, R., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., T, M.- F., and Flier, S. (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252.PubMedCrossRefGoogle Scholar
  96. 93a.
    Erickson, J., Hollopeter, G., and Palmiter, J. D. (1996) Attenuation of the obesity syndrone of ob/ob mice by the loss of neuropeptide Y. Science 274, 1704–1707.PubMedCrossRefGoogle Scholar
  97. 94.
    Friedman, J. M. (1997) The alphabet of weight control. Nature 385, 119–120.PubMedCrossRefGoogle Scholar
  98. 95.
    Gura, T. (1997) Obesity sheds its secrets. Science 275, 751–753.PubMedCrossRefGoogle Scholar
  99. 96.
    Cheung, C. C., Clifton, D. K., and Steiner, R. A. (1997) Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 138, 4489–4492.PubMedCrossRefGoogle Scholar
  100. 97.
    Halaas, J. L., Boozer, C.,Blair-West, J., Fidahusein, N., Denton, D. A., and Friedman, J. M. (1997) Physiological response to the long-term peripheral and central leptin infusion in lean and obese mice. Proc. Natl. Acad. Sci. U. S. A. 94, 8878–8883.PubMedCrossRefGoogle Scholar
  101. 98.
    Kesterson, R. A., Huszar, D., Lynch, C. A., Simerly, R. B., and Cone, R. D. (1997) Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. Mol. Endocrinol. 11, 630–637.PubMedCrossRefGoogle Scholar
  102. 99.
    Boston, B. A., Blaydon, K. M., Varnerin, J., and Cone, R. D. (1997) Independent and additive effects of central POMC and leptin pathways on murine obesity. Science 278, 1641–1644.PubMedCrossRefGoogle Scholar
  103. 100.
    Seeley, R. J., Yagaloff, K. A., Fischer, S. L., Burn, P., Thiele, T. E., van Dijk, G., Baskin, D. G., and Schwartz, M. W. (1997) Melanocortin receptors in leptin effects. Nature 390, 349.PubMedCrossRefGoogle Scholar
  104. 101.
    Thiele, T., van Dijk, G., Yagaloff, K. A., Fischer, S. L., Schwartz, M., Bum, P., and Seeley, R. J. (1998) Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion. Am. J. Physiol. 274, R248–R254.PubMedGoogle Scholar
  105. 102.
    Uehara, Y., Shimizu, H., Ohtani, K., Sato, N., and Mori, M. (1998) Hypothalamic corticotropin-releasing hormone is a mediator of the anorexigenic effect of leptin. Diabetes 47, 890–893.PubMedCrossRefGoogle Scholar
  106. 103.
    Goldstone, A. P., Mercer, J. G., Gunn, I., Moar, K. M., Edwards, C. M., Rossi, M., Howard, J. K., Rasheed, S., Turton, M. D., Small, C., Heath, M. M., O’Shea, D., Steere, J., Meeran, K., Ghatei, M. A., Hoggard, N., and Bloom, S. R. (1997) Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents. FEBS Lett. 415, 134–138.PubMedCrossRefGoogle Scholar
  107. 104.
    Marsh, D. J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K. A., Fisher, S. L., Burn, P., and Palmiter, R. D. (1999) Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat. Genet. 21, 119–122.PubMedCrossRefGoogle Scholar
  108. 105.
    Cowley, M. A., Prunchuk, N., Fan, W., Dinulescu, D. M., Colmers, W. F., and Cone, R. D. (1999) Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24, 155–163.PubMedCrossRefGoogle Scholar
  109. 106.
    Bronstein, D. M., Schafer, M. K., Watson, S.J., and Akil, H. (1992) Evidence that beta-endorphin is synthesized in cells in the nucleus tractus solitarius: detection of POMC mRNA. Brain Res. 587, 269–275.PubMedCrossRefGoogle Scholar
  110. 107.
    Jacobowitz, D. M. and O’Donohue, T. L. (1978) a-Melanocyte-stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc. Natl. Acad. Sci. U. S. A. 75, 6300–6304.PubMedCrossRefGoogle Scholar
  111. 108.
    Joseph, S. A., Pilcher, W. H., and Bennet-Clarke, C. (1983) Immunocytochemical localization of ACTH parikarya in nucleus tractus solitarius: evidence for a second opiocortin neuronal system. Neurosci. Lett. 38, 221–225.PubMedCrossRefGoogle Scholar
  112. 109.
    Nilaver, G., Zimmerman, E. A., Defendi, R., Liotta, A., Krieger, D. T., and Brownstein, M. J. (1979) Adrenocorticotropin and beta-lipotropin in the hypothalamus: localization in the same arcuate neurons by sequential immunocytochemical procedures. J. Cell Biol. 81, 50–58.PubMedCrossRefGoogle Scholar
  113. 110.
    Palkovits, M., Mezey, E., and Eskay, R. L. (1987) Pro-opiomelanocortin-derived peptides. (ACTH/beta-endorphin/alpha-MSH) in brainstem baroreceptor areas of the rat. Brain Res. 436, 323–328.PubMedCrossRefGoogle Scholar
  114. 111.
    Watson, S. J., Akil, H., Richard, C. W., and Barchas, J. D. (1978) Evidence for two separate opiate peptide neuronal systems and the coexistence of beta-lipotropin, beta-endorphin, and ACTH immunoreactivities in the same hypothalamic neurons. Nature 275, 226–228.PubMedCrossRefGoogle Scholar
  115. 112.
    Woods, S. C., Seeley, R. J., Porte, D. Jr., and Schwartz, M. W. (1998) Signals that regulate food intake and energy homeostasis. Science 280, 1378–1382.PubMedCrossRefGoogle Scholar
  116. 113.
    Giraudo, S. Q., Billington, C. J., and Levine, A. S. (1998) Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands. Brain Res. 809, 302–306.PubMedCrossRefGoogle Scholar
  117. 114.
    Stanley, B. G., Chin, A. S., and Leibowitz, S. F. (1985) Feeding and drinking elicited by central injection of neuropeptide Y: evidence for a hypothalamic site of action. Brain Res. Bull. 14, 521–524.PubMedCrossRefGoogle Scholar
  118. 115.
    Stanley, B. G., Magdalin, W., Seirafi, A., Thomas, W. J., and Leibowitz, S. F. (1993) The perifornical area: the major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Res. 604, 304–317.PubMedCrossRefGoogle Scholar
  119. 116.
    Ahlshog, J. E. and Hoebel, B. G. (1973) Overeating and obesity from damage to a noradrenergic system in the rat brain. Science 182, 166–169.CrossRefGoogle Scholar
  120. 117.
    Jin, S. L., Han, V. K., Simmons, J. G., Towle, A. C., Lauder, J. M., and Lund, P. K. (1988) Distribution of glucagon-like peptide I (GLP-I), glucagon, and glicentin in the rat brain, an immunocytochemical study. J. Comp. Neurol. 271, 519–532.PubMedCrossRefGoogle Scholar
  121. 118.
    Heinrichs, S.C., Menzaghi, F., Pich, E. M., Hauger, R. L., and Koob, G. F. (1993) Corticotropin-releasing factor in paraventricular nucleus modulates feeding induced by neuropeptide Y. Brain Res. 611, 18–24.PubMedCrossRefGoogle Scholar
  122. 119.
    Haynes, W. G., Morgan, D. A., Djalali, A., Sivitz, W. I., and Mark, A. L. (1999) Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension 33, 542–547.PubMedCrossRefGoogle Scholar
  123. 120.
    Grill, H. J, Ginsberg, A. B., Seeley, R. J., and Kaplan, J. M. (1998) Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight. J. Neurosci. 18, 10,128–10, 135.Google Scholar
  124. 121.
    Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., Cheetham, C. H., Earley, A. R., Barnett, A. H., Prins, J. B., and O’Rahilly, S. (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908.PubMedCrossRefGoogle Scholar
  125. 122.
    Clement, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J., Lacorte, J. M., Basdevant, A., Bougneres, P., Lebouc, Y., Froguel, P., and Guy-Grand, B. (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401.PubMedCrossRefGoogle Scholar
  126. 123.
    Jackson, R., Creemers, J., Ohagi, S., Raffin-Sanson, M. L., Sanders, L., Montague, C. T., Hutton, J. C., and O’Rahilly, S. (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16, 303–306.PubMedCrossRefGoogle Scholar
  127. 124.
    Krude, H., Biebermann, H., Luck, W., Horn, R., Brabant, G., and Gruters, A. (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155–157.PubMedCrossRefGoogle Scholar
  128. 125.
    Comuzzie, A. G., Hixson, J. E., Almasy, L., Mitchell, B. D., Mahaney, M. C., Dyer, T. D., Stern, M. P., MacCluer, J. W., and Blangero, J. (1997) A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat. Genet. 15, 273–276.PubMedCrossRefGoogle Scholar
  129. 126.
    Rotimi, C. N., Comuzzie, A. G., Lowe, W. L., Luke, A., Blangero, J., and Cooper, R. S. (1999) The quantitative trait locus on chromosome 2 for serum leptin levels is confirmed in African-Americans. Diabetes 48, 643–644.PubMedCrossRefGoogle Scholar
  130. 127.
    Hager, J., Dina, C., Francke, S., Dubois, S., Houari, M., Vatin, V., Vaillant, E., Lorentz, N., Basdevant, A., Clement, K., Guy-Grand, B., and Froguel, P. (1998) A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat. Genet. 20, 304–308.PubMedCrossRefGoogle Scholar
  131. 128.
    Hinney, A., Becker, I., Heibult, O., Nottebom, K., Schmidt, A., Ziegler, A., Mayer, H., Siegfried, W., Blum, W. F., Remschmidt, H., and Hebebrand, J. (1998) Systematic mutation screening of the pro-opiomelanocortin gene: identification of several genetic variants including three different insertions, one nonsense and two missense point mutations in probands of different weight extremes. J. Clin. Endocrinol. Metab. 83, 3737–3741.PubMedCrossRefGoogle Scholar
  132. 129.
    Vaisse, C., Clement, K., Guy-Grand, B., and Froguel, P. (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113–114.PubMedCrossRefGoogle Scholar
  133. 130.
    Yeo, G. S. H., Farooqi, I. S., Aminian, S., Halsall, D. J., Stanhope, R. G., and O’Rahilly, S. (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111–112.PubMedCrossRefGoogle Scholar
  134. 131.
    Gotoda, T., Scott, J., and Aitman, T. J. (1997) Molecular screening of the human melanocortin-4 receptor gene: identification of a missense variant showing no association with obesity, plasma glucose, or insulin. Diabetologia 40, 976–979.PubMedCrossRefGoogle Scholar
  135. 132.
    Hinney, A., Schmidt, A., Nottebom, K., Heibult, O., Becker, I., Ziegler, A., Gerger, G., Sina, M., Gorg, T., Mayer, H., Siegfried, W., Fichter, M., Remschmidt, H., and Hebebrand, J. (1999) 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. 84, 1483–1486.PubMedCrossRefGoogle Scholar
  136. 133.
    Gu, W., Tu, Z., Kleyn, P. W., Kissebah, A., Duprat, L., Lee, J., Chin, W., Maruti, S., Deng, N., Fisher, S. L., Franco, L. S., Burn, P., Yagaloff, K. A., Nathan, J., Heymsfield, S., Albu, J., Pi-Sunyer, F. X., and Allison, D. B. (1999) Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 48, 635–639.PubMedCrossRefGoogle Scholar
  137. 134.
    Lane, P. W. (1960) New mouse mutants. Mouse News Lett. 22, 35.Google Scholar
  138. 135.
    Lane, P. W. and Green, M. C. (1960) Mahogany, a recessive color mutation in linkage group V of the mouse. J. Hered. 51, 228–230.Google Scholar
  139. 136.
    Miller, K. A., Gunn, T. M., Carrasquillo, M. M., Lamoreux, M. L., Galbraith, D. B., and Barsh, G. S. (1997) Genetic studies of the mouse mutations mahogany and mahoganoid. Genetics. 146, 1407–1415.Google Scholar
  140. 137.
    Dinulescu, D. M., Fan, W., Boston, B. A., McCall, K., Lamoreux, M. L., Moore, K. J., Montagno, J., and Cone, R. D. (1998) Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti. Proc. Natl. Acad. Sci. U. S. A. 95, 12, 707–12, 712.Google Scholar
  141. 138.
    Gunn, T. M., Miller, K. A., He, L., Hyman, R. W., Davis, R. W., Azarani, A., Schlossman, S. F., Duke-Cohan, J. S., and Barsh, G. S. (1999) The mouse mahogany locus encodes a transmembrane form of human attractin. Nature 398, 1521–1526.Google Scholar
  142. 139.
    Nagle, D. L., McGrail, S. H., Vitale, J., Woolf, E. Z., Dussault, B. J. Jr., DiRocco, L., Holmgren, L., Montagno, J., Bork, P., Huszar, D., Fairchild-Huntress, V., Ge, P., Keilty, J., Ebeling, C., Baldini, L., Gilchrist, J., Burn, P., Carlson, G. A., and Moore, K. J. (1999) The mahogany protein is a receptor involved in suppression of obesity. Nature 398, 148–152.PubMedCrossRefGoogle Scholar
  143. 140.
    Duke-Cohan, J. S., Gu, J., McLaughlin, D. F., Xu, Y., Freeman, G. J., and Schlossman, S. F. (1998) Attractin (DPPT-L), a member of the CUB family of cell adhesions and guidance proteins, is secreted by activated human T lymphocytes and modulates immune cell interactions. Proc. Nati. Acad. Sci. U.S.A. 95,11, 336–11, 341.CrossRefGoogle Scholar
  144. 141.
    Tatro, J. B. (1997) Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides. Neuroimmunomodulation 3, 259–284.CrossRefGoogle Scholar
  145. 142.
    Huang, Q. H., Hruby, V. J., and Tatro, J. B. (1999) Role of central melanocortins in endotoxin-induced anorexia. Am. J. Physiol. 276, R864 — R871.PubMedGoogle Scholar
  146. 143.
    De Angelis, E., Sahm, U. G., Ahmed, A. R. H., Olivier, G. W. J., Notarianni, L. J., Branch, S. K., Moss, S. H., and Pouton, C. W. (1995) Identification of a melanocortin receptor expressed by murine brain microvascular endothelial cells in culture. Microvasc. Res. 50, 25–34.PubMedCrossRefGoogle Scholar
  147. 144.
    Li, S.-J., Varga, K., Archer, P., Hruby, V. J., Sharma, S. D., Kesterson, R. A., Cone, R. D., and Kunos, G. (1996) Melanocortin antagonists define two distinct pathways of cardiovascular control by cs-and y-melanocyte-stimulating hormones. J. Neurosci. 16, 5182–5188.PubMedGoogle Scholar
  148. 145.
    Mastrianni, J. A., Abbott, F. V., and Kunos, G. (1989) Activation of central µ-opioid receptors is involved in clonidine analgesia in rats. Brain Res. 479, 283–289.PubMedCrossRefGoogle Scholar
  149. 146.
    Mastrianni, J. A., Palkovits, M., and Kunos, G. (1989) Activation of brainstem endorphinergic neurons causes cardiovascular depression, and facilitates baroreflex bradycardia. Neuroscience 33, 559–566.PubMedCrossRefGoogle Scholar
  150. 147.
    Mosqueda-Garcia, R., Eskay, R., Zamir, N., Palkovits, M., and Kunos, G. (1986) Opioid-mediated cardiovascular effects of clonidine in spontaneously hypertensive rats: elimination by neonatal treatment with monosodium glutamate. Endocrinology 118, 1814–1822.PubMedCrossRefGoogle Scholar
  151. 148.
    Weigant, V. M., Jolles, J., Colbern, D. L., Zimmerman, E., and Gispen, W. H. (1979) Intracerebroventricular ACTH activates the pituitary adrenal system: dissociation from a behavioral response. Life Sci. 25, 1791–1796.CrossRefGoogle Scholar
  152. 149.
    Von Frijtag, J. C., Croiset, G., Gispen, W. H., Adan, R. A., and Wiegant, V. M. (1998) The role of central melanocortin receptors in the activation of the hypothalamus-pituitary-adrenal-axis and the induction of excessive grooming. Br. J. Pharmacol. 123, 1503–1508.CrossRefGoogle Scholar
  153. 150.
    Scimonelli, T. and Celis, M. E. (1990) A central action of alpha-melanocytestimulating hormone on serum levels of LH and prolactin in rats. J. Endocrinol. 124, 127–132.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2000

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  • Roger D. Cone

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