The Melanocortin agonist Melanotan-II reduces the orexigenic and adipogenic effects of neuropeptide Y (NPY) but does not affect the NPY-driven suppressive effects on the gonadotropic and somatotropic axes in the male rat

Journal of Neuroendocrinology

Volumn 15, Issue 2, 2003, Pages 173-181

  Raposinho, P D ^a,b   White, R B ^a   Aubert, M L ^a  

^a UNIVERSITY OF GENEVA MEDICAL SCHOOL   (Switzerland)

^b INSTITUTO TECNOLÓGICO E NUCLEAR   (Portugal)

Author keywords

Growth; MT II; NPY; Obesity; Reproduction

Indexed keywords

ALPHA INTERMEDIN; ANOREXIGENIC AGENT; APPETITE STIMULANT; HORMONE RECEPTOR STIMULATING AGENT; INSULIN; LEPTIN; MELANOCORTIN 3 RECEPTOR; MELANOCORTIN 4 RECEPTOR; MELANOCORTIN RECEPTOR STIMULATING AGENT; MELANOTAN II; MESSENGER RNA; NEUROPEPTIDE Y; NEUROTRANSMITTER; PROOPIOMELANOCORTIN; RECEPTOR SUBTYPE; UNCLASSIFIED DRUG;

ANOREXIA; BODY FAT; CONTROLLED STUDY; DRUG EFFECT; DRUG SELECTIVITY; FEEDING BEHAVIOR; GROWTH REGULATION; HORMONAL REGULATION; HORMONE RELEASE; HYPERPHAGIA; HYPOTHALAMUS HYPOPHYSIS SYSTEM; INSULIN RELEASE; INSULINEMIA; MALE; NEUROMODULATION; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; REVIEW;

ADIPOCYTES; ADIPOSE TISSUE; ALPHA-MSH; ANIMALS; CARRIER PROTEINS; DRINKING; DRUG INTERACTIONS; EATING; GENE EXPRESSION; GONADAL STEROID HORMONES; GROWTH HORMONE-RELEASING HORMONE; HYPOTHALAMUS; INSULIN; INSULIN-LIKE GROWTH FACTOR I; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LEPTIN; MALE; NEUROPEPTIDE Y; NEUROPEPTIDES; OBESITY; PEPTIDES, CYCLIC; PRO-OPIOMELANOCORTIN; RATS; RATS, SPRAGUE-DAWLEY; WEIGHT GAIN;

EID: 0037320466     PISSN: 09538194     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1365-2826.2003.00962.x     Document Type: Review

References (64)

1. 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.
2. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404: 661-671.
3. Cummings DE, Schwartz MW. Melanocortins and body weight: a tale of two receptors. Nature Genet 2000; 26: 8-9.
4. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science 1992; 257: 1248-1251.
5. 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: 1298-1308.
6. Cone RD. The central melanocortin system and energy homeostasis. Trends Endocrinol Metab 1999; 10: 211-216.
7. Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WE, Cone RD. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus evidence of a cellular basis for the adipostat. Neuron 1999; 24: 155-163.
8. Hahn TM, Breininger JF, Baskin DG, Schwartz MW. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nature Neurosci 1998; 1: 271-272.
9. Poggioli R, Vergoni AV, Bertolini A. ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa opiate agonists. Peptides 1986; 7: 843-848.
10. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385: 165-168.
11. Murphy B, Nunes CN, Ronan JJ, Harper CM, Beall MJ, Hanaway M, Fairhurst AM, Van der Ploeg LH, MacIntyre DE, Mellin TN. Melanocortin mediated inhibition of feeding behavior in rats. Neuropeptides 1998; 32: 491-497.
12. Grill HJ, Ginsberg AB, Seeley RJ, Kaplan JM. Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight. J Neurosci 1998; 18: 10128-10135.
13. Giraudo SQ, Billington CJ, Levine AS. Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands. Brain Res 1998; 809: 302-306.
14. Murphy B, Nunes CN, Ronan JJ, Hanaway M, Fairhurst AM, Mellin TN. Centrally administered MTII affects feeding, drinking, temperature, and activity in the Sprague-Dawley rat. J Appl Physiol 2000; 89: 273-282.
15. Hagan MM, Rushing PA, Pritchard LM, Schwartz MW, Strack AM, Van der Ploeg LH, Woods SC, Seeley RJ. Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol Regul Integr Comp Physiol 2000; 279: R47-R52.
16. Small CJ, Kim MS, Stanley SA, Mitchell JR, Murphy K, Morgan DG, Ghatei MA, Bloom SR. Effects of chronic central nervous system administration of agouti- related protein in pair-fed animals. Diabetes 2001; 50: 248-254.
17. 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: 131-141.
18. Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XMYuH, 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, Van der Ploeg LH. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nature Genet 2000; 26: 97-102.
19. Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, Baetscher M, Cone RD. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 2000; 141: 3518-3521.
20. 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. Nature Genet 1999; 21: 119-122.
21. Chen AS, Metzger JM, Trumbauer ME, Guan XMYuH, Frazier EG, Marsh DJ, Forrest MJ, Gopal-Truter S, Fisher J, Camacho RE, Strack AM, Mellin TN, MacIntyre DE, Chen HY, Van der Ploeg LH. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res 2000; 9: 145-154.
22. Benoit SC, Schwartz MW, Lachey JL, Hagan MM, Rushing PA, Blake KA, Yagaloff KA, Kurylko G, Franco L, Danhoo W, Seeley RJ. A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences. J Neurosci 2000; 20: 3442-3448.
23. Jegou S, Boutelet I, Vaudry H. Melanocortin-3 receptor mRNA expression in pro-opiomelanocortin neurones of the rat arcuate nucleus. J Neuroendocrinol 2000; 12: 501-505.
24. Fan W, Dinulescu DM, Butler AA, Zhou J, Marks DL, Cone RD. The central melanocortin system can directly regulate serum insulin levels. Endocrinology 2000; 141: 3072-3079.
25. Bagnol D, Lu XY, Kaelin CB, Day HE, Ollmann M, Gantz I, Akil H, Barsh GS, Watson SJ. Anatomy of an endogenous antagonist: relationship between Agouti- related protein and proopiomelanocortin in brain J Neurosci, 1999; 19: RC26.
26. Broberger C, Landry M, Wong H, Walsh JN, Hokfelt T. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in proopiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 1997; 66: 393-408.
27. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001; 411: 480-484.
28. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432.
29. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995; 377: 530-532.
30. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382: 250-252.
31. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996; 98: 1101-1106.
32. Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 1997; 46: 2119-2123.
33. Aubert ML, Pierroz DD, Gruaz NM, d'Allèves V, Vuagnat BA, Pralong FP, Blum WF, Sizonenko PC. Metabolic control of sexual function and growth role of neuropeptide Y and leptin. Mol Cell Endocrinol 1998; 140: 107-113.
34. Catzeflis C, Pierroz DD, Rohner-Jeanrenaud F, Rivier JE, Sizonenko PC, Aubert ML. Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats. Endocrinology 1993; 132: 224-234.
35. Pierroz DD, Catzeflis C, Aebi AC, Rivier JE, Aubert ML. Chronic administration of neuropeptide Y into the lateral ventricle inhibits both the pituitary-testicular axis and growth hormone and insulin-like growth factor I secretion in intact adult male rats: Endocrinology 1996; 137: 3-12.
36. Raposinho PD, Castillo E, d'Allèves V, Broqua P, Pralong FP, Aubert ML. Chronic blockade of the melanocortin 4 receptor subtype leads to obesity independently of neuropeptide Y action, with no adverse effects on the gonadotropic and somatotropic axes. Endocrinology 2000; 141: 4419-4427.
37. Zarjevski N, Cusin I, Vettor R, Rohner-Jeanrenaud F, Jeanrenaud B. Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology 1993; 133: 1753-1758.
38. Pierroz DD, Gruaz NM, d'Allèves V, Aubert ML. Chronic administration of neuropeptide Y into the lateral ventricle starting at 30 days of life delays sexual maturation in the female rat. Neuroendocrinology 1995; 61: 293-300.
39. Watanobe H, Schioth HB, Wikberg JE, Suda T. The melanocortin 4 receptor mediates leptin stimulation of luteinizing hormone and prolactin surges in steroid-primed ovariectomized rats. Biochem Biophys Res Commun 1999; 257: 860-864.
40. Stanley SA, Small CJ, Kim MS, Heath MM, Seal LJ, Russell SH, Ghatei MA, Bloom SR. Agouti related peptide (Agrp) stimulates the hypothalamo pituitary gonadal axis in vivo and in vitro in male rats. Endocrinology 1999; 140: 5459-5462.
41. Limone P, Calvelli P, Altare F, Ajmone-Catt P, Lima T, Molinatti GM. Evidence for an interaction between alpha-MSH and opioids in the regulation of gonadotropin secretion in man. J Endocrinol Invest 1997; 20: 207-210.
42. Schioth HB, Watanobe H. Melanocortins and reproduction. Brain Res Brain Res Rev 2002; 38: 340-350.
43. Cone RD. The central melanocortin system and its role in energy homeostasis. Ann Endocrinol (Paris) 1999; 60: 3-9.
44. Yaswen L, Diehl N, Brennan MB, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nature Med 1999; 5: 1066-1070.
45. Hohmann JG, Teal TH, Clifton DK, Davis J, Hruby VJ, Han G, Steiner RA. Differential role of melanocortins in mediating leptin's central effects on feeding and reproduction. Am J Physiol Regal Integr Comp Physiol 2000; 278: R50-R59.
46. Breier BH, Gallaher BW, Gluckman PD. Radioimmunoassay for insulin-like growth factor-I: solutions to some potential problems and pitfalls. J Endocrinol 1991; 128: 347-357.
47. Gruaz NM, Arsenijevic Y, Wehrenberg WB, Sizonenko PC, Aubert ML. Growth hormone (GH) deprivation induced by passive immunization against rat GH-releasing factor does not disturb the course of sexual maturation and fertility in the female rat. Endocrinology 1994; 135: 509-519.
48. Raposinho PD, Pierroz DD, Broqua P, White RB, Pedrazzini T, Aubert ML. Chronic administration of neuropeptide Y into the lateral ventricle of C57BL/6J male mice produces an obesity syndrome including hyperphagia, hyperleptinemia, insulin resistance, and hypogonadism. Mol Cell Endocrinol 2001; 185: 195-204.
49. Luo J. Oral melanocortin 4 receptor agonist for the treatment of obesity and type 2 diabetes, J3-abstract 310. Keystone Symposia, Keystone, Colorado, 2002.
50. Williams DL, Kaplan JM, Grill HJ. The role of the dorsal vagal complex and the vagus nerve in feeding effects of melanocortin-3/4 receptor stimulation. Endocrinology 2000; 141: 1332-1337.
51. Wirth MM, Olszewski PK, Yu C, Levine AS, Giraudo SQ. Paraventricular hypothalamic alpha-melanocyte-stimulating hormone and MTII reduce feeding without causing aversive effects. Peptides 2001; 22: 129-134.
52. Jonsson L, Skarphedinsson JO, Skuladottir GV, Watanobe H, Schioth HB. Food conversion is transiently affected during 4-week chronic administration of melanocortin agonist and antagonist in rats. J Endocrinol 2002; 173: 517-523.
53. Haynes WG, Morgan DA, Djalali A, Sivitz WI, Mark AL. Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension 1999; 33: 542-547.
54. Janssen SW, Martens GJ, Sweep CG, Ross HA, Hermus AR. In Zucker diabetic fatty rats plasma leptin levels are correlated with plasma insulin levels rather than with body weight. Horm Metab Res 1999; 31: 610-615.
55. Mantzoros CS, Qu D, Frederich RC, Susulic VS, Lowell BB, Maratos-Flier E, Flier JS. Activation of beta(3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 1996; 45: 909-914.
56. Nonogaki K. Obesity: autonomic circuits versus feeding. Nature Med 1999; 5: 742-743.
57. Kieffer TJ, Habener JF. The adipoinsular axis: effects of leptin on pancreatic beta-cells. Am J Physiol Endocrinol Metab 2000; 278: E1-E14.
58. Cunningham MJ, Clifton DK, Steiner RA. Leptin's actions on the reproductive axis: perspectives and mechanisms. Biol Reprod 1999; 60: 216-222.
59. Mizuno TM, Mobbs CV. Correction of metabolic defects in leptin-deficient ob/ob mice by transgenic neuronal expression of proopiomelanocortin gene, J3-abstract 310. Keystone Symposia, Keystone, Colorado, 2002.
60. Ichimaru T, Mori Y, Okamura H. A possible role of neuropeptide Y as a mediator of undernutrition to the hypothalamic gonadotropin-releasing hormone pulse generator in goats. Endocrinology 2001; 142: 2489-2498.
61. Blasquez C, Jegou S, Friard O, Tonon MC, Fournier A, Vaudry H. Effect of centrally administered neuropeptide Y hypothalamic and hypophyseal proopiomelanocortin-derived peptides in the rat. Neuroscience 1995; 68: 221-227.
62. King PJ, Widdowson PS, Doods HN, Williams G. Regulation of neuropeptide Y release by neuropeptide Y receptor ligands and calcium channel antagonists in hypothalamic slices. J Neurochem 1999; 73: 641-646.
63. Kesterson RA, Huszar D, Lynch CA, Simerly RB, Cone RD. Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. Mol Endocrinol 1997; 11: 630-637.
64. Kask A, Rago L, Korrovits P, Wikberg JE, Schioth HB. Evidence that orexigenic effects of melanocortin 4 receptor antagonist HS014 are mediated by neuropeptide Y. Biochem Biophys Res Commun 1998; 248: 245-249.