Bedeutung des melanokortinergen Systems für die Gewichtsregulation[1]

Die Hoffnung, mit Leptin ein potentes Medikament gegen die weit verbreitete „normale“ Adipositas zur Verfügung zu haben, hat sich nicht bestätigt ([39]). Die pharmakologischen Bemühungen konzentrieren sich daher auf nachgeschaltete Regelkreise; insbesondere rückt in jüngster Zeit das melanokortinerge System als neurohumorales Regelwerk des Energiehaushaltes in das Interesse der Forschung. Eine zentrale Stellung kommt dem Melanokortin-4-Rezeptor (MC4R) zu als vielversprechender Zielstruktur für die Einflussnahme auf das Körpergewicht.

1 Die Arbeit wurde unterstützt vom Bundesministerium für Bildung und Forschung (Deutsches Humangenomprojekt: 01 KW 0006 und Nationales Genomforschungsnetz: 01 GS 0118) und von der Deutschen Forschungsgemeinschaft (Re 471/11-2)

Literatur

• 1 Ahima R S, Flier J S. Leptin.  Annu Rev Physiol. 2000;  62 413-437
• 2 Butler A A, Kesterson R A, Khong K. et al . A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse.  Endocrinology. 2000;  141 3518-3521
• 3 Butler A A, Marks D L, Fan W, Kuhn C M, Bartolome M, Cone R D. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat.  Nat Neurosci. 2001;  4 605-611
• 4 Chen A S, Marsh D J, Trumbauer M E. et al . Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.  Nat Genet. 2000;  26 97-102
• 5 Chen A S, Metzger J M, Trumbauer M E. et al . Role of the melanocortin-4 receptor in metabolic rate and food intake in mice.  Transgenic Res. 2000;  9 145-154
• 6 Clapham J C, Arch J R, Tadayyon M. Anti-obesity drugs: a critical review of current therapies and future opportunities.  Pharmacol Ther. 2001;  89 81-121
• 7 Clement K, Vaisse C, Lahlou N. et al . A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction.  Nature. 1998;  392 398-401
• 8 Dubern B, Clement K, Pelloux V. et al . Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.  J Pediatr. 2001;  139 204-209
• 9 Elias L L, Clark A J. The expression of the ACTH receptor.  Braz J Med Biol Res. 2000;  33 1245-1248
• 10 Fan W, Boston B A, Kesterson R A, Hruby V J, Cone R D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.  Nature. 1997;  385 165-168
• 11 Farooqi I S, Yeo G S, Keogh J M. et al . Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency.  J Clin Invest. 2000;  106 271-279
• 12 Fehm H L, Smolnik R, Kern W, McGregor G P, Bickel U, Born J. The melanocortin melanocyte-stimulating hormone/adrenocorticotropin(4-10) decreases body fat in humans.  J Clin Endocrinol Metab. 2001;  86 1144-1148
• 13 Gantz I, Miwa H, Konda Y. et al . Molecular cloning, expression, and gene localization of a fourth melanocortin receptor.  J Biol Chem. 1993;  268 15174-15179
• 14 Gu W, Tu Z, Kleyn P W. et al . Identification and functional analysis of novel human melanocortin-4 receptor variants.  Diabetes. 1999;  48 635-639
• 15 Hani E H, Dupont S, Durand E. et al . Naturally occurring mutations in the melanocortin receptor 3 gene are not associated with type 2 diabetes mellitus in French Caucasians.  J Clin Endocrinol Metab. 2001;  86 2895-2898
• 16 Hebebrand J, Fichter M, Gerber G. et al . Genetic predisposition to obesity in bulimia nervosa: a mutation screen of the melanocortin-4 receptor gene.  Mol Psychiatry. 2002;  7 647-651
• 17 Hinney A, Schmidt A, Nottebom K. et al . 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 1483-1486
• 18 Huang Q H, Hruby V J, Tatro J B. Role of central melanocortins in endotoxin-induced anorexia.  Am J Physiol. 1999;  276 R864-871
• 19 Huszar D, Lynch C A, Fairchild-Huntress V. et al . Targeted disruption of the melanocortin-4 receptor results in obesity in mice.  Cell. 1997;  88 131-141
• 20 Jackson R S, Creemers J W, Ohagi S. et al . Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.  Nat Genet. 1997;  16 303-306
• 21 Jacobson P, Ukkola O, Rankinen T. et al . Melanocortin 4 Receptor Sequence Variations Are Seldom a Cause of Human Obesity: The Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis Cohort.  J Clin Endocrinol Metab. 2002;  87 4442-4446
• 22 Kask A, Rago L, Wikberg J E, Schioth H B. Differential effects of melanocortin peptides on ingestive behaviour in rats: evidence against the involvement of MC(3) receptor in the regulation of food intake.  Neurosci Lett. 2000;  283 1-4
• 23 Kobayashi H, Ogawa Y, Shintani M. et al . A Novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity.  Diabetes. 2002;  51 243-246
• 24 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;  19 155-157
• 25 Lee Y S, Poh L K, Loke K Y. A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity.  J Clin Endocrinol Metab. 2002;  87 1423-1426
• 26 Li W D, Joo E J, Furlong E B. et al . Melanocortin 3 receptor (MC3R) gene variants in extremely obese women.  Int J Obes Relat Metab Disord. 2000;  24 206-210
• 27 MacNeil D -J, Howard A -D, Guan X. et al . The role of melanocortins in body weight regulation: opportunities for the treatment of obesity.  European journal of pharmacology. 2002;  440 141-157
• 28 Marks D L, Ling N, Cone R D. Role of the central melanocortin system in cachexia.  Cancer Res. 2001;  61 1432-1438
• 29 Mergen M, Mergen H, Ozata M, Oner R, Oner C. A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity.  J Clin Endocrinol Metab. 2001;  86 3448
• 30 Miltenberger R J, Mynatt R L, Wilkinson J E, Woychik R P. The role of the agouti gene in the yellow obese syndrome.  J Nutr. 1997;  127 1902S-1907S
• 31 Miraglia Del Giudice E, Cirillo G, Nigro V. et al . Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity.  Int J Obes Relat Metab Disord. 2002;  26 647-651
• 32 Montague C T, Farooqi I S, Whitehead J P. et al . Congenital leptin deficiency is associated with severe early-onset obesity in humans.  Nature. 1997;  387 903-908
• 33 Mountjoy K G, Mortrud M T, Low M J, Simerly R B, Cone R D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.  Mol Endocrinol. 1994;  8 1298-1308
• 34 Naggert J K, Fricker L D, Varlamov O. et al . Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.  Nat Genet. 1995;  10 135-142
• 35 Ollmann M M, Wilson B D, Yang Y K. et al . Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.  Science. 1997;  278 135-138
• 36 Palmer J S, Duffy D L, Box N F. et al . Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?.  Am J Hum Genet. 2000;  66 176-186
• 37 Pierroz D D, Ziotopoulou M, Ungsunan L, Moschos S, Flier J S, Mantzoros C S. Effects of acute and chronic administration of the melanocortin agonist MTII in mice with diet-induced obesity.  Diabetes. 2002;  51 1337-1345
• 38 Reizes O, Lincecum J, Wang Z. et al . Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3.  Cell. 2001;  106 105-116
• 39 Schwartz M W, Woods S C, Porte D , Seeley R J, Baskin D G. Central nervous system control of food intake.  Nature. 2000;  404 661-671
• 40 Sina M, Hinney A, Ziegler A. et al . Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene.  Am J Hum Genet. 1999;  65 1501-1507
• 41 Ste Marie L, Miura G I, Marsh D J, Yagaloff K, Palmiter R D. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors.  Proc Natl Acad Sci USA. 2000;  97 12339-12344
• 42 Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.  J Clin Invest. 2000;  106 253-262
• 43 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;  20 113-114
• 44 Vergoni A V, Bertolini A. Role of melanocortins in the central control of feeding.  Eur J Pharmacol. 2000;  405 25-32
• 45 Wessells H, Gralnek D, Dorr R, Hruby V J, Hadley M E, Levine N. Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction.  Urology. 2000;  56 641-646
• 46 Wisse B E, Frayo R S, Schwartz M W, Cummings D E. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats.  Endocrinology. 2001;  142 3292-3301
• 47 Yaswen L, Diehl N, Brennan M B, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.  Nat Med. 1999;  5 1066-1070
• 48 Yeo G S, Farooqi I S, Aminian S, Halsall D J, Stanhope R G, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity.  Nat Genet. 1998;  20 111-112

1 Die Arbeit wurde unterstützt vom Bundesministerium für Bildung und Forschung (Deutsches Humangenomprojekt: 01 KW 0006 und Nationales Genomforschungsnetz: 01 GS 0118) und von der Deutschen Forschungsgemeinschaft (Re 471/11-2)