The role of the leptin-melanocortin signalling pathway in the control of food intake

Critical Reviews in Eukaryotic Gene Expression

Volumn 19, Issue 4, 2009, Pages 267-287

  Beckers, Sigri ^a   Zegers, Doreen ^a   Van Gaal, Luc F ^b   Van Hul, Wim ^a  

^a UNIVERSITY OF ANTWERP   (Belgium)

^b ANTWERP UNIVERSITY HOSPITAL   (Belgium)

Author keywords

BDNF; Leptin; Leptin receptor; MC3R; MC4R; Nesfatin; Obesity; PC1; POMC; SIM1

Indexed keywords

AGOUTI PROTEIN; BRAIN DERIVED NEUROTROPHIC FACTOR; FURIN; HORMONE RECEPTOR; LEPTIN; LEPTIN RECEPTOR; MELANOCORTIN; MELANOCORTIN 4 RECEPTOR; PROOPIOMELANOCORTIN; PROTEIN NESFATIN 1; PROTEIN PROHORMONE CONVERTASE 1; PROTEIN SIM 1; UNCLASSIFIED DRUG;

ADIPOCYTE; ADIPOSE TISSUE; DISEASE ASSOCIATION; FEEDING BEHAVIOR; FOOD INTAKE; GENE MUTATION; HORMONE DEFICIENCY; HORMONE DETERMINATION; HUMAN; NONHUMAN; OBESITY; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN DEFICIENCY; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION;

AGOUTI-RELATED PROTEIN; ANIMALS; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; BRAIN-DERIVED NEUROTROPHIC FACTOR; EATING; HUMANS; LEPTIN; MELANOCORTINS; MICE; OBESITY; RECEPTOR, MELANOCORTIN, TYPE 3; RECEPTOR, MELANOCORTIN, TYPE 4; RECEPTOR, TRKB; RECEPTORS, LEPTIN; REPRESSOR PROTEINS; SIGNAL TRANSDUCTION;

EID: 70349972614     PISSN: 10454403     EISSN: None     Source Type: Journal    
DOI: 10.1615/CritRevEukarGeneExpr.v19.i4.20     Document Type: Review

References (211)

1. Kopelman PG. Obesity as a medical problem. Nature. 2000;404(6778):635-643
2. National Institutes of Health NH, Blood and Lung Institute in cooperation with Te National Institute of Diabetes and Digestive and Kidney Diseases. Clinical guidelines on the identifcation, evaluation, and treatment of overweight and obesity in adults. NIH Publication. 1998;98-4083.
3. Malnick SD, Knobler H. Te medical complications of obesity. QJM. 2006;99(9):565-579
4. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444(7121):875-880
5. Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight, overweight, and obesity. JAMA. 2005;293(15):1861-1867
6. Pischon T, Boeing H, Hofmann K, Bergmann M, Schulze MB, Overvad K, van der Schouw Y T, Spencer E, Moons KG, Tjonneland A, Halkjaer J, Jensen MK, Stegger J, Clavel-Chapelon F, Boutron-Ruault MC, Chajes V, Linseisen J, Kaaks R, Trichopoulou A, Trichopoulos D, Bamia C, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, May AM, Bueno-de-Mesquita HB, van Duijnhoven FJ, Hallmans G, Weinehall L, Manjer J, Hedblad B, Lund E, Agudo A, Arriola L, Barricarte A, Navarro C, Martinez C, Quiros JR, Key T, Bingham S, Khaw KT, Bofetta P, Jenab M, Ferrari P, Riboli E. General and abdominal adiposity and risk of death in Europe. N Engl J Med. 2008;359(20):2105-2120
7. www.who.int [homepage on the internet]. World Health Organization 2008 [cited 25/09/2008]. Available from: www.who.int
8. Fry J, Finley W. Te prevalence and costs of obesity in the EU. Proc Nutr Soc. 2005;64(3):359-362
9. Finkelstein EA, Fiebelkorn IC, Wang G. State-level estimates of annual medical expenditures attributable to obesity. Obes Res. 2004;12(1):18-24.
10. Oswal A, Yeo GS. Te leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics. Obes Rev. 2007;8(4): 293-306.
11. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF. Serum immunoreactive- leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334(5):292-295
12. Mafei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1(11):1155-1161
13. Cone RD. Anatomy and regulation of the central mel-anocortin system. Nat Neurosci. 2005;8(5):571-578
14. Zhang Y, Proenca R, Mafei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425-432
15. Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M, Mori K, Tamura N, Hosoda K, Yoshimasa Y. Human obese gene expression. Adipocyte-specifc expression and regional diferences in the adipose tissue. Diabetes. 1995;44(7):855-858
16. Hamilton BS, Paglia D, Kwan AY, Deitel M. Increased obese mRNA expression in omental fat cells from massively obese humans. Nat Med. 1995;1(9):953-956
17. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med. 1997;3(9):1029-1033
18. Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature. 1998;393(6686): 684-688
19. Sobhani I, Bado A, Vissuzaine C, Buyse M, Kermorgant S, Laigneau JP, Attoub S, Lehy T, Henin D, Mignon M, Lewin MJ. Leptin secretion and leptin receptor in the human stomach. Gut. 2000;47(2):178-183
20. Van Gaal LF, Wauters MA, Mertens IL, Considine RV, De Leeuw IH. Clinical endocrinology of human leptin. Int J Obes Relat Metab Disord. 1999;23(Suppl 1):29-36.
21. Wauters M, Considine RV, Van Gaal LF. Human leptin: from an adipocyte hormone to an endocrine mediator. Eur J Endocrinol. 2000;143(3):293-311.
22. Shalitin S, Phillip M. Role of obesity and leptin in the pubertal process and pubertal growth--a review. Int J Obes Relat Metab Disord. 2003;27(8):869-874
23. Lebrethon MC, Vandersmissen E, Gerard A, Parent AS, Junien JL, Bourguignon JP. In vitro stimulation of the prepubertal rat gonadotropin- releasing hormone pulse generator by leptin and neuropeptide Y through distinct mechanisms. Endocrinology. 2000;141(4):1464-1469
24. Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci U S A. 1997;94(3):1023-1028
25. Biason-Lauber A, Zachmann M, Schoenle EJ. Efect of leptin on CYP17 enzymatic activities in human adrenal cells: new insight in the onset of adrenarche. Endocrinology. 2000;141(4):1446-1454
26. Fruhbeck G, Salvador J. Relation between leptin and the regulation of glucose metabolism. Diabetologia. 2000;43(1):3-12.
27. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosup-pression. Nature. 1998;394(6696):897-901.
28. Flier JS, Harris M, Hollenberg AN. Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. J Clin Invest. 2000;105(7):859-861
29. Gat-Yablonski G, Phillip M. Leptin and regulation of linear growth. Curr Opin Clin Nutr Metab Care. 2008;11(3):303-308
30. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395(6704):763-770
31. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia. 1978;14(3):141-148
32. Moon BC, Friedman JM. The molecular basis of the obese mutation in ob2J mice. Genomics. 1997;42(1):152-156
33. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S. Congenital leptin defciency is associated with severe early-onset obesity in humans. Nature. 1997;387(6636):903-908
34. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O'Rahilly S. Benefcial efects of leptin on obesity, T cell hyporesponsive-ness, and neuroendocrine/metabolic dysfunction of human congenital leptin defciency. J Clin Invest. 2002;110(8):1093-1103
35. Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O'Rahilly S, Trussell RA. Congenital leptin defciency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab. 2004;89(10):4821-4826
36. Rau H, Reaves BJ, O'Rahilly S, Whitehead JP. Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport Endocrinology 1999 140 4 1718-1723
37. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18(3):213-215
38. Ozata M, Ozdemir IC, Licinio J. Human leptin def-ciency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the efects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab. 1999;84(10):3686-3695
39. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S. Efects of recombinant leptin therapy in a child with congenital leptin defciency. N Engl J Med. 1999;341(12):879-884
40. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML. Phenotypic efects of lep-tin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-defcient adults. Proc Natl Acad Sci U S A. 2004;101(13):4531-4536
41. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfeld LA, Clark F T, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identifcation and expression cloning of a leptin receptor, OB-R. Cell. 1995;83(7):1263-1271
42. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996;379(6566):632-635
43. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, Friedman JM. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci U S A. 1997;94(13):7001-7005
44. Bjorbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem. 1997;272(51):32686-32695
45. Ghilardi N, Skoda RC. Te leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol Endocrinol. 1997;11(4):393-399
46. Banks AS, Davis SM, Bates SH, Myers MG Jr. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem. 2000;275(19):14563-14572
47. Takahashi Y, Okimura Y, Mizuno I, Iida K, Takahashi T, Kaji H, Abe H, Chihara K. Leptin induces mitogen-activated protein kinase-dependent proliferation of C3H10T1/2 cells. J Biol Chem. 1997;272(20):12897-12900
48. Carpenter LR, Farruggella TJ, Symes A, Karow ML, Yancopoulos GD, Stahl N. Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor. Proc Natl Acad Sci U S A. 1998;95(11):6061-6066
49. Defective STAT signaling by the leptin Ghilardi N, Ziegler S, Wiestner A, Stofel R, Heim MH, Skoda RC. Defective STAT signaling by the leptin receptor in diabetic mice Proc Natl Acad Sci U S A 1996 93 13 6231-6235
50. Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr., Stofel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet. 1996;14(1):95-97
51. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003;421(6925):856-859
52. Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identifcation of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell. 1998;1(4):619-625
53. Bjorbaek C, El-Haschimi K, Frantz JD, Flier JS. Te role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem. 1999;274(42):30059-30065
54. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 1999;283(5407):1544-1548
55. Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, McGlade CJ, Kennedy B P, Tremblay ML. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell. 2002;2(4):497-503.
56. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG. PTP1B regulates leptin signal transduction in vivo. Dev Cell. 2002;2(4):489-495
57. Li C, Iofe E, Fidahusein N, Connolly E, Friedman JM. Absence of soluble leptin receptor in plasma from dbPas/dbPas and other db/db mice. J Biol Chem. 1998;273(16):10078-10082
58. Ge H, Huang L, Pourbahrami T, Li C. Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. J Biol Chem. 2002;277(48):45898-45903
59. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP. Evidence that the diabetes gene encodes the leptin receptor: identifcation of a mutation in the leptin receptor gene in db/db mice. Cell. 1996;84(3):491-495
60. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392(6674):398-401.
61. S, Barroso I, Undlien DE, O'Rahilly S. Clinical and molecular genetic spectrum of congenital defciency of the leptin receptor. N Engl J Med. 2007;356(3):237-247
62. 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(5335):135-138
63. 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(5):593-602.
64. Fong TM, Mao C, MacNeil T, Kalyani R, Smith T, Weinberg D, Tota MR, Van der Ploeg LH. ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem Biophys Res Commun. 1997;237(3):629-631
65. Rossi M, Kim MS, Morgan DG, Small CJ, Edwards CM, Sunter D, Abusnana S, Goldstone AP, Russell SH, Stanley SA, Smith DM, Yagalof K, Ghatei MA, Bloom SR. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the efect of alpha-melanocyte stimulating hormone in vivo. Endocrinology. 1998;139(10):4428-4431
66. Mizuno TM, Mobbs CV. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology. 1999;140(2):814-817
67. Bultman SJ, Michaud EJ, Woychik RP. Molecular characterization of the mouse agouti locus. Cell. 1992;71(7):1195-1204
68. 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(3):454-467
69. 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 U S A. 1994;91(7):2562-2566
70. Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark KL. Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet. 1997;17(3):273-274
71. Qian S, Chen H, Weingarth D, Trumbauer ME, Novi DE, Guan X, Yu H, Shen Z, Feng Y, Frazier E, Chen A, Camacho RE, Shearman LP, Gopal-Truter S, MacNeil DJ, Van der Ploeg LH, Marsh DJ. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol. 2002;22(14):5027-5035
72. Xu AW, Kaelin CB, Morton GJ, Ogimoto K, Stanhope K, Graham J, Baskin DG, Havel P, Schwartz MW, Barsh GS. Efects of hypothalamic neurodegeneration on energy balance. PLoS Biol. 2005;3(12):e415.
73. Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z, Ghatei MA, Bloom SR. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypo-phagic phenotype. FASEB J. 2005;19(12):1680-1682
74. Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T, Plum L, Balthasar N, Hampel B, Waisman S, Barsh GS, Horvath TL, Bruning JC. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci. 2005;8(10):1289-1291
75. Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. 2005;310(5748):683-685
76. Wortley KE, Anderson KD, Yasenchak J, Murphy A, Valenzuela D, Diano S, Yancopoulos GD, Wiegand SJ, Sleeman MW. Agouti-related protein-defcient mice display an age-related lean phenotype. Cell Metab. 2005;2(6):421-427
77. Sozen MA, de Jonge LH, Greenway F, Ravussin E, Smith SR, Argyropoulos G. A rare mutation in AgRP, +79GA, afects promoter activity. Eur J Clin Nutr. 2007;61(6):809-812
78. Marks DL, Boucher N, Lanouette CM, Perusse L, Brookhart G, Comuzzie AG, Chagnon YC, Cone RD. Ala67Tr polymorphism in the Agouti-related peptide gene is associated with inherited leanness in humans. Am J Med Genet A. 2004;126A(3):267-271
79. Loos RJ, Rankinen T, Rice T, Rao DC, Leon AS, Skinner JS, Bouchard C, Argyropoulos G. Two ethnic-specifc polymorphisms in the human Agouti-related protein gene are associated with macronutrient intake. Am J Clin Nutr. 2005;82(5):1097-1101
80. Vink T, Hinney A, van Elburg AA, van Goozen SH, Sandkuijl LA, Sinke RJ, Herpertz-Dahlmann BM, Hebebrand J, Remschmidt H, van Engeland H, Adan RA. Association between an agouti-related protein gene polymorphism and anorexia nervosa. Mol Psychiatry. 2001;6(3):325-328
81. Bonilla C, Panguluri RK, Taliaferro-Smith L, Argyropoulos G, Chen G, Adeyemo AA, Amoah A, Owusu S, Acheampong J, Agyenim-Boateng K, Eghan BA, Oli J, Okafor G, Abbiyesuku F, Johnson T, Rufus T, Fasanmade O, Chen Y, Collins FS, Dunston GM, Rotimi C, Kittles RA. Agouti-related protein promoter variant associated with leanness and decreased risk for diabetes in West Africans. Int J Obes (Lond). 2006;30(4):715-721
82. Dardennes RM, Zizzari P, Tolle V, Foulon C, Kipman A, Romo L, Iancu-Gontard D, Boni C, Sinet PM, Terese Bluet M, Estour B, Mouren MC, Guelf JD, Rouillon F, Gorwood P, Epelbaum J. Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset. Psychoneuroendocrinology. 2007;32(2):106-113
83. Bertagna X. Proopiomelanocortin-derived peptides. Endocrinol Metab Clin North Am. 1994;23(3):467-485
84. Castro MG, Morrison E. Post-translational processing of proopiomelanocortin in the pituitary and in the brain. Crit Rev Neurobiol. 1997;11(1):35-57.
85. Abdel-Malek ZA. Melanocortin receptors: their functions and regulation by physiological agonists and antagonists. Cell Mol Life Sci. 2001;58(3):434-441
86. Yaswen L, Diehl N, Brennan MB, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin defciency responds to peripheral melanocortin Nat Med 1999 5 9 1066-1070
87. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insuf-fciency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19(2):155-157
88. Krude H, Biebermann H, Schnabel D, Tansek MZ, Teunissen P, Mullis PE, Gruters A. Obesity due to proopiomelanocortin defciency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab. 2003;88(10):4633-4640
89. Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka J, Lowenbein S, Challis BG, O'Rahilly S. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes. 2006;55(9):2549-2553
90. Clement K, Dubern B, Mencarelli M, Czernichow P, Ito S, Wakamatsu K, Barsh G, Vaisse C, Leger J. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J Clin Endocrinol Metab. 2008.
91. Echwald SM, Sorensen TI, Andersen T, Tybjaerg-Hansen A, Clausen JO, Pedersen O. Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity. Int J Obes Relat Metab Disord. 1999;23(3):293-298
92. Miraglia del Giudice E, Cirillo G, Santoro N, D'Urso L, Carbone MT, Di Toro R, Perrone L. Molecular screening of the proopiomelanocortin (POMC) gene in Italian obese children: report of three new mutations. Int J Obes Relat Metab Disord. 2001;25(1):61-67
93. Challis BG, Pritchard LE, Creemers JW, Delplanque J, Keogh JM, Luan J, Wareham NJ, Yeo GS, Bhattacharyya S, Froguel P, White A, Farooqi IS, O'Rahilly S. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet. 2002;11(17):1997-2004.
94. Hinney A, Becker I, Heibult O, Nottebom K, Schmidt A, Ziegler A, Mayer H, Siegfried W, Blum WF, Remschmidt H, Hebebrand J. Systematic mutation screening of the pro-opiomelanocortin gene: identifca-tion of several genetic variants including three diferent insertions, one nonsense and two missense point muta tions in probands of diferent weight extremes. J Clin Endocrinol Metab. 1998;83(10):3737-3741
95. Lee YS, Challis BG, Tompson DA, Yeo GS, Keogh JM, Madonna ME, Wraight V, Sims M, Vatin V, Meyre D, Shield J, Burren C, Ibrahim Z, Cheetham T, Swift P, Blackwood A, Hung CC, Wareham NJ, Froguel P, Millhauser GL, O'Rahilly S, Farooqi IS. A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab. 2006;3(2):135-140
96. Biebermann H, Castaneda TR, van Landeghem F, von Deimling A, Escher F, Brabant G, Hebebrand J, Hinney A, Tschop MH, Gruters A, Krude H. A role for beta-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab. 2006;3(2):141-146
97. Dubern B, Lubrano-Berthelier C, Mencarelli M, Ersoy B, Frelut ML, Bougle D, Costes B, Simon C, Tounian P, Vaisse C, Clement K. Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identifcation of a novel deleterious heterozygous mutation located in the alpha-melanocyte stimulating hormone domain. Pediatr Res. 2008;63(2):211-216
98. Rouille Y, Duguay SJ, Lund K, Furuta M, Gong Q, Lipkind G, Oliva AA Jr., Chan SJ, Steiner DF. Proteolytic processing mechanisms in the biosynthesis of neuroendocrine peptides: the subtilisin-like proprotein convertases. Front Neuroendocrinol. 1995;16(4):322-361
99. Seidah NG, Chretien M. Proprotein and prohormone convertases: a family of subtilases generating diverse bio-active polypeptides. Brain Res. 1999;848(1-2):45-62.
100. Bloomquist BT, Eipper BA, Mains RE. Prohormone-converting enzymes: regulation and evaluation of function using antisense RNA. Mol Endocrinol. 1991;5(12):2014-2024
101. Wilson HE, White A. Prohormones: their clinical relevance. Trends Endocrinol Metab. 1998;9(10): 396-402.
102. Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst JJ, Steiner DF. Disruption of PC1/3 expression in mice causes dwarfsm and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci U S A. 2002;99(16):10293-10298
103. Lloyd DJ, Bohan S, Gekakis N. Obesity, hyperphagia and increased metabolic efciency in Pc1 mutant mice. Hum Mol Genet. 2006;15(11):1884-1893
104. Fricker LD. Carboxypeptidase E. Annu Rev Physiol. 1988;50:309-321
105. Fricker LD, Berman YL, Leiter EH, Devi LA. Carboxypeptidase E activity is defcient in mice with the fat mutation. Efect on peptide processing. J Biol Chem. 1996;271(48):30619-30624
106. Coleman DL, Eicher EM. Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J Hered. 1990;81(6):424-427
107. 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(2):135-142
108. Jackson RS, Creemers JW, Ohagi S, Rafn-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(3):303-306
109. Jackson RS, Creemers JW, Farooqi IS, Rafn-Sanson ML, Varro A, Dockray GJ, Holst JJ, Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A, Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S. Small-intestinal dysfunction accompanies the complex endo-crinopathy of human proprotein convertase 1 defciency. J Clin Invest. 2003;112(10):1550-1560
110. Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, Lank E, Keogh J, O'Rahilly S, Creemers JW. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohor-mone convertase 1/3. J Clin Endocrinol Metab. 2007;92(9):3369-3373
111. 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 melano-cortin receptor. J Biol Chem. 1993;268(20):15174-15179
112. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and auto-nomic control circuits in the brain. Mol Endocrinol. 1994;8(10):1298-1308
113. Nijenhuis WA, Oosterom J, Adan RA. AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol Endocrinol. 2001;15(1):164-171
114. Adan RA. Constitutive receptor activity series: endogenous inverse agonists and constitutive receptor activity in the melanocortin system. Trends Pharmacol Sci. 2006;27(4):183-186
115. Srinivasan S, Lubrano-Berthelier C, Govaerts C, Picard F, Santiago P, Conklin BR, Vaisse C. 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. 2004;114(8):1158-1164
116. Haskell-Luevano C, Monck EK. Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor. Regul Pept. 2001;99(1):1-7.
117. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfeld LA, Burn P, Lee F. Targeted disruption of the melano-cortin-4 receptor results in obesity in mice. Cell. 1997;88(1):131-141
118. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. 1997;385(6612):165-168 (Pubitemid 27034218)
119. Chen AS, Metzger JM, Trumbauer ME, Guan XM, Yu H, 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(2):145-154
120. Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, Ferreira M, Tang V, McGovern RA, Kenny CD, Christiansen LM, Edelstein E, Choi B, Boss O, Aschkenasi C, Zhang CY, Mountjoy K, Kishi T, Elmquist JK, Lowell BB. Divergence of melanocor-tin pathways in the control of food intake and energy expenditure. Cell. 2005;123(3):493-505.
121. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt LF. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci. 2003;6(7):736-742
122. Ste Marie L, Miura GI, Marsh DJ, Yagalof K, Palmiter RD. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci U S A. 2000;97(22):12339-12344
123. 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(2):111-112
124. 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(2):113-114
125. Larsen LH, Echwald SM, Sorensen TI, Andersen T, Wulf BS, Pedersen O. Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identifed among 750 men with juvenile-onset obesity. J Clin Endocrinol Metab. 2005;90(1):219-224
126. Lubrano-Berthelier C, Dubern B, Lacorte JM, Picard F, Shapiro A, Zhang S, Bertrais S, Hercberg S, Basdevant A, Clement K, Vaisse C. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classifcation, genotype-phenotype relationship, and lack of association with binge eating. J Clin Endocrinol Metab. 2006;91(5):1811-1818
127. Buono P, Pasanisi F, Nardelli C, Ieno L, Capone S, Liguori R, Finelli C, Oriani G, Contaldo F, Sacchetti L. Six novel mutations in the proopiomelanocortin and mel-anocortin receptor 4 genes in severely obese adults living in southern Italy. Clin Chem. 2005;51(8):1358-1364
128. Branson R, Potoczna N, Kral JG, Lentes KU, Hoehe MR, Horber FF. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med. 2003;348(12):1096-1103
129. Dubern B, Clement K, Pelloux V, Froguel P, Girardet JP, Guy-Grand B, Tounian P. Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. J Pediatr. 2001;139(2):204-209
130. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085-1095 (Pubitemid 36337319)
131. Hainerova I, Larsen LH, Holst B, Finkova M, Hainer V, Lebl J, Hansen T, Pedersen O. Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis. J Clin Endocrinol Metab. 2007;92(9):3689-3696
132. Hinney A, Bettecken T, Tarnow P, Brumm H, Reichwald K, Lichtner P, Scherag A, Nguyen T T, Schlumberger P, Rief W, Vollmert C, Illig T, Wichmann HE, Schafer H, Platzer M, Biebermann H, Meitinger T, Hebebrand J. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J Clin Endocrinol Metab. 2006;91(5):1761-1769
133. Jacobson P, Ukkola O, Rankinen T, Snyder EE, Leon AS, Rao DC, Skinner JS, Wilmore JH, Lonn L, Cowan GS Jr., Sjostrom L, Bouchard C. 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(10):4442-4446
134. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O'Rahilly S. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor defciency. J Clin Invest. 2000;106(2):271-279
135. Kobayashi H, Ogawa Y, Shintani M, Ebihara K, Shimodahira M, Iwakura T, Hino M, Ishihara T, Ikekubo K, Kurahachi H, Nakao K. A Novel homozygous mis-sense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity. Diabetes. 2002;51(1):243-246
136. Lubrano-Berthelier C, Le Stunf C, Bougneres P, Vaisse C. A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans. J Clin Endocrinol Metab. 2004;89(5):2028-2032
137. Dubern B, Bisbis S, Talbaoui H, Le Beyec J, Tounian P, Lacorte JM, Clement K. Homozygous null mutation of the melanocortin-4 receptor and severe early-onset obesity. J Pediatr. 2007;150(6):613-617, 617 e1.
138. 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(2):253-262
139. Farooqi S, O'Rahilly S. Genetics of obesity in humans. Endocr Rev. 2006;27(7):710-718
140. Stutzmann F, Tan K, Vatin V, Dina C, Jouret B, Tichet J, Balkau B, Potoczna N, Horber F, O'Rahilly S, Farooqi IS, Froguel P, Meyre D. Prevalence of melanocortin-4 receptor defciency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes. 2008;57(9):2511-2518
141. Tao YX. Molecular mechanisms of the neural melano-cortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol. 2005;239(1-2):1-14.
142. Govaerts C, Srinivasan S, Shapiro A, Zhang S, Picard F, Clement K, Lubrano-Berthelier C, Vaisse C. Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function. Peptides. 2005;26(10):1909-1919
143. Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J, Ferron C, Froguel P, Vaisse C. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet. 2003;12(2):145-153
144. Yeo GS, Lank EJ, Farooqi IS, Keogh J, Challis BG, O'Rahilly S. Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet. 2003;12(5):561-574
145. Ho G, MacKenzie RG. Functional characterization of mutations in melanocortin-4 receptor associated with human obesity. J Biol Chem. 1999;274(50):35816-35822
146. Biebermann H, Krude H, Elsner A, Chubanov V, Gudermann T, Gruters A. Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative efect caused by receptor dimeriza-tion. Diabetes. 2003;52(12):2984-2988
147. Tarnow P, Rediger A, Brumm H, Ambrugger P, Rettenbacher E, Widhalm K, Hinney A, Kleinau G, Schaefer M, Hebebrand J, Krause G, Grüters A, Biebermann H. A Heterozygous Mutation in the Tird Transmembrane Domain Causes a Dominant-Negative Efect on Signalling Capability of the MC4R. Obesity Facts. 2008;1(3):155-162.
148. Nargund RP, Strack AM, Fong TM. Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J Med Chem. 2006;49(14):4035-4043
149. 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(11):8246-8250
150. Roselli-Rehfuss L, Mountjoy KG, Robbins LS, Mortrud MT, Low MJ, Tatro JB, Entwistle ML, Simerly RB, Cone RD. Identifcation of a receptor for gamma mel-anotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci U S A. 1993;90(19):8856-8860
151. 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, Van der Ploeg LH. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet. 2000;26(1):97-102.
152. Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, Baetscher M, Cone RD. A unique metabolic syndrome causes obesity in the mel-anocortin-3 receptor-defcient mouse. Endocrinology. 2000;141(9):3518-3521
153. Lee M, Kim A, Conwell IM, Hruby V, Mayorov A, Cai M, Wardlaw SL. Efects of selective modulation of the central melanocortin-3-receptor on food intake and hypothalamic POMC expression. Peptides. 2008;29(3):440-447
154. Sutton GM, Trevaskis JL, Hulver MW, McMillan RP, Markward NJ, Babin MJ, Meyer EA, Butler AA. Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or-4 receptors. Endocrinology. 2006;147(5):2183-2196
155. Lee YS, Poh LK, Loke KY. A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. J Clin Endocrinol Metab. 2002;87(3):1423-1426
156. Lee YS, Poh LK, Kek BL, Loke KY. Te role of mel-anocortin 3 receptor gene in childhood obesity. Diabetes. 2007;56(10):2622-2630
157. Tao YX, Segalof DL. 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. 2004;89(8):3936-3942
158. Rached M, Buronfosse A, Begeot M, Penhoat A. Inactivation and intracellular retention of the human I183N mutated melanocortin 3 receptor associated with obesity. Biochim Biophys Acta. 2004;1689(3):229-234
159. Tao YX. Functional characterization of novel melanocor-tin-3 receptor mutations identifed from obese subjects. Biochim Biophys Acta. 2007;1772(10):1167-1174
160. Mencarelli M, Walker GE, Maestrini S, Alberti L, Verti B, Brunani A, Petroni ML, Tagliaferri M, Liuzzi A, Di Blasio AM. Sporadic mutations in melanocortin receptor 3 in morbid obese individuals. Eur J Hum Genet. 2008;16(5):581-586
161. Huang EJ, Reichardt LF. Neurotrophins: roles in neu-ronal development and function. Annu Rev Neurosci. 2001;24:677-736.
162. Lipsky RH, Marini AM. Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci. 2007;1122:130-143
163. Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA. Biosynthesis and post-transla-tional processing of the precursor to brain-derived neu-rotrophic factor. J Biol Chem. 2001;276(16):12660-12666
164. Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem. 2003;72:609-642
165. Pelleymounter MA, Cullen MJ, Wellman CL. Characteristics of BDNF-induced weight loss. Exp Neurol. 1995;131(2):229-238
166. Komori T, Morikawa Y, Nanjo K, Senba E. Induction of brain-derived neurotrophic factor by leptin in the ventromedial hypothalamus. Neuroscience. 2006;139(3):1107-1115
167. Tsao D, Tomsen HK, Chou J, Stratton J, Hagen M, Loo C, Garcia C, Sloane DL, Rosenthal A, Lin JC. TrkB agonists ameliorate obesity and associated metabolic conditions in mice. Endocrinology. 2008;149(3):1038-1048
168. Allen SJ, Dawbarn D. Clinical relevance of the neurotrophins and their receptors. Clin Sci (Lond). 2006;110(2):175-191
169. Hu Y, Russek SJ. BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem. 2008;105(1):1-17.
170. Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, Wihler C, Koliatsos VE, Tessarollo L. Brain-derived neurotrophic factor-defcient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A. 1999;96(26):15239-15244
171. Kernie SG, Liebl DJ, Parada LF. BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 2000;19(6):1290-1300
172. Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R, Lechan RM, Jaenisch R. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol. 2001;15(10):1748-1757
173. Friedel S, Horro FF, Wermter AK, Geller F, Dempfe A, Reichwald K, Smidt J, Bronner G, Konrad K, Herpertz-Dahlmann B, Warnke A, Hemminger U, Linder M, Kief H, Goldschmidt HP, Siegfried W, Remschmidt H, Hinney A, Hebebrand J. Mutation screen of the brain derived neurotrophic factor gene (BDNF): iden-tifcation of several genetic variants and association studies in patients with obesity, eating disorders, and attention-defcit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2005;132B(1):96-99
174. Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL, Keogh JM, Yanovski JA, El Gharbawy A, Han JC, Tung YC, Hodges JR, Raymond FL, O'Rahilly S, Farooqi IS. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes. 2006;55(12):3366-3371
175. Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O'Rahilly S, Farooqi IS. A de novo mutation afecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci. 2004;7(11):1187-1189
176. Gray J, Yeo G, Hung C, Keogh J, Clayton P, Banerjee K, McAulay A, O'Rahilly S, Farooqi IS. Functional characterization of human NTRK2 mutations identifed in patients with severe early-onset obesity. Int J Obes (Lond). 2007;31(2):359-364
177. Marlin S, Couet D, Lacombe D, Cessans C, Bonneau D. Obesity: a new feature of WAGR (del 11p) syndrome. Clin Dysmorphol. 1994;3(3):255-257
178. McGaughran JM, Ward HB, Evans DG. WAGR syndrome and multiple exostoses in a patient with del(11) (p11.2p14.2). J Med Genet. 1995;32(10):823-824
179. Tiberio G, Digilio MC, Giannotti A. Obesity and WAGR syndrome. Clin Dysmorphol. 2000;9(1):63-64
180. Barnikol-Watanabe S, Gross NA, Gotz H, Henkel T, Karabinos A, Kratzin H, Barnikol HU, Hilschmann N. Human protein NEFA, a novel DNA binding/ EF-hand/leucine zipper protein. Molecular cloning and sequence analysis of the cDNA, isolation and characterization of the protein. Biol Chem Hoppe Seyler. 1994;375(8):497-512.
181. Miura K, Titani K, Kurosawa Y, Kanai Y. Molecular cloning of nucleobindin, a novel DNA-binding protein that contains both a signal peptide and a leucine zipper structure. Biochem Biophys Res Commun. 1992;187(1):375-380
182. Karabinos A, Bhattacharya D, Morys-Wortmann C, Kroll K, Hirschfeld G, Kratzin HD, Barnikol-Watanabe S, Hilschmann N. Te divergent domains of the NEFA and nucleobindin proteins are derived from an EF-hand ancestor. Mol Biol Evol. 1996;13(7):990-998
183. Oh IS, Shimizu H, Satoh T, Okada S, Adachi S, Inoue K, Eguchi H, Yamamoto M, Imaki T, Hashimoto K, Tsuchiya T, Monden T, Horiguchi K, Yamada M, Mori M. Identifcation of nesfatin-1 as a satiety molecule in the hypothalamus. Nature. 2006;443(7112):709-712
184. Brailoiu GC, Dun SL, Brailoiu E, Inan S, Yang J, Chang JK, Dun NJ. Nesfatin-1: distribution and interaction with a G protein-coupled receptor in the rat brain. Endocrinology. 2007;148(10):5088-5094
185. Ward MP, Mosher JT, Crews ST. Regulation of bHLH-PAS protein subcellular localization during Drosophila embryogenesis. Development. 1998;125(9):1599-1608
186. Nambu JR, Franks RG, Hu S, Crews ST. Te single-minded gene of Drosophila is required for the expression of genes important for the development of CNS midline cells. Cell. 1990;63(1):63-75.
187. Fan CM, Kuwana E, Bulfone A, Fletcher CF, Copeland NG, Jenkins NA, Crews S, Martinez S, Puelles L, Rubenstein JL, Tessier-Lavigne M. Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome. Mol Cell Neurosci. 1996;7(1):1-16.
188. Michaud JL, Rosenquist T, May NR, Fan CM. Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1. Genes Dev. 1998;12(20):3264-3275
189. Chrast R, Scott HS, Chen H, Kudoh J, Rossier C, Minoshima S, Wang Y, Shimizu N, Antonarakis SE. Cloning of two human homologs of the Drosophila single-minded gene SIM1 on chromosome 6q and SIM2 on 21q within the Down syndrome chromosomal region. Genome Res. 1997;7(6):615-624
190. Holder JL Jr., Butte NF, Zinn AR. Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet. 2000;9(1): 101-108
191. Michaud JL, Boucher F, Melnyk A, Gauthier F, Goshu E, Levy E, Mitchell GA, Himms-Hagen J, Fan CM. Sim1 haploinsufciency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypo-thalamus. Hum Mol Genet. 2001;10(14):1465-1473
192. Kublaoui BM, Holder JL Jr., Tolson KP, Gemelli T, Zinn AR. SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake. Endocrinology. 2006;147(10):4542-4549
193. Kublaoui BM, Holder JL Jr., Gemelli T, Zinn AR. Sim1 haploinsufciency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons. Mol Endocrinol. 2006;20(10):2483-2492
194. Kublaoui BM, Gemelli T, Tolson KP, Wang Y, Zinn AR. Oxytocin defciency mediates hyperphagic obesity of Sim1 haploinsufcient mice. Mol Endocrinol. 2008;22(7):1723-1734
195. Fyfe SL, Neul JL, Samaco RC, Chao H T, Ben-Shachar S, Moretti P, McGill BE, Goulding EH, Sullivan E, Tecott LH, Zoghbi HY. Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron. 2008;59(6):947-958
196. Holder JL Jr., Zhang L, Kublaoui BM, DiLeone RJ, Oz OK, Bair CH, Lee YH, Zinn AR. Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice. Am J Physiol Endocrinol Metab. 2004;287(1):E105-13.
197. Faivre L, Cormier-Daire V, Lapierre JM, Colleaux L, Jacquemont S, Genevieve D, Saunier P, Munnich A, Turleau C, Romana S, Prieur M, De Blois MC, Vekemans M. Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype. J Med Genet. 2002;39(8):594-596
198. Gilhuis HJ, van Ravenswaaij CM, Hamel BJ, Gabreels FJ. Interstitial 6q deletion with a Prader-Willi-like phenotype: a new case and review of the literature. Eur J Paediatr Neurol. 2000;4(1):39-43.
199. Turleau C, Demay G, Cabanis MO, Lenoir G, de Grouchy J. 6q1 monosomy: a distinctive syndrome. Clin Genet. 1988;34(1):38-42.
200. Villa A, Urioste M, Bofarull JM, Martinez-Frias ML. De novo interstitial deletion q16.2q21 on chromosome 6. Am J Med Genet. 1995;55(3):379-383
201. Varela MC, Simoes-Sato AY, Kim CA, Bertola DR, De Castro CI, Koifmann CP. A new case of interstitial 6q16.2 deletion in a patient with Prader-Willi-like phenotype and investigation of SIM1 gene deletion in 87 patients with syndromic obesity. Eur J Med Genet. 2006;49(4):298-305.
202. Klein OD, Cotter PD, Moore MW, Zanko A, Gilats M, Epstein CJ, Conte F, Rauen KA. Interstitial deletions of chromosome 6q: genotype-phenotype correlation utilizing array CGH. Clin Genet. 2007;71(3):260-266
203. Wang JC, Turner L, Lomax B, Eydoux P. A 5-Mb micro-deletion at 6q16.1-q16.3 with SIM gene deletion and obesity. Am J Med Genet A. 2008;146A(22):2975-2978
204. Hung CC, Luan J, Sims M, Keogh JM, Hall C, Wareham NJ, O'Rahilly S, Farooqi IS. Studies of the SIM1 gene in relation to human obesity and obesity-related traits. Int J Obes (Lond). 2007;31(3):429-434
205. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, Inouye M, Freathy RM, Attwood AP, Beckmann JS, Berndt SI, Jacobs KB, Chanock SJ, Hayes RB, Bergmann S, Bennett AJ, Bingham SA, Bochud M, Brown M, Cauchi S, Connell JM, Cooper C, Smith GD, Day I, Dina C, De S, Dermitzakis ET, Doney AS, Elliott KS, Elliott P, Evans DM, Sadaf Farooqi I, Froguel P, Ghori J, Groves CJ, Gwilliam R, Hadley D, Hall AS, Hattersley AT, Hebebrand J, Heid IM, Lamina C, Gieger C, Illig T, Meitinger T, Wichmann HE, Herrera B, Hinney A, Hunt SE, Jarvelin MR, Johnson T, Jolley JD, Karpe F, Keniry A, Khaw KT, Luben RN, Mangino M, Marchini J, McArdle WL, McGinnis R. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008;40(6):768-775
206. Duarte SF, Francischetti EA, Genelhu VA, Cabello PH, Pimentel MM. LEPR p.Q223R, beta3-AR p.W64R and LEP c.-2548GA gene variants in obese Brazilian subjects. Genet Mol Res. 2007;6(4):1035-1043
207. Benzinou M, Creemers JW, Choquet H, Lobbens S, Dina C, Durand E, Guerardel A, Boutin P, Jouret B, Heude B, Balkau B, Tichet J, Marre M, Potoczna N, Horber F, Le Stunf C, Czernichow S, Sandbaek A, Lauritzen T, Borch-Johnsen K, Andersen G, Kiess W, Korner A, Kovacs P, Jacobson P, Carlsson LM, Walley AJ, Jorgensen T, Hansen T, Pedersen O, Meyre D, Froguel P. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet. 2008;40(8):943-945
208. Prpic V, Watson PM, Frampton IC, Sabol MA, Jezek GE, Gettys TW. Diferential mechanisms and development of leptin resistance in A/J versus C57BL/6J mice during diet-induced obesity. Endocrinology. 2003;144(4):1155-1163
209. Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, Sybertz EJ, Strader CD, Davis HR Jr. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest. 1997;99(3):385-390
210. Heymsfeld SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999;282(16):1568-1575
211. Martin WJ, MacIntyre DE. Melanocortin receptors and erectile function. Eur Urol. 2004;45(6):706-713