Genetics of obesity in humans

Endocrine Reviews

Volumn 27, Issue 7, 2006, Pages 710-718

  Farooqi, I Sadaf ^a   O'Rahilly, Stephen ^a  

^a ADDENBROOKE S HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BETA ENDORPHIN; BRAIN DERIVED NEUROTROPHIC FACTOR RECEPTOR; FURIN; HYDROCORTISONE; LEPTIN RECEPTOR; MELANOCORTIN; MELANOCORTIN 4 RECEPTOR; MELANOCORTIN RECEPTOR; NEUROTROPHIN RECEPTOR; PROHORMONE CONVERTASE 1; PROOPIOMELANOCORTIN; RECOMBINANT LEPTIN; THYROTROPIN;

BODY WEIGHT; CLINICAL FEATURE; DISEASE ASSOCIATION; DOSE RESPONSE; DRUG MECHANISM; ENDOCRINE FUNCTION; FOOD INTAKE; FRAMESHIFT MUTATION; GENE MUTATION; GENETIC CORRELATION; GENETIC DAMAGE; GENETIC VARIABILITY; HORMONE ACTION; HORMONE DEFICIENCY; HUMAN; HYPOGONADISM; HYPOTHYROIDISM; MISSENSE MUTATION; NEUROENDOCRINE SYSTEM; NONHUMAN; OBESITY; PHENOTYPE; PRIORITY JOURNAL; REVIEW;

BODY WEIGHT; HUMANS; LEPTIN; MELANOCORTINS; MUTATION; NEUROSECRETORY SYSTEMS; OBESITY; PRO-OPIOMELANOCORTIN; PROPROTEIN CONVERTASE 1; RECEPTOR, MELANOCORTIN, TYPE 4; RECEPTOR, TRKB; SIGNAL TRANSDUCTION;

EID: 33845567553     PISSN: 0163769X     EISSN: 0163769X     Source Type: Journal    
DOI: 10.1210/er.2006-0040     Document Type: Review

References (67)

1. Kopelman PG 2000 Obesity as a medical problem. Nature 404:635-643
2. Ogden CL, Flegal KM, Carroll MD, Johnson CL 2002 Prevalence and trends in overweight among US children and adolescents, 1999-2000. JAMA 288:1728-1732
3. Barsh GS, Farooqi IS, O'Rahilly S 2000 Genetics of body-weight regulation. Nature 404:644-651
4. Comuzzie AG 2002 The emerging pattern of the genetic contribution to human obesity. Best Pract Res Clin Endocrinol Metab 16:611-621
5. Maes HH, Neale MC, Eaves LJ 1997 Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 27:325-351
6. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE 1990 The body-mass index of twins who have been reared apart. N Engl J Med 322:1483-1487
7. Silventoinen K, Kaprio J, Lahelma E 2000 Genetic and environmental contributions to the association between body height and educational attainment: a study of adult Finnish twins. Behav Genet 30:477-485
8. Carmichael CM, McGue M 1995 A cross-sectional examination of height, weight, and body mass index in adult twins. J Gerontol A Biol Sci Med Sci 50:B237-B244
9. Farooqi IS, O'Rahilly S 2005 Monogenic obesity in humans. Annu Rev Med 56:443-458
10. 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 1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903-908
11. 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 2002 Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110:1093-1103
12. Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O'Rahilly S, Trussell RA 2004 Congenital leptin deficiency due to homozygosity for the Δ133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 89:4821-4826
13. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD 1998 A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 18:213-215
14. 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 1998 A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398-401
15. Lahlou N, Landais P, De Boissieu D, Bougneres PF 1997 Circulating leptin in normal children and during the dynamic phase of juvenile obesity: relation to body fatness, energy metabolism, caloric intake, and sexual dimorphism. Diabetes 46:989-993
16. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S 1999 Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879-884
17. Ozata M, Ozdemir IC, Licinio J 1999 Human leptin deficiency 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 effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 84:3686-3695
18. Flier JS, Harris M, Hollenberg AN 2000 Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. J Clin Invest 105:859-861
19. Mantzoros CS, Ozata M, Negrao AB, Suchard MA, Ziotopoulou M, Caglayan S, Elashoff RM, Cogswell RJ, Negro P, Liberty V, Wong ML, Veldhuis J, Ozdemir IC, Gold PW, Flier JS, Licinio J 2001 Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans. J Clin Endocrinol Metab 86:3284-3291
20. 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 2004 Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 101:4531-4536
21. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M 1999 Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568-1575
22. Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, Jebb SA, Lip GY, O'Rahilly S 2001 Partial leptin deficiency and human adiposity. Nature 414:34-35
23. Chung WK, Belfi K, Chua M, Wiley J, Mackintosh R, Nicolson M, Boozer CN, Leibel RL 1998 Heterozygosity for Lep(ob) or Lep(rdb) affects body composition and leptin homeostasis in adult mice. Am J Physiol 274:R985-R990
24. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A 1998 Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155-157
25. Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka J, Lowenbein S, Challis BG, O'Rahilly S 2006 Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55:2549-2553
26. Coll AP, Challis BG, Lopez M, Piper S, Yeo GS, O'Rahilly S 2005 Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Diabetes 54:2269-2276
27. Rees JL 2003 Genetics of hair and skin color. Annu Rev Genet 37:67-90
28. Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, Gruters A 2003 Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab 88:4633-4640
29. 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 2002 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 11:1997-2004
30. Lee YS, Challis BG, Thompson 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 2006 A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab 3:135-140
31. Biebermann H, Castaneda TR, van Landeghem F, et al 2006 A role for β-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab 3:141-146
32. Mountjoy KG, Wong J 1997 Obesity, diabetes and functions for proopiomelanocortin-derived peptides. Mol Cell Endocrinol 128:171-177
33. Hsiung HM, Hertel J, Zhang XY, Smith DP, Smiley DL, Heiman ML, Yang DD, Husain S, Mayer JP, Zhang L, Mo H, Yan LZ 2005 A novel and selective β-melanocyte-stimulating hormone-derived peptide agonist for melanocortin 4 receptor potently decreased food intake and body weight gain in diet-induced obese rats. Endocrinology 146:5257-5266
34. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, MacCluer JW, 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
35. Delplanque J, Barat-Houari M, Dina C, Gallina P, Clement K, Guy-Grand B, Vasseur F, Boutin P, Froguel P 2000 Linkage and association studies between the proopiomelanocortin (POMC) gene and obesity in Caucasian families. Diabetologia 43:1554-1557
36. Hixson JE, Almasy L, Cole S, Birnbaum S, Mitchell BD, Mahaney MC, Stern MP, MacCluer JW, Blangero J, Comuzzie AG 1999 Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC. J Clin Endocrinol Metab 84:3187-3191
37. Baker M, Gaukrodger N, Mayosi BM, Imrie H, Farrall M, Watkins H, Connell JM, Avery PJ, Keavney B 2005 Association between common polymorphisms of the proopiomelanocortin gene and body fat distribution: a family study. Diabetes 54:2492-2496
38. Challis BG, Coll AP, Yeo GS, Pinnock SB, Dickson SL, Thresher RR, Dixon J, Zahn D, Rochford JJ, White A, Oliver RL, Millington G, Aparicio SA, Colledge WH, Russ AP, Carlton MB, O'Rahilly S 2004 Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36). Proc Natl Acad Sci USA 101:4695-4700
39. Cai G, Cole SA, Bastarrachea-Sosa RA, Maccluer JW, Blangero J, Comuzzie AG 2004 Quantitative trait locus determining dietary macronutrient intakes is located on human chromosome 2p22. Am J Clin Nutr 80:1410-1414
40. Seidah NG, Chretien M 1999 Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res 848:45-62
41. O'Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, White A, Gibson S, Taylor K, Carr C 1995 Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med 333:1386-1390
42. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S 1997 Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16:303-306
43. Jackson RS, Creemers JW, Farooqi IS, Raffin-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 2003 Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest 112:1550-1560
44. Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst JJ, Steiner DF 2002 Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci USA 99:10293-10298
45. Lloyd DJ, Bohan S, Gekakis N 2006 Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum Mol Genet 15:1884-1893
46. Yeo GS, Farooqi IS, Challis BG, Jackson RS, O'Rahilly S 2000 The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models. QJM 93:7-14
47. 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 1997 Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131-141
48. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S 1998 A frameshift mutation in MC4R associated with dominantly inherited human obesity [letter]. Nat Genet 20:111-112
49. Vaisse C, Clement K, Guy-Grand B, Froguel P 1998 A frameshift mutation in human MC4R is associated with a dominant form of obesity [letter]. Nat Genet 20:113-114
50. Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O'Rahilly S 2000 Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 106:271-279
51. Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P 2000 Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 106:253-262
52. Hinney A, Schmidt A, Nottebom K, Heibult O, Becker I, Ziegler A, Gerber G, Sina M, Gorg T, Mayer H, Siegfried W, Fichter M, Remschmidt H, Hebebrand J 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
53. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S 2003 Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 348:1085-1095
54. Larsen LH, Echwald SM, Sorensen TI, Andersen T, Wulff BS, Pedersen O 2005 Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. J Clin Endocrinol Metab 90:219-224
55. Fan W, Dinulescu DM, Butler AA, Zhou J, Marks DL, Cone RD 2000 The central melanocortin system can directly regulate serum insulin levels. Endocrinology 141:3072-3079
56. Yeo GS, Lank EJ, Farooqi IS, Keogh J, Challis BG, O'Rahilly S 2003 Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms. Hum Mol Genet 12:561-574
57. Lubrano-Berthelier C, Durand E, Dubern B, Shapiro A, Dazin P, Weill J, Ferron C, Froguel P, Vaisse C 2003 Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Hum Mol Genet 12:145-153
58. Nargund RP, Strack AM, Fong TM 2006 Melanocortin-4 receptor (MC4R) agonists for the treatment of obesity. J Med Chem 49:4035-4043
59. Bouret SG, Draper SJ, Simerly RB 2004 Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304:108-110
60. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL 2004 Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304:110-115
61. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, Reichardt LF 2003 Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6:736-742
62. Snider WD 1994 Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77:627-638
63. Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O'Rahilly S, Farooqi IS 2004 A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat Neurosci 7:1187-1189
64. Gray J, Yeo GSH, Cox JJ, Keogh JM, Morton J, Adlam ALR, Yanovski JA, El Gharbawy A, Han C, Tung YCL, Hodges JR, Raymond FL, O'Rahilly S, Faroogi IS, Impaired cognitive function, hyperactivity and severe obesity in a child with functional loss of one copy of BDNF. Diabetes, in press.
65. Farooqi IS 2006 The severely obese patient - a genetic work-up. Nat Clin Pract Endocrinol Metab 2:172-177
66. Forbes GB, Sauer EP, Weitkamp LR 1995 Lean body mass in twins. Metabolism 44:1442-1446
67. Laskarzewski PM, Khoury P, Morrison JA, Kelly K, Mellies MJ, Glueck CJ 1983 Familial obesity and leanness. Int J Obes 7:505-527