1. World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation on obesity. Geneva: WHO, 1998:1–276.
2. Friedman JM. Obesity in the new millennium. Nature 2000;404: 632–634.
3. Lean MEJ, Hans TS, Seidell JC. Impairment of health and quality of life in people with large waist circumference. Lancet 1998;351: 853–856.
4. Lichtman SW, Pisarska K, Berman ER, et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med 1992;327:1893–1898.
5. Bandini LG, Schoeller DA, Cyr HN, et al. Validity of reported energy intake in obese and nonobese adolescents. Am J Clin Nutr 1990;52:421–425.
6. Drenick EJ, Johnson D. Weight reduction by fasting and semistarvation in morbid obesity. Int J Obes 1978;2:123–132.
7. Comuzzie AG, et al. Genetic and environmental correlations among hormone levels and measures of body fat accumulation and topography. J Clin Endocrinol Metab 1996;81:597–600.
8. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997;27: 325–351.
9. Karlin S, Williams PT, Jensen S, et al. Genetic analysis of the Stanford LRC family study data. I. Structured exploratory data analysis of height and weight measurements. Am J Epidemiol 1981;113:307–324.
10. Borecki IB, Bonney GE, Rice T, et al. Influence of genotype-dependent effects of covariates on the outcome of segregation analysis of the body mass index. Am J Hum Genet 1993;53:676–687.
11. Lecomte E, Herbeth B, Nicaud V, et al. Segregation analysis of fat mass and fat-free mass with age-dependent and sex-dependent effects—the Stanislaz family study. Gen Epidemiol 1997;14:51–62.
12. Tiret L, Andre JL, Ducimetiere P, et al. Segregation analysis of height-adjusted weight with generation- and age-dependent effects. Gen Epidemiol 1992;9:389–403.
13. Borecki IB, Rice T, Perusse L, et al. Major gene influence on the propensity to store fat in trunk versus extremity depots—evidence from the Quebec family study. Obes Res 1995;3:1–8.
14. Zonta LA, Jayakar SD, Bosisio M, et al. Genetic analysis of human obesity in an Italian sample. Hum Heredity 1987;37:129–139.
15. Byard PJ, Siervogel RM, Roche AF. Sibling correlations for weight/ stature and calf circumference. Hum Biol 1983;55:677–685.
16. Nirmala A, Mitchell LE, Rice T, et al. Assessment of adiposity in an Indian population: familial correlations. Gen Epidemiol 1993;10: 133–143.
17. Heller R, Garrison RJ, Havlik RJ, et al. Family resemblances in height and relative weight in the Framingham Heart Study. Int J Obes 1984;8:399–405.
18. Friedlander Y, Kark JD, Kaufmann NA, et al. Familial aggregation of body mass index in ethnically diverse families in Jerusalem. The Jerusalem Lipid Research Clinic. Int J Obes 1988;12:237–247.
19. Bouchard C, Rice T, Lemieux S, et al. Major gene for abdominal visceral fat area in the Quebec Family Study. Int J Obes 1996;20: 420–427.
20. Rice T, Borecki IB, Bouchard C, et al. Segregation analysis of fat mass and other body-composition measures derived from underwater weighing. Am J Hum Gen 1993;52:967–973.
21. Hasstedt SJ, Ramirez ME, Kuida H, et al. Recessive inheritance of a relative fat pattern. Am J Hum Genet 1989;45:917–925.
22. Comuzzie AG, Blangero J, Mahaney MC, et al. Major gene with sex-specific effects influences fat mass in Mexican Americans. Gen Epidemiol 1995;12:475–488.
23. Price RA, Ness R, Laskarzewski P. Common major gene inheritance of extreme overweight. Hum Biol 1990;62:747–765.
24. Moll PP, Burns TL, Lauer RM. The genetic and environmental sources of body mass index variability. Am J Hum Genet 1991;49: 1234–1255.
25. Sørensen T, Sonne-Holm S. Risk in childhood of development of severe adult obesity: retrospective population-based case-cohort study. Am J Epidemiol 1988;127:104–113.
26. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997;27: 325–351.
27. Carey DG, Nguyen TV, Campbell LV, et al. Genetic influences on central abdominal fat: a twin study. Int J Obes 1996;20:722–726.
28. Bouchard C, Perusse L, Leblanc C, et al. Inheritance of the amount and distribution of human body fat. Int J Obes 1988;12:212–215.
29. Korkeila M, Kaprio J, Rissanen A, et al. Effects of gender and age on the heritability of body mass index. Int J Obes 1991;15:647–654.
30. Korkeila M, Kaprio J, Rissanen A, et al. Consistency and change of body mass index and weight: a study on 5967 adult Finnish twin pairs. Int J Obes 1995;19:310–317.
31. Herskind AM, McGue M, Sørensen T, et al. Sex and age specific assessment of genetic and environmental influences on body mass index in twins. Int J Obes 1996;20:106–113.
32. Allison DB, Heshka S, Neale MC, et al. A genetic analysis of relative weight amongst 4,020 twin pairs with an emphasis on sex effects. Health Psychol 1994;13:362–365.
33. Pietilainen KH, Kaprio J, Rissanen A, et al. Distribution and heritability of BMI in Finish adolescents aged 16y and 17y: a study of 4884 twins and 2509 singletons. Int J Obes Rel Metab Disord 1999; 23:107–115.
34. Fabsitz RR, Carmelli D, Hewitt JK. Evidence for independent genetic influences on obesity in middle age. Int J Obes Rel Metab Disord 1992;16:657–666.
35. Bouchard C, Tremblay A, Despres JP, et al. The response to long-term overfeeding in identical twins. N Engl J Med 1990;322:1477–1482.
36. Bouchard C, Savard R, Despres JP, et al. Body composition in adopted and biological siblings. Hum Biol 1985;57:61–75.
37. Allison DB, Kaprio J, Korkeila M, et al. The heritability of body-mass index amongst an international sample of monozygotic twins reared apart. Int J Obes 1996;20:501–506.
38. Stunkard AJ, Sørensen T, Hanis C, et al. An adoption study of human obesity. N Engl J Med 1986;314:193–198.
39. Price RA, Cadoret RJ, Stunkard AJ, et al. Genetic contributions to human fatness. Am J Psychiatry 1987;144:1003–1008.
40. Sørensen T, Price RA, Stunkard AJ, et al. Genetics of obesity in adult adoptees and their biological siblings. BMJ 1989;298:87–90.
41. Sørensen T, Stunkard AJ. Does obesity run in families because of genes? An adoption study using silhouettes as a measure of obesity. Acta Psychiatr Scand Suppl 1996;370:67–72.
42. Sørensen T, Holst C, Stunkard AJ. Childhood body mass index—genetic and familial environmental influences assessed in a longitudinal adoption study. Int J Obes 1992;16:705–714.
43. Vogler GP, Sørensen T, Stunkard AJ, et al. Influences of genes and shared family environment on adult body mass index assessed in an adoption study by a comprehensive path model. Int J Obes 1995;19: 40–45.
44. Price RA, Gottesman II. Body fat in identical twins reared apart. Behav Gen 1991;21:1–7.
45. McCarthy MI. Susceptibility gene discovery for common metabolic and endocrine traits. J Mol Endocrinol 2002;28:1–17.
46. Reed DR, Ding Y, Xu W, et al. Human obesity does not segregate with the chromosomal regions of Prader-Willi, Bardet-Biedl, Cohen, Borjeson or Wilson-Turner syndromes. Int J Obes 1995;19:599–603.
47. Chagnon YC, Rankinen T, Snyder EE, et al. The human obesity gene map: the 2002 update. Obes Res 2003;11:313–367.
48. Bultman SJ, Michaud EJ, Woychik RP. Molecular characterization of the mouse agouti locus. Cell 1992;71:1195–1204.
49. Michaud EJ, Bultman SJ, Klebig ML, et al. A molecular-model for the genetic and phenotypic characteristics of the mouse lethal yellow (a (y)) mutation. Proc Natl Acad Sci USA 1994;91:2562–2566.
50. Siracusa LD. The agouti gene: turned on to yellow. Trends Genet 1994;10:423–428.
51. Zhang Y, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–432.
52. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor ob-R. Cell 1995;83:1263–1271.
53. Chua SC, Chung WK, Wupeng XS, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the ob (leptin) receptor. Science 1996;271:994–996.
54. Naggert JK, Fricker LD, 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.
55. Kleyn PW, Fan W, Kovats SG, et al. Identification and characterization of the mouse obesity gene tubby—a member of a novel gene family. Cell 1996;85:281–290.
56. Seeley RJ, Yagaloff KA, Fisher L, et al. Melanocortin receptors in leptin effects. Nature 1997;390:349.
57. Fan W, Boston BA, Kesterson RA, et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385:165–168.
58. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–770.
59. Ahima RS, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250–252.
60. Woods SC, Seeley RJ, Porte D, et al. Signals that regulate food intake and energy homeostasis. Science 1998;280:1378–1383.
61. Ahima RS, Kelly J, Elmquist J, et al. Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia. Endocrinology 1999;140:4923–4931.
62. Rossi M, et al. A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 1998;139:4428–4431.
63. Wilson BD, Ollmann M, Barsh GS. The role of agouti-related protein in regulating body weight. Mol Med Today 1999;5:250–256.
64. Shutter JR, et al. Hypothalamic expression of CART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev 1997;11:593–602.
65. Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 1999;22: 221–232.
66. Elias CF, et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 1999;23: 775–786.
67. Mizuno TM, Mobbs CV. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 1999;140:814–817.
68. Broberger C, Johansen J, Johansson C, et al. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate–treated mice. Proc Natl Acad Sci USA 1998;95:15043–15048.
69. Elmquist JK, Maratos-Flier E, Saper CB, et al. Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 1998;1:445–450.
70. Seeley R, et al. Melanocortin receptors in leptin effects. Nature 1997; 390:349.
71. Cheung CC, Clifton DK, Steiner RA. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997;138:4489–4492.
72. Marsh DJ, et al. Response of melanocortin-4 receptor–deficient mice to anorectic and orexigenic peptides. Nat Genet 1999;21: 119–122.
73. Boston B, Blaydon K, Varnerin J, et al. Independent and additive effects of central POMC and leptin pathways on murine obesity. Science 1997;278:1641–1644.
74. Yaswen L, Diehl N, Brennan, MB, et al. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 1999;5:1066–1070.
75. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903–908.
76. Strobel A, Issad T, Camoin L, et al. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18: 213–215.
77. 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.
78. Krude H, Biebermann H, Luck W, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998;19:155–157.
79. Jackson RS, Creemers JW, 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.
80. Vaisse C, Clement K, Guy-Grand B, et al. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998;20:113–114.
81. 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.
82. Nishigori H, Tomura H, Tonooka N, et al. Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc Natl Acad Sci USA 2001;98:575–580.
83. Ristow M, Muller-Wieland D, Pfeiffer A, et al. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med 1998;339:953–959.
84. Coleman DL. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 1973;9:294–298.
85. Coleman DL, Hummel KP. Effects of parabiosis of normal with genetically diabetic mice. Am J Physiol 1969;217:1298–1304.
86. Jacobsen 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.
87. Miraglia Del Giudice E, Cirillo G, Nigro V, et al. Low frequency of melaocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity. Int J Obes Rel Metab Disord 2002; 26:647–651.
88. Gu W, Tu Z, Kleyn PW, et al. Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 1999; 48:635–639.
89. Vaisse C, Clement K, Durand E, et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest 2000;106:253–262.
90. Farooqi IS, Keogh JM, Yeo GSH, et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003;348:1085–1095.
91. Branson R, Potoczna N, Kral JG, et al. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med 2003;348:1096–1103.
92. Kersten S. Peroxisome proliferators activated receptors and obesity. Eur J Pharmacol 2002;440:223–234.
93. Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet 2001;28:178–183.
94. Echwald SM, Sørensen TI, Andersen T, et al. Mutational analysis of the proopiomelanacortin gene in Caucasians with early onset obesity. Int J Obes 1999; 23:293–298.
95. Challis BG, Pritchard LE, Creemers JWM, et al. 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;17 (11):1997–2004.
96. Norman RA, Thompson DB, Foroud T, et al. Genomewide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21–q22. Am J Hum Genet 1997;60:166–173.
97. Norman RA, Tataranni PA, Pratley R, et al. Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians. Am J Hum Genet 1998;62:659–668.
98. Hanson RL, Ehm MG, Pettitt DJ, et al. An autosomal genomic scan for loci linked to type II diabetes mellitus and body mass index in Pima Indians. Am J Hum Genet 1998;63:1130–1138.
99. Walder K, Hanson RL, Kobes S, et al. An autosomal genomic scan for loci linked to plasma leptin concentration in Pima Indians. Int J Obes 2000;24:559–565.
100. Duggirala R, Blangero J, Almasy L, et al. A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans. Am J Hum Genet 2000;66: 1237–1245.
101. Duggirala R, Blangero J, Almasy L, et al. A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet 2001;68:1149–1164.
102. Comuzzie AG, Hixson JE, Almasy L, et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997;15:273–276.
103. Kissebah AH, Sonnenberg GE, Myklebust J, et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 2000;97:14478–14483.
104. Lee JH, Reed DR, Li WD, et al. Genome scan for human obesity and linkage to markers in 20q13. Am J Hum Genet 1999;64:196–209.
105. Zhu X, Cooper RS, Luke A, et al. A genome-wide scan for obesity in African-Americans. Diabetes 2002;51:541–544.
106. Feitosa MF, Borecki IB, Rich SS, et al. Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart, Lung, and Blood Institute Family Heart Study. Am J Hum Genet 2002;70:72–82.
107. Chagnon YC, Borecki IB, Perusse L, et al. Genome-wide search for genes related to the fat-free body mass in the Quebec Family Study. Metabolism 2000;49:203–207.
108. Perusse L, Rice T, Chagnon YC, et al. A genome-wide scan for abdominal fat assessed by computed tomography in the Quebec Family Study. Diabetes 2001;50:614–621.
109. Hsueh WC, Mitchell BD, Schneider JL, et al. Genome-wide scan of obesity in the Old Order Amish. J Clin Endocrinol Metab 2001;86: 1199–1205.
110. Hager J, Dina C, Francke S, et al. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat Genet 1998;20:304–308.
111. Öhmann M, Oksanen L, Kaprio J, et al. Genome-wide scan of obesity in Finnish sibpairs reveals linkage to chromosome Xq24. J Clin Endocrinol Metab 2000;85:3183–3190.
112. Parker A, Meyer J, Lewitzky S, et al. A gene conferring susceptibility to type 2 diabetes in conjunction with obesity is located on chromosome 18p11. Diabetes 2001;50:675–680.
113. Perola M, Öhmann M, Hiekkalinna T, et al. Quantitative-trait-locus analysis of body-mass index and of stature, by combined analysis of genome scans of five Finnish study groups. Am J Hum Genet 2001; 69:117–123.
114. van der Kallen CJH, Lindgren CM, Daly MJ, et al. Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A. Int J Obes 2000;24:1381–1391.
115. Clement K, Garner C, Hager J, et al. Indication for linkage of the human OB gene region with extreme obesity. Diabetes 1996;45: 687–690.
116. Reed DR, Ding Y, Xu W, et al. Extreme obesity may be linked to markers flanking the human OB gene. Diabetes 1996;45:691–694.
117. Wu X, Cooper RS, Borecki I, et al. A combined analysis of genomewide linkage scans for body mass index from the National Heart, Lung, and Blood Institute Family Blood Pressure Program. Am J Hum Genet 2002;70:1247–1256.
118. Duggirala R, Stern MP, Mitchell BD, et al. Quantitative variation in obesity-related traits and insulin precursors linked to the OB gene region on human chromosome 7. Am J Hum Genet 1996;59:694–703.
119. Lapsys NM, Furler SM, Moore KR, et al. Relationship of a novel polymorphic marker near the human obese (OB) gene to fat mass in healthy women. Obes Res 1997;5:430–433.
120. Roth H, Hinney A, Ziegler A, et al. Further support for linkage of extreme obesity to the obese gene in a study group of obese children and adolescents. Exp Clin Endocrinol Diabetes 1997;105:341–344.
121. Hinney A, Ziegler A, Oeffner F, et al. Independent confirmation of a major locus for obesity on chromosome 10. J Clin Endocrinol Metab 2000;85:2962–2965.
122. Price RA, Li WD, Bernstein A, et al. A locus affecting obesity in human chromosome region 10p12. Diabetologia 2001;44:363–366.
123. Hunt SC, Abkevich V, Hensel CH, et al. Linkage of body mass index to chromosome 20 in Utah pedigrees. Hum Genet 2001;109:279–285.
124. Pietilainen KH, Kaprio J, Rissanen A, et al. Distribution and heritability of BMI in Finnish adolescents aged 16 y and 17 y: a study of 4884 twins and 2509 singletons. Int J Obes Rel Metab Disord 1999; 23:107–115.
125. Farooqi S, Jebb S, Langmak G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879–884.
126. O’Rahilly S. Insights into obesity and insulin resistance from the study of extreme human phenotypes. Eur J Endocrinol 2002;147: 435–441.
127. Dagogo-Jack S. Human leptin regulation and promise in pharmacotherapy. Curr Drug Targets 2001;2:181–195.
128. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999;282:1568–1575.
129. Lambert PD, Anderson KD, Sleeman MW, et al. Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc Natl Acad Sci USA 2001;98:4652–4657.
130. Fehm HL, Smolnik R, Kern W, et al. The melanocortin melanocyte-stimulating hormone/adrenocorticotropin (4–10) decreases body fat in humans. J Clin Endocrinol Metab 2001;86:1144–1148.