Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Genetics of body-weight regulation

Abstract

The role of genetics in obesity is twofold. Studying rare mutations in humans and model organisms provides fundamental insight into a complex physiological process, and complements population-based studies that seek to reveal primary causes. Remarkable progress has been made on both fronts, and the pace of advance is likely to accelerate as functional genomics and the human genome project expand and mature. Approaches based on mendelian and quantitative genetics may well converge, and lead ultimately to more rational and selective therapies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chromosomal location of obesity genes.
Figure 2: Action of leptin on melanocortinergic pathways.

Similar content being viewed by others

References

  1. Falconer, D. S. & Mackay, T. F. C. Introduction to Quantitative Genetics (Addison-Wesley, Harlow,1995 ).

    Google Scholar 

  2. Bouchard, C. et al. The response to long-term overfeeding in identical twins. N. Engl. J. Med. 322, 1477–1482 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Stunkard, A. J. et al. An adoption study of human obesity. N. Engl. J. Med. 314, 193–198 ( 1986).

    Article  CAS  PubMed  Google Scholar 

  4. Allison, D. B. et al. The heritability of body mass index among an international sample of monozygotic twins reared apart. Int. J. Obes. Relat. Metab. Disord. 20, 501–506 (1996).

    CAS  PubMed  Google Scholar 

  5. Comuzzie, A. G. et al. Genetic and environmental correlations among hormone levels and measures of body fat accumulation and topography. J. Clin. Endocrinol. Metab. 81, 597–600 (1996).

    CAS  PubMed  Google Scholar 

  6. Price, R. A. & Gottesman, I. I. Body fat in identical twins reared apart: roles for genes and environment. Behav. Genet. 21, 1–7 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Maes, H. H., Neale, M. C. & Eaves, L. J. Genetic and environmental factors in relative body weight and human adiposity. Behav. Genet. 27, 325–351 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Hill, J. O. & Peters, J. C. Environmental contributions to the obesity epidemic. Science 280, 1371– 1374 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  9. World Health Organization. Obesity: Preventing and Managing the Global Epidemic (World Health Organization, Geneva, 1998).

  10. West, D. B., Waguespack, J. & McCollister, S. Dietary obesity in the mouse: interaction of strain with diet composition. Am. J. Physiol. 268, R658–R665 (1995).

    CAS  PubMed  Google Scholar 

  11. Comuzzie, A. G. & Allison, D. B. The search for human obesity genes. Science 280, 1374 –1377 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Kissebah, A. H. & Krakower, G. R. Regional adiposity and morbidity. Physiol. Rev. 74, 761– 811 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Frankel, W. N. & Schork, N. J. Who's afraid of epistasis? Nature Genet. 14, 371– 373 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  15. Comuzzie, A. G. et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nature Genet. 15, 273–276 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  16. Hager, J. et al. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nature Genet. 20, 304–308 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Rotimi, C. N. et al. The quantitative trait locus on chromosome 2 for serum leptin levels is confirmed in African-Americans. Diabetes 48, 643–644 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Hixson, J. E. et al. Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC. J. Clin. Endocrinol. Metab. 84, 3187–3191 ( 1999).

    CAS  PubMed  Google Scholar 

  19. Perusse, L., Chagnon, Y. C., Weisnagel, J. & Bouchard, C. The human obesity gene map: the 1998 update. Obes. Res. 7, 111–129 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Fisler, J. S. & Warden, C. H. Mapping of mouse obesity genes: a generic approach to a complex trait. J. Nutr. 127 , 1909S–1916S (1997).

    Article  CAS  PubMed  Google Scholar 

  22. West, D. B. Genetics of obesity in humans and animal models. Endocrinol. Metab. Clin. North Am. 25, 801–813 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Pomp, D. & Nielsen, M. K. Quantitative genetics of energy balance — lessons from animal models. Obes. Res. 7, 106–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Brockmann, G. A., Haley, C. S., Renne, U., Knott, S. A. & Schwerin, M. Quantitative trait loci affecting body weight and fatness from a mouse line selected for extreme high growth. Genetics 150, 369–381 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Moody, D. E., Pomp, D., Nielsen, M. K. & Van Vleck, L. D. Identification of quantitative trait loci influencing traits related to energy balance in selection and inbred lines of mice. Genetics 152, 699–711 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Goodale, H. A study of the inheritance of body weight in the albino mouse by selection . J. Hered. 29, 101–112 (1938).

    Article  Google Scholar 

  27. MacArthur, J. Genetics of body size and related characters. I. Selection of small and large races of the laboratory mouse. Am. Nat. 78, 142–157 (1944).

    Article  Google Scholar 

  28. Cheverud, J. M. & Routman, E. J. Epistasis and its contribution to genetic variance components. Genetics 139, 1455–1461 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cheverud, J. M. et al. Quantitative trait loci for murine growth. Genetics 142, 1305–1319 ( 1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. West, D. B., Goudey-Lefevre, J., York, B. & Truett, G. E. Dietary obesity linked to genetic loci on chromosomes 9 and 15 in a polygenic mouse model. J. Clin. Invest. 94, 1410– 1416 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. York, B. et al. Gene-environment interaction: a significant diet-dependent obesity locus demonstrated in a congenic segment on mouse chromosome 7. Mamm. Genome 10, 457–462 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. West, D. B., Waguespack, J., York, B., Goudey-Lefevre, J. & Price, R. A. Genetics of dietary obesity in AKR/J x SWR/J mice: segregation of the trait and identification of a linked locus on chromosome 4. Mamm. Genome 5, 546– 552 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Chagnon, Y. C. & Bouchard, C. Genetics of obesity: advances from rodent studies. Trends Genet. 12, 441–444 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Leibel, R. L., Chung, W. K. & Chua, S. C. Jr The molecular genetics of rodent single gene obesities. J. Biol. Chem. 272, 31937–31940 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Coleman, D. L. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294–298 (1973).

    Article  CAS  PubMed  Google Scholar 

  36. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue . Nature 372, 425–432 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  38. Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 ( 1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  39. Woods, S. C., Seeley, R. J., Porte, D. Jr & Schwartz, M. W. Signals that regulate food intake and energy homeostasis. Science 280, 1378–1383 ( 1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Ahima, R. S., Kelly, J., Elmquist, J. K. & Flier, J. S. Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia . Endocrinology 140, 4923– 4931 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Siracusa, L. D. The agouti gene: turned on to yellow. Trends Genet. 10, 423–428 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Michaud, E. J. et al. A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. Proc. Natl Acad. Sci. USA 91, 2562–2566 ( 1994).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 139, 4428– 4431 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Wilson, B. D., Ollmann, M. M. & Barsh, G. S. The role of agouti-related protein in regulating body weight. Mol. Med. Today 5, 250– 256 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Shutter, J. R. et al. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 11, 593–602 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Graham, M., Shutter, J. R., Sarmiento, U., Sarosi, I. & Stark, K. L. Overexpression of Agrt leads to obesity in transgenic mice. Nature Genet. 17, 273–274 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131– 141 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Elmquist, J. K., Elias, C. F. & Saper, C. B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221– 232 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Elias, C. F. et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Mizuno, T. M. & Mobbs, C. V. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting . Endocrinology 140, 814– 817 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Broberger, C., Johansen, J., Johansson, C., Schalling, M. & Hokfelt, T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc. Natl Acad. Sci. USA 95, 15043 –15048 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  53. Elmquist, J. K., Maratos-Flier, E., Saper, C. B. & Flier, J. S. Unraveling the central nervous system pathways underlying responses to leptin . Nature Neurosci. 1, 445– 450 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Seeley, R. et al. Melanocortin receptors in leptin effects. Nature 390, 349 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  55. Cheung, C. C., Clifton, D. K. & Steiner, R. A. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 138, 4489–4492 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Marsh, D. J. et al. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nature Genet. 21, 119–122 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Boston, B., Blaydon, K., Varnerin, J. & Cone, R. Independent and additive effects of central POMC and leptin pathways on murine obesity . Science 278, 1641–1644 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  58. Yaswen, L., Diehl, N., Brennan, M. B. & Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nature Med. 5, 1066–1070 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Tecott, L. H. et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 374, 542– 546 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  60. Hahm, S. et al. Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance. Neuron 23, 537– 548 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Shimada, M., Tritos, N. A., Lowell, B. B., Flier, J. S. & Maratos- Flier, E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396, 670–674 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  62. Ohta, T. et al. Imprinting-mutation mechanisms in Prader-Willi syndrome. Am. J. Hum. Genet. 64, 397–413 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kolehmainen, J. et al. Refined mapping of the Cohen syndrome gene by linkage disequilibrium . Eur. J. Hum. Genet. 5, 206– 213 (1997).

    CAS  PubMed  Google Scholar 

  64. Russell-Eggitt, I. M. et al. Alstrom syndrome. Report of 22 cases and literature review . Ophthalmology 105, 1274– 1280 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Beales, P. L., Warner, A. M., Hitman, G. A., Thakker, R. & Flinter, F. A. Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families. J. Med. Genet. 34, 92–98 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bruford, E. A. et al. Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21. Genomics 41, 93–99 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  67. Mathews, K. D. et al. Linkage localization of Borjeson-Forssman-Lehmann syndrome . Am. J. Med. Genet. 34, 470– 474 (1989).

    Article  CAS  PubMed  Google Scholar 

  68. Gunay-Aygun, M., Cassidy, S. B. & Nicholls, R. D. Prader-Willi and other syndromes associated with obesity and mental retardation. Behav. Genet. 27, 307–324 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Strobel, A., Issad, T., Camoin, L., Ozata, M. & Strosberg, A. D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genet. 18, 213 –215 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903– 908 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  71. Clement, K. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398 –401 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  72. Bray, G. A. & York, D. A. Genetically transmitted obesity in rodents. Physiol. Rev. 51, 598– 646 (1971).

    Article  CAS  PubMed  Google Scholar 

  73. Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genet. 19, 155–157 ( 1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  74. Yeo, G. S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genet. 20, 111– 112 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Hinney, A. 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. 84, 1483–1486 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genet. 20, 113– 114 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Gu, W. et al. Identification and functional analysis of novel human melanocortin-4 receptor variants. Diabetes 48, 635– 639 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Ho, G. & MacKenzie, R. G. Functional characterization of mutations in melanocortin-4 receptor associated with human obesity. J. Biol. Chem. 274, 35816–35822 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Sina, M. et al. Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufficiency mutations in the melanocortin-4 receptor gene . Am. J. Hum. Genet. 65, 1501– 1507 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Farooqi, I. S. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Naggert, J. K. et al. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet. 10, 135–142 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  82. Jackson, R. S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genet. 16, 303–306 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  83. Thomson, G. Mapping disease genes: family-based association studies. Am. J. Hum. Genet. 57, 487–498 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Spielman, R. S. & Ewens, W. J. The TDT and other family-based tests for linkage disequilibrium and association. Am. J. Hum. Genet. 59, 983–989 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Odunsi, K. & Kidd, K. K. A paradigm for finding genes for a complex human trait: polycystic ovary syndrome and follistatin. Proc. Natl Acad. Sci. USA 96, 8315– 8317 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lowell, B. B. & Flier, J. S. Brown adipose tissue, beta 3-adrenergic receptors, and obesity. Annu. Rev. Med. 48, 307–316 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Pietri-Rouxel, F., St John Manning, B., Gros, J. & Strosberg, A. D. The biochemical effect of the naturally occurring Trp64→Arg mutation on human beta3-adrenoceptor activity. Eur. J. Biochem. 247, 1174–1179 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Li, L. S., Lonnqvist, F., Luthman, H. & Arner, P. Phenotypic characterization of the Trp64Arg polymorphism in the beta3-adrenergic receptor gene in normal weight and obese subjects. Diabetologia 39, 857–860 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  89. Allison, D. B., Heo, M., Faith, M. S. & Pietrobelli, A. Meta-analysis of the association of the Trp64Arg polymorphism in the beta3 adrenergic receptor with body mass index. Int. J. Obes. Relat. Metab. Disord. 22, 559–566 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Fujisawa, T., Ikegami, H., Kawaguchi, Y. & Ogihara, T. Meta-analysis of the association of Trp64Arg polymorphism of beta3-adrenergic receptor gene with body mass index. J. Clin. Endocrinol. Metab. 83, 2441–2444 ( 1998).

    CAS  PubMed  Google Scholar 

  91. 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 385, 165–168 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  92. Urbanek, M. et al. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc. Natl Acad. Sci. USA 96, 8573–8578 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139– 144 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Long, A. D. & Langley, C. H. The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. Genome Res. 9, 720– 731 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Allison, D. B. et al. Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure. Am. J. Hum. Genet. 65, 531–544 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Allison, D. B. & Schork, N. J. Selected methodological issues in meiotic mapping of obesity genes in humans: issues of power and efficiency. Behav. Genet. 27, 401– 421 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Marth, G. T. et al. A general approach to single-nucleotide polymorphism discovery . Nature Genet. 23, 452– 456 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Hrabe de Angelis, M. & Balling, R. Large scale ENU screens in the mouse: genetics meets genomics. Mutat. Res. 400, 25–32 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Brown, S. D. & Nolan, P. M. Mouse mutagenesis-systematic studies of mammalian gene function. Hum. Mol. Genet. 7, 1627–1633 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Zambrowicz, B. P. et al. Disruption and sequence identification of 2,000 genes in mouse embryonic stem cells. Nature 392, 608– 611 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  101. Brennan, J. & Skarnes, W. C. Gene trapping in mouse embryonic stem cells. Methods Mol. Biol. 97, 123– 138 (1999).

    CAS  PubMed  Google Scholar 

  102. Miller, K. A. et al. Genetic studies of the mouse mutations mahogany and mahoganoid . Genetics 146, 1407–1415 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Gunn, T. M. et al. The mouse mahogany locus encodes a transmembrane form of human attractin. Nature 398, 152– 156 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  104. Norman, R. A. et al. Genomewide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21-q22. Pima Diabetes Gene Group. Am. J. Hum. Genet. 60, 166– 173 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Hanson, R. L. 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. 63, 1130–1138 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lee, J. H. et al. Genome scan for human obesity and linkage to markers in 20q13 . Am. J. Hum. Genet. 64, 196– 209 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Collins, A. C., Martin, I. C. & Kirkpatrick, B. W. Growth quantitative trait loci (QTL) on mouse chromosome 10 in a Quackenbush-Swiss x C57BL/6J backcross. Mamm. Genome 4, 454–458 (1993).

    Article  CAS  PubMed  Google Scholar 

  108. Warden, C. H. et al. Identification of four chromosomal loci determining obesity in a multifactorial mouse model. J. Clin. Invest. 95 , 1545–1552 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Dragani, T. A. et al. Mapping of body weight loci on mouse chromosome X. Mamm. Genome 6, 778–781 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. Taylor, B. A. & Phillips, S. J. Detection of obesity QTLs on mouse chromosomes 1 and 7 by selective DNA pooling. Genomics 34, 389–398 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  111. York, B., Lei, K. & West, D. B. Sensitivity to dietary obesity linked to a locus on chromosome 15 in a CAST/Ei x C57BL/6J F2 intercross. Mamm. Genome 7, 677–681 (1996).

    Article  CAS  PubMed  Google Scholar 

  112. Keightley, P. D., Hardge, T., May, L. & Bulfield, G. A genetic map of quantitative trait loci for body weight in the mouse. Genetics 142, 227–235 ( 1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Taylor, B. A. & Phillips, S. J. Obesity QTLs on mouse chromosomes 2 and 17. Genomics 43, 249–257 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Lembertas, A. V. et al. Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q. J. Clin. Invest. 100, 1240–1247 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mehrabian, M., Wen, P. Z., Fisler, J., Davis, R. C. & Lusis, A. J. Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model. J. Clin. Invest. 101, 2485–2496 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Suto, J., Matsuura, S., Imamura, K., Yamanaka, H. & Sekikawa, K. Genetics of obesity in KK mouse and effects of A(y) allele on quantitative regulation. Mamm. Genome 9, 506–510 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  117. Taylor, B. A., Tarantino, L. M. & Phillips, S. J. Gender-influenced obesity QTLs identified in a cross involving the KK type II diabetes-prone mouse strain. Mamm. Genome 10, 963–968 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  118. Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).

    Article  CAS  PubMed  Google Scholar 

  119. Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  120. Lee, G. H. et al. Abnormal splicing of the leptin receptor in diabetic mice . Nature 379, 632–635 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  121. Miller, M. W. et al. Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the Lethal-Yellow mutation. Genes Dev. 7, 454–467 ( 1993).

    Article  CAS  PubMed  Google Scholar 

  122. Bultman, S. J., Michaud, E. J. & Woychik, R. P. Molecular characterization of the mouse agouti locus . Cell 71, 1195–1204 (1992).

    Article  CAS  PubMed  Google Scholar 

  123. Good, D. J. et al. Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene. Nature Genet. 15, 397 –401 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Boggon, T. J., Shan, W. S., Santagata, S., Myers, S. C. & Shapiro, L. Implication of tubby proteins as transcription factors by structure-based functional analysis. Science 286, 2119–2125 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  125. Noben-Trauth, K., Naggert, J. K., North, M. A. & Nishina, P. M. A candidate gene for the mouse mutation tubby. Nature 380, 534–538 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank K. Clement, N. Risch and G. Yeo for helpful advice and discussion. G.S.B. is an Associate Investigator of the Howard Hughes Medical Institute. I.S.F. is a Wellcome Trust Clinical Training Fellow.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barsh, G., Farooqi, I. & O'Rahilly, S. Genetics of body-weight regulation. Nature 404, 644–651 (2000). https://doi.org/10.1038/35007519

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35007519

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing