Mammalian Genome

, Volume 1, Issue 3, pp 130–144

Molecular mapping of obesity genes

  • Jeffrey M. Friedman
  • Rudolph L. Leibel
  • Nathan Bahary
Review

Abstract

Advances in molecular genetics have made it possible to clone mutant genes from mammals. This capability should facilitate efforts to determine the genetic factors that control food intake and body composition. In order to identify these genetic factors, we have been making use of mouse mutations that cause obesity. The basic premise of this approach is to take advantage of the mouse as a genetic system for the analysis of genetically complex disorders and to then apply that information to the study of human disease. This paper reviews: (1) current concepts concerning the control of body weight in man and other mammals; (2) the biologic characteristics of the mouse obesity mutations; (3) our progress in the use of positional cloning techniques to clone the mouse obese (ob) and diabetes (db) genes; (4) an approach to polygenic obesity in mice; and (5) the possible relevance of the mouse obesity mutations to human obesity.

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References

  1. Abbs, S., Roberts, R.G., Mathew, C.G., Bentley, D.R., and Bobrow, M.: Accurate assessment of intragenic recombination frequency within the Duchenne muscular dystrophy gene. Genomics 7: 602–606, 1990.CrossRefPubMedGoogle Scholar
  2. Altman, P.L.: Inbred and Genetically Defined Strains of Laboratory Animals: Part I, Mouse and Rat, 16–20, Federation of American Societies for Experimental Biology, Bethesda MD, 1979.Google Scholar
  3. Arase, K., Shargill, N.S., and Bray, G.A.: Effects of corticotropin releasing factor on genetically obese (fatty) rats. Physiol Behav 45, 565–570, 1989.CrossRefPubMedGoogle Scholar
  4. Bahary, N., Leibel, R.L., Joseph L., and Friedman, J.M.: Molecular mapping of the mouse db mutation. Proc Natl Acad Sci USA 87: 8642–8646, 1990.CrossRefPubMedGoogle Scholar
  5. Balling, R., Deutsch, U., and Gruss, P: Undulated, a mutation affecting the development of the mouse skeleton, has a point mutation in the paired box of Pax-1. Cell 55: 531–535, 1988.CrossRefPubMedGoogle Scholar
  6. Batt, R.A.: Decreased food intake in response to cholecystokinin (pancreozymin) in wild-type and obese mice (genotype oblob). Int J Obes 7: 25–29, 1983.PubMedGoogle Scholar
  7. Begin-Heick, NL: Absence of the inhibitory effect of guanine nucleotides on adenylate cyclase activity in white adipocyte membranes of the oblob mouse: Effect of the ob gene. J Biol Chem 260: 6187–6193, 1985.PubMedGoogle Scholar
  8. Bielschowsky, M., and Bielschowsky, F.: A new strain of mice with hereditary obesity. Proc Univ Otago M School 31: 29, 1953.Google Scholar
  9. Bjorkland, A., Hokfelt, T., and Swanson, L.W.: Integrated systems of the CNS, Part I. Hypothalamus, hippocampus, amygdala, retina. In Handbook of Chemical Neuroanatomy. Elsevier Press, New York, 1987.Google Scholar
  10. Bray, G.A.: An approach to control of food intake in humans. Med Clin N Amer 73: 29–45, 1989a.PubMedGoogle Scholar
  11. Bray, G.A.: Genetic and hypothalamic mechanisms for obesity—finding the needle in the haystack. Am J Clin Nutr 50: 891–902, 1989b.PubMedGoogle Scholar
  12. Bray, G.A., Shimomura, Y., Ohtake, M., and Walker, P.: Salivary gland weight and nerve growth factor in the genetically obese (oblob) mouse. Endocrinology 110: 47–50, 1982.CrossRefPubMedGoogle Scholar
  13. Bray, G.A., York, D.A., and Fisler, J.S.: Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Vitamins and Hormones 45: 1–125, 1989.CrossRefPubMedGoogle Scholar
  14. Brown, M.R., and Fisher, L.A.: Corticotropin-releasing factor: Effects on the autonomic nervous system and visceral systems. Federation Proc 44: 243–248, 1985.Google Scholar
  15. Brown, M.R., Fisher, L.A., Spiess, J., Rivier, C., Rivier, J., and Vale, W.: Corticotropin-releasing factor: Actions on the sympathetic nervous system and metabolism. Endocrinology 111: 928–931, 1982.CrossRefPubMedGoogle Scholar
  16. Burke, D.T., Rossi, J.M., Leung, J., Koos, D.S., and Tilghman, S.M.: A mouse genomic library of yeast artificial chromosome clones. Mammalian Genome 1: 65, 1991.CrossRefPubMedGoogle Scholar
  17. Camper, S.A., Saunders, T.L., Katz, R.W., and Reeves, R.H.: The Pit-1 transcription factor gene is a candidate for the murine snell dwarf mutation. Genomics 8: 586–590, 1990.CrossRefPubMedGoogle Scholar
  18. Cebra-Thomas, J.A., Decker, C.L., Snyder, L.C., Pilder, S.H., and Silver, L.M.: Allele- and haploid-specific product generated by alternative splicing from a mouse t complex responder locus candidate. Nature 349: 239, 1991.CrossRefPubMedGoogle Scholar
  19. Chabot, B., Stephenson, D.A., Chapman, V.M., Besmer, P., and Bernstein, A.: The protooncogene c-kit encoding a trasmembrane tyrosine kinase receptor maps to the mouse W locus. Nature 335: 88–89, 1988.CrossRefPubMedGoogle Scholar
  20. Coleman, D.L.: Effects of parabiosis of obese with diabetes and normal mice. Diabetologid 9: 294–298, 1973.CrossRefGoogle Scholar
  21. Coleman, D.L.: Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14: 141–148, 1978.CrossRefPubMedGoogle Scholar
  22. Coleman, D.L.: Increased metablic efficiency in obese mutant mice. Intl J Obesity 9: 69–73, 1985.Google Scholar
  23. Coleman, D.L., and Eicher, E.M.: Fat (fat) and tubby (tub), two autosomal recessive mutations causing obesity syndromes in the mouse. J Heredity 81: 424–427, 1990.Google Scholar
  24. Coleman, D.L., and Hummel, K.P.: Hyperinsulinemia in preweaning diabetes (db) mice. Diabetologia 10: 607–610, 1974.CrossRefPubMedGoogle Scholar
  25. Coleman, D.L., and Hummel, K.P.: Influence of genetic background on the expression of mutations at the diabetes locus in the mouse. II. Studies on background modifiers. Isr J Med 11: 708–718, 1975.Google Scholar
  26. Copeland, N.G., Gilbert, D.J., Cho, B.C., Donovan, P.J., Jenkins, N.A., Cosman, D., Anderson, D., Lyman, S.D., and Williams, D.E.: Mast cell growth factor maps near the Steel locus on mouse Chromosome 10 and is deleted in a number of Steel alleles. Cell 63: 175–183, 1990.CrossRefPubMedGoogle Scholar
  27. D'Urso, M., Zucchi, I., Ciccodicola, A., Palmieri, G., Abidi, F.E., and Schlessinger, D.: Human glucose-6-phosphate dehydrogenase gene carried on a yeast artificial chromosome encodes active enzyme in monkey cells. Genomics 7: 531–534, 1990.CrossRefPubMedGoogle Scholar
  28. Dickie, M.M., and Lane, P.W.: Mapping of the ob locus. Mouse News Lett 17: 52, 1957.Google Scholar
  29. Drumm, M.L., Smith, C.L., Dean, M., Cole, J.L., Iannuzzi, M.C., and Collins, F.S.: Physical mapping of the cystic fibrosis region by pulsed-field gel electrophoresis. Genomics 2: 346–354, 1988.CrossRefPubMedGoogle Scholar
  30. Elvin, P., Slynn, G., Black, D., Graham, A., Butler, R., Anand, R., and Markham, A.F.: Isolation of cDNA clone using yeast artificial chromosome probes. Nucl Acids Res 18: 3913–3917, 1990.CrossRefPubMedGoogle Scholar
  31. Fisher, E.M.C., Cavanna, J.S., and Brown, S.D.M.: Microdissection and microcloning of the mouse X Chromosome. Proc Natl Acad Sci USA 82: 5846–5849, 1985.CrossRefPubMedGoogle Scholar
  32. Flatt, J.P.: Dietary fat, carbohydrate balance, and weight maintenance: Effects of exercise. Am J Clin Nutr 45: 296–306, 1987.PubMedGoogle Scholar
  33. Fletcher, C., Norman, D.J., and Heintz, N.: Genetic mapping of meander tail, a mouse mutation affecting cerebellar development. Genomics, in press, 1991.Google Scholar
  34. Foch, T.T., and McClearn, G.E.: Genetics, body weight and obesity. In A.J. Stunkard (ed.), Obesity, 48–71. Saunders, Philadelphia, 1980.Google Scholar
  35. Friedman, J.M., Leibel, R.L., Bahary, N. and Segal, D.A.: Molecular mapping of the mouse ob mutation. Submitted, 1991.Google Scholar
  36. Frohman, L.A., and Bernardis, L.L.: Effect of hypothalamic stimulation on plasma glucose, insulin, and glucagon levels. Am J Physiol 221: 1596–1603, 1971.PubMedGoogle Scholar
  37. Garthwaite, T.L., Martinson, D.R., Tseng, L.F., Hagen, T.C., and Menahan, L.A.: A longitudinal hormonal profile of the genetically obese mouse. Endocrinology 107: 671–676, 1980.CrossRefPubMedGoogle Scholar
  38. Glaser, T., Rose, E., Morse, H., Housman, D., and Jones, C.: A panel of irradiation-reduced hybrids selectively retaining human Chromosome 11p13: Their structure and use to purify the WAGR gene complex. Genomics 6: 48–64, 1990.CrossRefPubMedGoogle Scholar
  39. Green, E.D., and Olson, M.V.: Chromosomal region of the cystic fibrosis gene in yeast artificial chromosomes: A model for human genome mapping. Science 250: 94–98, 1990.CrossRefPubMedGoogle Scholar
  40. Harris, R.B.S.: Role of set-point theory in regulation of body weight. FASEB J 4: 3310–3318, 1990.PubMedGoogle Scholar
  41. Harris, R.B.S., Hervey, E., Hervey, G.R., and Tobin, G.: Body fat content in Zucker rats in parabiosis. J Physiol 312: 52, 1981.Google Scholar
  42. Herberg, L., and Coleman, D.L.: Laboratory animals exhibiting obesity and diabetes syndromes. Metabolism 26: 59, 1977.CrossRefPubMedGoogle Scholar
  43. Herrmann, B.G.: Labeit, S., Poustka, A., King, T.R., and Lehrach, H.: Cloning of the T gene required in mesoderm formation in the mouse. Nature 343: 617–622, 1990.CrossRefPubMedGoogle Scholar
  44. Hervey, G.R.: The effects of lesions in the hypothalamus in parabiotic rats. J Physiol 145: 336, 1959.PubMedGoogle Scholar
  45. Hoebel, B.G.: Neurotransmitters in the control of feeding and its rewards: Manoanines, apiates and brain-gut peptides. In Eating and Its Disorders, 15–38, Raven Press, New York, 1984.Google Scholar
  46. Hummel, K.P., Coleman, D.L., and Lane, P.W.: The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL/KsJ and C57BL/6J strains. Biochem Genet 7: 1–3, 1972.CrossRefPubMedGoogle Scholar
  47. Jeanrenaud, B.: An hypothesis on the aetiology of obesity: Dysfunction of the central nervous system as a primary cause. Diabetologia 28: 502–513, 1985.CrossRefPubMedGoogle Scholar
  48. Johnson, P.R., Stern, J.S., Greenwood, M.R.C., Zucker, L.M., and Hirsch, J.: Effect of early nutrition on adipose cellularity and pancreatic insulin release in the Zucker rat. J Nutr 103: 738–743, 1973.PubMedGoogle Scholar
  49. Keesey, R.E.: Physiological regulation of body weight and the issue of obesity. Med Clinics N Amer 73: 15–27, 1989.Google Scholar
  50. Keesey, R.E., and Pawley, T.L.: The regulation of body weight. Ann Rev Psychol 37: 109–133, 1986.CrossRefGoogle Scholar
  51. Knowler, W.C., Pettitt, D.J., Bennett P.H., and Williams, R.C.: Diabetes mellitus in the Pima Indians: Genetic and evolutionary considerations. Am J Phys Anthr 82: 107–114, 1983.CrossRefGoogle Scholar
  52. Lander, E.S., and Botstein, D.: Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121: 185–199, 1989.PubMedGoogle Scholar
  53. Lane, P.W.: Mapping of the db locus. Mouse News Lett 38: 24, 1968.Google Scholar
  54. Larin, Z., Monaco, A.P., and Lehrach, H.: Yeast artificial chromosome libraries containing large inserts from mouse and human DNA. Proc Natl Acad Sci USA, in press, 1991.Google Scholar
  55. Leibel, R.L., Bahary, N. and Friedman, J.M.: Genetic variation and nutrition in obesity: Approaches to the molecular genetics of obesity. In A.P. simopoulos and B. Childs (eds.); Genetic Variation and Nutrition, pp. 90–101, Kanger, Basel, 1990a.Google Scholar
  56. Leibel, R.L.: Is obesity due to a heritable difference in “set point” for adiposity? West J Med 153: 429–431, 1990b.PubMedGoogle Scholar
  57. Leibel, R.L., Edens, N.K., and Fried, S.K.: Physiologic basis for the control of body fat distribution in humans. Ann Rev Nutr 9: 417–443, 1989.CrossRefGoogle Scholar
  58. Leibel, R.L., and Hirsch, J.: Diminished energy requirements in reduced-obese patients. Metabolism 33: 164–170, 1984.CrossRefPubMedGoogle Scholar
  59. Leibowitz, S.F.: Brain monoamines and peptides: Roles in the control of eating behavior. Fed Proc 45: 1396–1403, 1986.PubMedGoogle Scholar
  60. Leiter, E.H.: The influence of genetic background on expression of mutations at the diabetes locus in the mouse. IV. Male lethal syndrome in CBA/Lt mice. Diabetes 30: 1035–1044, 1981a.CrossRefPubMedGoogle Scholar
  61. Leiter, E.H., Coleman, D.L., and Hummel, K.P.: The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. III. Effect of H-2 haplotype and sex. Diabetes 30: 1029–1034, 1981b.CrossRefPubMedGoogle Scholar
  62. Lyons, M.J., Faust, I.M., Hemmes, R.B., Buskirk, D.R., Hirsch, J., and Zabriskie, J.B.: A virally-induced obesity syndrome in mice. Science 216: 82–85, 1982.CrossRefPubMedGoogle Scholar
  63. Mansour, S.L., Thomas, K.R., and Capecchi, M.R.: Disruption of the protooncogene Int-2 in mouse embryo-derived stem cells: A general strategy for targeting mutations to non-selectable genes. Nature 336: 348–352, 1988.CrossRefPubMedGoogle Scholar
  64. Marshall, N.B., Barrnett, R.S., and Mayer, J.: Hypothalamic lesions in goldthioglucose injected mice. PSEBM 90: 240–244, 1955.Google Scholar
  65. Mayer, J., French, R.G., Zighera, C.F., and Barrnett, R.J.: Hypothalamic obesity in the mouse production, description and metabolic characteristics. Am J Physiol 182: 75–82, 1955.PubMedGoogle Scholar
  66. Monaco, A.P., Neve, R.L., Colletti-Feener, C., Bertelson, C.J., Kurnit, D.M., and Kunkel, L.M.: Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 323: 646–650, 1985.CrossRefGoogle Scholar
  67. Morley, J.: Neuropeptide regulation of appetite and weight. Endocrine Reviews 8: 256–286, 1987.CrossRefPubMedGoogle Scholar
  68. Mrosovsky, N., and Powley, T.L.: Set points for body weight and fat. Behav Biol 20: 205–223, 1977.CrossRefPubMedGoogle Scholar
  69. Nadeau, J.H.: Linkage and synteny homologies between mouse and man. Trends Genet 5: 82–86, 1990.CrossRefGoogle Scholar
  70. Paterson, A.H., Lander, E.S., Hewitt, J.D., Peterson, S., Lincoln, S.E., and Tanksley, S.D.: Resolution of quantitative traits into Mendelian factors by using a complete linkage map of restriction fragment length polymorphisms. Nature 335: 721, 1988.CrossRefPubMedGoogle Scholar
  71. Pavan, W.J., Hieter, P., and Reeves, R.H.: Generation of deletion derivatives by targeted transformation of human-derived yeast artificial chromosomes. Proc Natl Acad Sci USA 87: 1300–1304, 1990.CrossRefPubMedGoogle Scholar
  72. Prochazka, M., Leiter, E.H., and Serreze, D.V.: Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science 237: 286–289, 1987.CrossRefPubMedGoogle Scholar
  73. Ravelli, G.P., Stein, Z., and Susser, M.W.: Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 295: 349–353, 1976.PubMedCrossRefGoogle Scholar
  74. Ravussin, E., Abbott, W., Zawakzki, J.K., Young, A., Knowler, W.C., Jacobowitz, R., and Moll, P.P.: Familial dependence of the resting metabolic rate. N Engl J Med 315: 96–100, 1986.PubMedGoogle Scholar
  75. Ravussin, E., Lillioja, S., Knowler, W.C., Dr., P.H., Christin, L., Freymond, D., Abbot, W.G.H., Boyce, V., Howard, B., and Bogardus, C.: Reduced rate of energy expenditure as a risk factor for body-weight gain. N Eng J Med 318: 467–472, 1988.CrossRefGoogle Scholar
  76. Readhead, C., Popko, B., Takahashi, N., David Shine, H., Saavedra, P.A., Sidman, R.L., and Hood, L.: Expression of a myelin basic protein gene in transgenic shiverer mice: Correction of the dysmyelinating phenotype. Cell 48: 703–712, 1987.CrossRefPubMedGoogle Scholar
  77. Reeders, S.T., Keith, T., Green, P., Germino, G.G., Barton, N.J., Lehmann, O.J., Brown, V.A., Phipps, P., Morgan, J., Bear, J.C., and Parfrey, P.: Regional localization of the autosomal dominant polycyctic kidney disease locus. Genomics 3: 150–155, 1988.CrossRefPubMedGoogle Scholar
  78. Reeves, R.H., Crowley, M.R., O'Hara, B.F., and Gearhart, J.D.: Sex, strain, and species differences affect recombination across an evolutionarily conserved segment of mouse Chromosome 16. Genomics 8: 141–148, 1990.CrossRefPubMedGoogle Scholar
  79. Robert, B., Barton, P., Minty, A., Daubas, P., Weydert, A., Bonhomme, F., Catalan, J., Chazottes, D., Guénet, J.-L., and Buckingham, M.: Investigation of genetic linkage between myosin and actin genes using an interspecific mouse backcross. Nature 314: 181–183, 1985.CrossRefPubMedGoogle Scholar
  80. Roberts, S.B., Savage, J., Coward, W.A., Chew, B., and Lucas, A.: Energy expenditure and intake in infants born to learn and overweight mothers. N Eng J Med 318: 461–466, 1988.CrossRefGoogle Scholar
  81. Robertson, E.J.: Pluripotent stem cell lines as a route into the mouse germ line. TIG (January): 9–13, 1986.Google Scholar
  82. Rohner-Jeanrenaud, F., and Jeanrenaud, B.: A role for the vagus nerve in the etiology and maintenance of the hyperinsulinemia of genetically obese falfa rats. Intl J Obesity 9: 71–75, 1985.Google Scholar
  83. Rohner-Jeanrenaud, F., Walker, C.-L., Greco-Perotto, R., and Jeanrenaud, B.: Central corticotropin-releasing factor administration prevents the excessive body weight gain of genetically obese (falfa) rats. Endocrinology 124: 733–739, 1989.CrossRefPubMedGoogle Scholar
  84. Rommens, J.M., Iannuzzi, M.C., Kerem, B., Drumm, M.L., Melmer, G., Dean, M., Rozmahel, R., Cole, J.L., Kennedy, D., Hidaka, N., Zsiga, M., Buchwald, M., Riordan, J.R., Tsui, L.-C., and Collins, F.S.: Identification of the cystic fibrosis gene: Chromosome walking and jumping. Science 245: 1059–1065, 1989.CrossRefPubMedGoogle Scholar
  85. Rosen, B.S., Cook, K.S., Yaglom, J., Groves, D.L., Volanakis, J.E., Damm, D., White, T., and Spiegelman, B.M.: Adipsin and the alternative pathway of complement in the regulation of energy balance. In G.A. Bray, D. Ricquier, and B.M. Spiegelman (eds.); Obesity: Towards a Molecular Approach, 273–287, Wiley-Liss, New York, 1990.Google Scholar
  86. Rutman, R.J., Lewis, F.S., and Bloomer, W.D.: Bispiperidyl mustard, a new obesifying agent in the mouse. Science 153: 1000–1002, 1966.CrossRefPubMedGoogle Scholar
  87. Sawchenko, P.E.: Evidence for a local site of action for glucocorticoids in inhibiting CRF and vasopressin expression in the paraventricular nucleus. Brain Res 403: 213–224, 1987.CrossRefPubMedGoogle Scholar
  88. Scambler, P.J., Law, H.-Y., Williamson, R., and Cooper, C.S.: Chromosome mediated gene transfer of six DNA markers linked to the cystic fibrosis locus on human Chromosome 7. Nucl Acids Res 14: 7159–7174, 1986.CrossRefPubMedGoogle Scholar
  89. Schlessinger, D.: Yeast artificial chromosomes: Tools for mapping and analysis of complex genomes. Trends Genet 6: 248–258, 1990.CrossRefPubMedGoogle Scholar
  90. Shor-Posner, G., Azar, A.P., Insinga, S., and Leibowitz, S.F.: Deficits in the control of food intake after hypothalamic paraventricular nucleus lesions. Physiol Behavior 35: 883–890, 1985.CrossRefGoogle Scholar
  91. Silverman, G.A., Jockel, J.I., Domer, P.H., Mohr, R.M., Taillon-Miller, P., and Korsmeyer, S.J.: Yeast artificial chromosome cloning of a two-megabase-size contig within chromosomal band 18q21 established physical linkage between BCL2 and plasminogen activator inhibitor type-2. Genomics 9: 219–228, 1991.CrossRefPubMedGoogle Scholar
  92. Sims, E.A., and Danforth, A.: Expenditure and storage of energy in man. J Clin Invest 79: 1019–1025, 1987.CrossRefPubMedGoogle Scholar
  93. Smith, D.R., Smyth, A.P., and Moir, D.T.: Amplification of large artificial chromosomes. Proc Natl Acad Sci USA 87: 8242–8246, 1990a.CrossRefPubMedGoogle Scholar
  94. Smith, G.P., Greenberg, D., Carp, E., and Gibbs, J.: Afferent information in the control of eating. In Obesity: Towards a Molecular Approach, 63–79, Wiley-Liss, New York, 1990b.Google Scholar
  95. Sorenson, T.I.A., Price, R.A., Stunkard, A.J., and Schulsinger, F.: Genetics of obesity in adult adoptess and their biological siblings. Br Med J 298: 87–90, 1989.CrossRefGoogle Scholar
  96. Stunkard, A.J., Harris, J.R., Pedersen, N.L., and McClearn, G.E.: The body-mass index of twins who have been reared apart. N Engl J Med 322: 1483–1487, 1990.PubMedCrossRefGoogle Scholar
  97. Subhatme, P.V., and Margen, S.: Autoregulatory hemeostatic nature of energy balance. Am J Clin Nutr 35: 355–365, 1982.Google Scholar
  98. Thoday, J.M.: Location of polygenes. Nature 191: 368–370, 1961.CrossRefGoogle Scholar
  99. Tomita, T., Doull, V., Kimmel, J.R., and Pollock, H.G.: Pancreatic polypeptide and other hormones in pancreas of obese (oblob) mice. Diabetologia 27: 454–459, 1984.CrossRefPubMedGoogle Scholar
  100. Tremblay, A., Poehlman, E.T., Nadeau, A., Dessault, J., and Bouchard, C.: Heredity and overfeeding-induced changes insubmaximal exercise VO2. J Appl Physiol 62: 539–544, 1987.PubMedGoogle Scholar
  101. Truett, G.E., Bahary, N., Friedman, J.M., and Leibel, R.L.: The rat obesity gene fatty (fa) maps to Chromosome 5: Evidence for homology with mouse gene diabetes (db). Submitted, 1991.Google Scholar
  102. Wallace, M.R., Marchuk, D.A., Andersen, L.B., Letcher, R., Odeh, H.M., Saulino, A.M., Fountain, J.W., Brereton, A., Nicholson, J., Mitchell, A.L., Brownstein, B.H., and Collins, F.S.: Type I neurofibromatosis gene: Identification of a large transcript disrupted in three NF1 patients. Science 249: 181–186, 1990.CrossRefPubMedGoogle Scholar
  103. Weber, J.L., and May, P.E.: Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 44: 388–396, 1989.PubMedGoogle Scholar
  104. Weigle, D.S.: Contribution of decreased body mass to diminished termic/effect of exercise in reduced-obese men. Int J Obesity 12: 567–578, 1988.Google Scholar
  105. White, R., and Lalowel, J.M.: Investigation of genetic linkage in human families. Adv Human Genet 16: 121–228, 1987.Google Scholar
  106. Wilson, B.E., Meyer, G.E., J.C. Cleveland, J., and Weigle, D.S.: Identification of candidate genes for a factor regulating body weight in primates. Am J Physiol, in press, 1991.Google Scholar
  107. York, D.A., Marchinton, D., Holt, S.J., and Allars, J.: Regulation of sympathetic activity in lean and obese Zucker (falfa) rats. Am J Physiol 249: 1985.Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Jeffrey M. Friedman
    • 1
    • 2
  • Rudolph L. Leibel
    • 3
  • Nathan Bahary
    • 2
  1. 1.Howard Hughes Medical InstituteThe Rockefeller UniversityNew YorkUSA
  2. 2.Laboratory of Molecular Cell BiologyThe Rockefeller UniversityNew YorkUSA
  3. 3.Laboratory of Human Behavior and MetabolismThe Rockefeller UniversityNew YorkUSA

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