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
  • Published:

The role of GNAS and other imprinted genes in the development of obesity

International Journal of Obesity volume 34, pages 6–17 (2010)Cite this article

Abstract

Genomic imprinting is an epigenetic phenomenon affecting a small number of genes, which leads to differential expression from the two parental alleles. Imprinted genes are known to regulate fetal growth and a ‘kinship’ or ‘parental conflict’ model predicts that paternally and maternally expressed imprinted genes promote and inhibit fetal growth, respectively. In this review we examine the role of imprinted genes in postnatal growth and metabolism, with an emphasis on the GNAS/Gnas locus. GNAS is a complex imprinted locus with multiple oppositely imprinted gene products, including the G-protein α-subunit Gsα that is expressed primarily from the maternal allele in some tissues and the Gsα isoform XLαs that is expressed only from the paternal allele. Maternal, but not paternal, Gsα mutations lead to obesity in Albright hereditary osteodystrophy. Mouse studies show that this phenomenon is due to Gsα imprinting in the central nervous system leading to a specific defect in the ability of central melanocortins to stimulate sympathetic nervous system activity and energy expenditure. In contrast mutation of paternally expressed XLαs leads to opposite metabolic effects in mice. Although these findings conform to the ‘kinship’ model, the effects of other imprinted genes on body weight regulation do not conform to this model.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

Similar content being viewed by others

References

  1. Reik W, Walter J . Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001; 2: 21–32.

    CAS  PubMed  Google Scholar 

  2. Moore T, Haig D . Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet 1991; 7: 45–49.

    CAS  PubMed  Google Scholar 

  3. Haig D . Genomic imprinting and kinship: how good is the evidence? Annu Rev Genet 2004; 38: 553–585.

    CAS  PubMed  Google Scholar 

  4. Lindsay RS, Kobes S, Knowler WC, Bennett PH, Hanson RL . Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in Pima Indians. Diabetes 2001; 50: 2850–2857.

    CAS  PubMed  Google Scholar 

  5. Gorlova OY, Amos CI, Wang NW, Shete S, Turner ST, Boerwinkle E . Genetic linkage and imprinting effects on body mass index in children and young adults. Eur J Hum Genet 2003; 11: 425–432.

    CAS  PubMed  Google Scholar 

  6. Dong C, Li WD, Geller F, Lei L, Li D, Gorlova OY et al. Possible genomic imprinting of three human obesity-related genetic loci. Am J Hum Genet 2005; 76: 427–437.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Rance KA, Fustin JM, Dalgleish G, Hambly C, Bunger L, Speakman JR . A paternally imprinted QTL for mature body mass on mouse chromosome 8. Mamm Genome 2005; 16: 567–577.

    PubMed  Google Scholar 

  8. Weinstein LS, Xie T, Zhang QH, Chen M . Studies of the regulation and function of the Gsα gene Gnas using gene targeting technology. Pharmacol Ther 2007; 115: 271–291.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kozasa T, Itoh H, Tsukamoto T, Kaziro Y . Isolation and characterization of the human Gsα gene. Proc Natl Acad Sci USA 1988; 85: 2081–2085.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Montminy M . Transcriptional regulation by cyclic AMP. Annu Rev Biochem 1997; 66: 807–822.

    CAS  PubMed  Google Scholar 

  11. Bray P, Carter A, Simons C, Guo V, Puckett C, Kamholz J et al. Human cDNA clones for four species of Gαs signal transduction protein. Proc Natl Acad Sci USA 1986; 83: 8893–8897.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hayward BE, Kamiya M, Strain L, Moran V, Campbell R, Hayashizaki Y et al. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci USA 1998; 95: 10038–10043.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Peters J, Wroe SF, Wells CA, Miller HJ, Bodle D, Beechey CV et al. A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proc Natl Acad Sci USA 1999; 96: 3830–3835.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu J, Yu S, Litman D, Chen W, Weinstein LS . Identification of a methylation imprint mark within the mouse Gnas locus. Mol Cell Biol 2000; 20: 5808–5817.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Davies SJ, Hughes HE . Imprinting in Albright's hereditary osteodystrophy. J Med Genet 1993; 30: 101–103.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Campbell R, Gosden CM, Bonthron DT . Parental origin of transcription from the human GNAS1 gene. J Med Genet 1994; 31: 607–614.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu S, Yu D, Lee E, Eckhaus ME, Lee R, Corria Z et al. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein α-subunit (Gsα) knockout mice is due to tissue-specific imprinting of the Gsα gene. Proc Natl Acad Sci USA 1998; 95: 8715–8720.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Hayward BE, Barlier A, Korbonits M, Grossman AB, Jacquet P, Enjalbert A et al. Imprinting of the Gsα gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 001; 107: R31–R36.

    Google Scholar 

  19. Weinstein LS, Yu S, Warner DR, Liu J . Endocrine manifestations of stimulatory G protein α-subunit mutations and the role of genomic imprinting. Endocr Rev 2001; 22: 675–705.

    CAS  PubMed  Google Scholar 

  20. Germain-Lee EL, Ding C, Deng Z, Crane JL, Saji M, Ringel MD et al. Paternal imprinting of Gαs in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochem Biophys Res Commun 2002; 296: 67–72.

    CAS  PubMed  Google Scholar 

  21. Mantovani G, Ballare E, Giammona E, Beck-Peccoz P, Spada A . The Gsα gene: predominant maternal origin of transcription in human thyroid gland and gonads. J Clin Endocrinol Metab 2002; 87: 4736–4740.

    CAS  PubMed  Google Scholar 

  22. Liu J, Erlichman B, Weinstein LS . The stimulatory G protein α-subunit Gsα is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metab 2003; 88: 4336–4341.

    CAS  PubMed  Google Scholar 

  23. Chen M, Wang J, Dickerson KE, Kelleher J, Xie T, Gupta D et al. Central nervous system imprinting of the G protein Gsα and its role in metabolic regulation. Cell Metab 2009; 9: 548–555.

    PubMed  PubMed Central  Google Scholar 

  24. Williamson CM, Turner MD, Ball ST, Nottingham WT, Glenister P, Fray M et al. Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nat Genet 2006; 38: 350–355.

    CAS  PubMed  Google Scholar 

  25. Germain-Lee EL, Schwindinger W, Crane JL, Zewdu R, Zweifel LS, Wand G et al. A mouse model of Albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology 2005; 146: 4697–4709.

    CAS  PubMed  Google Scholar 

  26. Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen AT et al. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci USA 2005; 102: 7386–7391.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Mantovani G, Bondioni S, Locatelli M, Pedroni C, Lania AG, Ferrante E et al. Biallelic expression of the Gsα gene in human bone and adipose tissue. J Clin Endocrinol Metab 2004; 89: 6316–6319.

    CAS  PubMed  Google Scholar 

  28. Xie T, Plagge A, Gavrilova O, Pack S, Jou W, Lai EW et al. The alternative stimulatory G protein α-subunit XLαs is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice. J Biol Chem 2006; 281: 18989–18999.

    CAS  PubMed  Google Scholar 

  29. Crawford JA, Mutchler KJ, Sullivan BE, Lanigan TM, Clark MS, Russo AF . Neural expression of a novel alternatively spliced and polyadenylated Gsα transcript. J Biol Chem 1993; 268: 9879–9885.

    CAS  PubMed  Google Scholar 

  30. Hayward BE, Moran V, Strain L, Bonthron DT . Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci USA 1998; 95: 15475–15480.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kelsey G, Bodle D, Miller HJ, Beechey CV, Coombes C, Peters J et al. Identification of imprinted loci by methylation-sensitive representational difference analysis: application to mouse distal chromosome 2. Genomics 1999; 62: 129–138.

    CAS  PubMed  Google Scholar 

  32. Ischia R, Lovisetti-Scamihorn P, Hogue-Angeletti R, Wolkersdorfer M, Winkler H, Fischer-Colbrie R . Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem 1997; 272: 11657–11662.

    CAS  PubMed  Google Scholar 

  33. Bauer R, Weiss C, Marksteiner J, Doblinger A, Fischer-Colbrie R, Laslop A . The new chromogranin-like protein NESP55 is preferentially localized in adrenaline-synthesizing cells of the bovine and rat adrenal medulla. Neurosci Lett 1999; 263: 13–16.

    CAS  PubMed  Google Scholar 

  34. Bauer R, Ischia R, Marksteiner J, Kapeller I, Fischer-Colbrie R . Localization of neuroendocrine secretory protein 55 messenger RNA in the rat brain. Neuroscience 1999; 91: 685–694.

    CAS  PubMed  Google Scholar 

  35. Lovisetti-Scamiform P, Fischer-Colbrie R, Leitner B, Scherzer G, Winkler H . Relative amounts and molecular forms of NESP55 in various bovine tissues. Brain Res 1999; 829: 99–106.

    Google Scholar 

  36. Li T, Vu TH, Zeng ZL, Nguyen BT, Hayward BE, Bonthron DT et al. Tissue-specific expression of antisense and sense transcripts at the imprinted Gnas locus. Genomics 2000; 69: 295–304.

    CAS  PubMed  Google Scholar 

  37. Kehlenbach RH, Matthey J, Huttner WB . XLαs is a new type of G protein. Nature 1994; 372: 804–809.

    CAS  PubMed  Google Scholar 

  38. Abramowitz J, Grenet D, Birnbaumer M, Torres HN, Birnbaumer L . XLαs, the extra-long form of the α-subunit of the Gs G protein, is significantly longer than suspected, and so is its companion Alex. Proc Natl Acad Sci USA 2004; 101: 8366–8371.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bastepe M, Gunes Y, Perez-Villamil B, Hunzelman J, Weinstein LS, Jüppner H . Receptor-mediated adenylyl cyclase activation through XLαs, the extra-large variant of the stimulatory G protein alpha subunit. Mol Endocrinol 2002; 16: 1912–1919.

    CAS  PubMed  Google Scholar 

  40. Pasolli HA, Klemke M, Kehlenbach RH, Wang Y, Huttner WB . Characterization of the extra-large G protein α-subunit XLαs. I. Tissue distribution and subcellular localization. J Biol Chem 2000; 275: 33622–33632.

    CAS  PubMed  Google Scholar 

  41. Pasolli HA, Huttner WB . Expression of the extra-large G protein α-subunit XLαs in neuroepithelial cells and young neurons during development of the rat nervous system. Neurosci Lett 2001; 301: 119–122.

    CAS  PubMed  Google Scholar 

  42. Plagge A, Gordon E, Dean W, Boiani R, Cinti S, Peters J et al. The imprinted signaling protein XLαs is required for postnatal adaptation to feeding. Nat Genet 2004; 36: 818–826.

    CAS  PubMed  Google Scholar 

  43. Klemke M, Kehlenbach RH, Huttner WB . Two overlapping reading frames in a single exon encode interacting proteins-a novel way of gene usage. EMBO J 2001; 20: 3849–3860.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Freson K, Jaeken J, Van Helvoirt M, de Zegher F, Wittevrongel C, Thys C et al. Functional polymorphisms in the paternally expressed XLαs and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation. Hum Mol Genet 2003; 12: 1121–1130.

    CAS  PubMed  Google Scholar 

  45. Hayward BE, Bonthron DT . An imprinted antisense transcript at the human GNAS1 locus. Hum Mol Genet 2000; 9: 835–841.

    CAS  PubMed  Google Scholar 

  46. Wroe SF, Kelsey G, Skinner JA, Bodle D, Ball ST, Beechey CV et al. An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci USA 2000; 97: 3342–3346.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Williamson CM, Skinner JA, Kelsey G, Peters J . Alternative non-coding splice variants of Nespas, an imprinted gene antisense to Nesp in the Gnas imprinting cluster. Mamm Genome 2002; 13: 74–79.

    CAS  PubMed  Google Scholar 

  48. Coombes C, Arnaud P, Gordon E, Dean W, Coar EA, Williamson CM et al. Epigenetic properties and identification of an imprint mark in the Nesp-Gnasxl domain of the mouse Gnas imprinted locus. Mol Cell Biol 2003; 23: 5475–5488.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ishikawa Y, Bianchi C, Nadal-Ginard B, Homcy CJ . Alternative promoter and 5′ exon generate a novel Gsα mRNA. J Biol Chem 1990; 265: 8458–8462.

    CAS  PubMed  Google Scholar 

  50. Liu J, Litman D, Rosenberg MJ, Yu S, Biesecker LG, Weinstein LS . A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J Clin Invest 2000; 106: 1167–1174.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu J, Nealon JG, Weinstein LS . Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB. Hum Mol Genet 2005; 14: 95–102.

    CAS  PubMed  Google Scholar 

  52. Bastepe M, Pincus JE, Sugimoto T, Tojo K, Kanatani M, Azuma Y et al. Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type Ib and the associated methylation defect at exon A/B: evidence for a long-range regulatory element within the imprinted GNAS1 locus. Hum Mol Genet 2001; 10: 1231–1241.

    CAS  PubMed  Google Scholar 

  53. Jan de Beur S, Ding C, Germain-Lee EL, Cho J, Maret A, Levine MA . Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1. Am J Hum Genet 2003; 73: 314–322.

    PubMed  PubMed Central  Google Scholar 

  54. Williamson CM, Ball ST, Nottingham WT, Skinner JA, Plagge A, Turner MD et al. A cis-acting control region is required exclusively for the tissue-specific imprinting of Gnas. Nat Genet 2004; 36: 894–899.

    CAS  PubMed  Google Scholar 

  55. Liu J, Chen M, Deng C, Bourc'his D, Nealon JG, Erlichman B et al. Identification of the control region for tissue-specific imprinting of the stimulatory G protein α-subunit. Proc Natl Acad Sci USA 2005; 102: 5513–5518.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Weinstein LS, Chen M, Xie T, Liu J . Genetic diseases associated with heterotrimeric G proteins. Trends Pharmacol Sci 2006; 27: 260–266.

    CAS  PubMed  Google Scholar 

  57. Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL . Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism implicate paternal imprinting of Gαs in the development of human obesity. J Clin Endocrinol Metab 2007; 92: 1073–1079.

    CAS  PubMed  Google Scholar 

  58. Carel JC, Le Stunff C, Condamine L, Mallet E, Chaussain JL, Adnot P et al. Resistance to the lipolytic action of epinephrine: a new feature of protein Gs deficiency. J Clin Endocrinol Metab 1999; 84: 4127–4131.

    CAS  PubMed  Google Scholar 

  59. Dekelbab BH, Aughton DJ, Levine MA . Pseudohypoparathyroidism type 1A and morbid obesity in infancy. Endocr Pract 2009; 15: 249–253.

    PubMed  Google Scholar 

  60. Germain-Lee EL, Groman J, Crane JL, Jan de Beur SM, Levine MA . Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 2003; 88: 4059–4069.

    CAS  PubMed  Google Scholar 

  61. Nwosu BU, Lee MM . Pseudohypoparathyroidism type 1a and insulin resistance in a child. Nat Rev Endocrinol 2009; 5: 345–350.

    PubMed  Google Scholar 

  62. Hahn S, Frey UH, Siffert W, Tan S, Mann K, Janssen OE . The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome. Eur J Endocrinol 2006; 155: 763–770.

    CAS  PubMed  Google Scholar 

  63. Frey UH, Michalsen A, Merse S, Dobos GJ, Siffert W . A functional GNAS promoter polymorphism is associated with altered weight loss during short-term fasting. Eur J Med Res 2008; 13: 576–578.

    CAS  PubMed  Google Scholar 

  64. Frey UH, Hauner H, Jockel KH, Manthey I, Brockmeyer N, Siffert W . A novel promoter polymorphism in the human gene GNAS affects binding of transcription factor upstream stimulatory factor 1, Gαs protein expression and body weight regulation. Pharmacogenet Genomics 2008; 18: 141–151.

    CAS  PubMed  Google Scholar 

  65. Yu S, Gavrilova O, Chen H, Lee R, Liu J, Pacak K et al. Paternal versus maternal transmission of a stimulatory G protein α subunit knockout produces opposite effects on energy metabolism. J Clin Invest 2000; 105: 615–623.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Yu S, Castle A, Chen M, Lee R, Takeda K, Weinstein LS . Increased insulin sensitivity in Gsα knockout mice. J Biol Chem 2001; 276: 19994–19998.

    CAS  PubMed  Google Scholar 

  67. Plagge A, Isles AR, Gordon E, Humby T, Dean W, Gritsch S et al. Imprinted Nesp55 influences behavioral reactivity to novel environments. Mol Cell Biol 2005; 25: 3019–3026.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kelly ML, Moir L, Jones L, Whitehill E, Anstee QM, Goldin RD et al. A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity. Int J Obes (Lond) 2009; 33: 507–518.

    CAS  Google Scholar 

  69. Xie T, Chen M, Gavrilova O, Lai EW, Liu J, Weinstein LS . Severe obesity and insulin resistance due to deletion of the maternal Gsα allele is reversed by paternal deletion of the Gsα imprint control region. Endocrinology 2008; 149: 2443–2450.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Xie T, Chen M, Zhang QH, Ma Z, Weinstein LS . β-Cell specific deficiency of the stimulatory G protein α-subunit Gsα leads to reduced β cell mass and insulin-deficient diabetes. Proc Natl Acad Sci USA 2007; 104: 19601–19606.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Nguyen A, Gupta D, Gavrilova O, Chen M, Weinstein LS . Mice with adipose-tissue specific deficiency of the stimulatory G protein α-subunit Gsα are resistant to diet-induced obesity and maintain diet-induced, but not cold-induced, thermogenesis. Diabetes 2006; 55(suppl): A71.

    Google Scholar 

  72. Chen M, Gavrilova O, Zhao W-Q, Nguyen A, Lorenzo J, Shen L et al. Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gsα deficiency. J Clin Invest 2005; 115: 3217–3227.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen M, Feng HZ, Gupta D, Kelleher J, Dickerson KE, Wang J et al. Gsα deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency. Am J Physiol Cell Physiol 2009; 296: C930–C940.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM et al. The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 2007; 117: 3475–3488.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Butler AA, Cone RD . The melanocortin receptors: lessons from knockout models. Neuropeptides 2002; 36: 77–84.

    CAS  PubMed  Google Scholar 

  76. Brito MN, Brito NA, Baro DJ, Song CK, Bartness TJ . Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation. Endocrinology 2007; 148: 5339–5347.

    CAS  PubMed  Google Scholar 

  77. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131–141.

    CAS  PubMed  Google Scholar 

  78. 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: 1085–1095.

    CAS  PubMed  Google Scholar 

  79. Marsh DJ, Hollopeter G, Huszar D, Laufer R, Yagaloff KA, Fisher SL et al. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet 1999; 21: 119–122.

    CAS  PubMed  Google Scholar 

  80. Chen AS, Metzger JM, Trumbauer ME, Guan XM, Yu H, Frazier EG et al. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res 2000; 9: 145–154.

    CAS  PubMed  Google Scholar 

  81. Fan W, Dinulescu DM, Butler AA, Zhou J, Marks DL, Cone RD . The central melanocortin system can directly regulate serum insulin levels. Endocrinology 2000; 141: 3072–3079.

    CAS  PubMed  Google Scholar 

  82. Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L . Central melanocortin receptors regulate insulin action. J Clin Invest 2001; 108: 1079–1085.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Butler AA, Marks DL, Fan W, Kuhn CM, Bartolome M, Cone RD . Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci 2001; 4: 605–611.

    CAS  PubMed  Google Scholar 

  84. Voss-Andreae A, Murphy JG, Ellacott KLJ, Stuart RC, Nillni EA, Cone RD et al. Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology 2007; 148: 1550–1560.

    CAS  PubMed  Google Scholar 

  85. Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med 2009; 360: 44–52.

    CAS  PubMed  Google Scholar 

  86. Tallam LS, Stec DE, Willis MA, da Silva AA, Hall JE . Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia. Hypertension 2005; 46: 326–332.

    CAS  PubMed  Google Scholar 

  87. Kublaoui BM, Holder Jr JL, Tolson KP, Gemelli T, Zinn AR . SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake. Endocrinology 2006; 147: 4542–4549.

    CAS  PubMed  Google Scholar 

  88. Kublaoui BM, Holder Jr JL, Gemelli T, Zinn AR . Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons. Mol Endocrinol 2006; 20: 2483–2492.

    CAS  PubMed  Google Scholar 

  89. Holder Jr JL, Butte NF, Zinn AR . Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 2000; 9: 101–108.

    CAS  PubMed  Google Scholar 

  90. Kublaoui BM, Gemelli T, Tolson KP, Wang Y, Zinn AR . Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. Mol Endocrinol 2008; 22: 1723–1734.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Holder Jr JL, Zhang L, Kublaoui BM, DiLeone RJ, Oz OK, Bair CH et al. Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice. Am J Physiol Endocrinol Metab 2004; 287: E105–E113.

    CAS  PubMed  Google Scholar 

  92. Faivre L, Cormier-Daire V, Lapierre JM, Colleaux L, Jacquemont S, Genevieve D et al. Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype. J Med Genet 2002; 39: 594–596.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen M, Haluzik M, Wolf NJ, Lorenzo J, Dietz KR, Reitman ML et al. Increased insulin sensitivity in paternal Gnas knockout mice is associated with increased lipid clearance. Endocrinology 2004; 145: 4094–4102.

    CAS  PubMed  Google Scholar 

  94. Genevieve D, Sanlaville D, Faivre L, Kottler ML, Jambou M, Gosset P et al. Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. Eur J Hum Genet 2005; 13: 1033–1039.

    CAS  PubMed  Google Scholar 

  95. Jhala US, Canettieri G, Screaton RA, Kulkarni RN, Krajewski S, Reed J et al. cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2. Genes Dev 2003; 17: 1575–1580.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Goldstone AP . Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab 2004; 15: 12–20.

    CAS  PubMed  Google Scholar 

  97. Tan TM, Vanderpump M, Khoo B, Patterson M, Ghatei MA, Goldstone AP . Somatostatin infusion lowers plasma ghrelin without reducing appetite in adults with Prader-Willi syndrome. J Clin Endocrinol Metab 2004; 89: 4162–4165.

    CAS  PubMed  Google Scholar 

  98. Schwartz RS, Brunzell JD, Bierman EL . Elevated adipose tissue lipoprotein lipase in the pathogenesis of obesity in the Prader-Willi syndrome. Trans Assoc Am Physicians 1979; 92: 89–95.

    CAS  PubMed  Google Scholar 

  99. Horsthemke B, Wagstaff J . Mechanisms of imprinting of the Prader-Willi/Angelman region. Am J Med Genet 2008; 146A: 2041–2052.

    CAS  PubMed  Google Scholar 

  100. Caqueret A, Yang C, Duplan S, Boucher F, Michaud JL . Looking for trouble: a search for developmental defects of the hypothalamus. Horm Res 2005; 64: 222–230.

    CAS  PubMed  Google Scholar 

  101. Clayton-Smith J, Laan L . Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 2003; 40: 87–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Jiang YH, Armstrong D, Albrecht U, Atkins CM, Noebels JL, Eichele G et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 1998; 21: 799–811.

    CAS  PubMed  Google Scholar 

  103. Miura K, Kishino T, Li E, Webber H, Dikkes P, Holmes GL et al. Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiol Dis 2002; 9: 149–159.

    CAS  PubMed  Google Scholar 

  104. Dhar MS, Sommardahl CS, Kirkland T, Nelson S, Donnell R, Johnson DK et al. Mice heterozygous for Atp10c, a putative amphipath, represent a novel model of obesity and type 2 diabetes. J Nutr 2004; 134: 799–805.

    CAS  PubMed  Google Scholar 

  105. Dhar MS, Yuan JS, Elliott SB, Sommardahl C . A type IV P-type ATPase affects insulin-mediated glucose uptake in adipose tissue and skeletal muscle in mice. J Nutr Biochem 2006; 17: 811–820.

    CAS  PubMed  Google Scholar 

  106. Keverne EB, Fundele R, Narasimha M, Barton SC, Surani MA . Genomic imprinting and the differential roles of parental genomes in brain development. Brain Res Dev Brain Res 1996; 92: 91–100.

    CAS  PubMed  Google Scholar 

  107. Curley JP, Pinnock SB, Dickson SL, Thresher R, Miyoshi N, Surani MA et al. Increased body fat in mice with a targeted mutation of the paternally expressed imprinted gene Peg3. FASEB J 2005; 19: 1302–1304.

    CAS  PubMed  Google Scholar 

  108. Jones BK, Levorse J, Tilghman SM . Deletion of a nuclease-sensitive region between the Igf2 and H19 genes leads to Igf2 misregulation and increased adiposity. Hum Mol Genet 2001; 10: 807–814.

    CAS  PubMed  Google Scholar 

  109. Smas CM, Sul HS . Characterization of Pref-1 and its inhibitory role in adipocyte differentiation. Int J Obes Relat Metab Disord 1996; 20 (Suppl 3): S65–S72.

    CAS  PubMed  Google Scholar 

  110. Moon YS, Smas CM, Lee K, Villena JA, Kim KH, Yun EJ et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol Cell Biol 2002; 22: 5585–5592.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Lee K, Villena JA, Moon YS, Kim KH, Lee S, Kang C et al. Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1). J Clin Invest 2003; 111: 453–461.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Takahashi M, Kamei Y, Ezaki O . Mest/Peg1 imprinted gene enlarges adipocytes and is a marker of adipocyte size. Am J Physiol Endocrinol Metab 2005; 288: E117–E124.

    CAS  PubMed  Google Scholar 

  113. Shi W, Lefebvre L, Yu Y, Otto S, Krella A, Orth A et al. Loss-of-imprinting of Peg1 in mouse interspecies hybrids is correlated with altered growth. Genesis 2004; 39: 65–72.

    CAS  PubMed  Google Scholar 

  114. Koza RA, Nikonova L, Hogan J, Rim JS, Mendoza T, Faulk C et al. Changes in gene expression foreshadow diet-induced obesity in genetically identical mice. PLoS Genet 2006; 2: e81.

    PubMed  PubMed Central  Google Scholar 

  115. Nikonova L, Koza RA, Mendoza T, Chao PM, Curley JP, Kozak LP . Mesoderm-specific transcript is associated with fat mass expansion in response to a positive energy balance. FASEB J 2008; 22: 3925–3937.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services.

Author information

Authors and Affiliations

  1. Signal Transduction Section, National Institute of Diabetes, Digestive, and Kidney Disease, National Institutes of Health, Bethesda, MD, USA

    L S Weinstein, T Xie, A Qasem, J Wang & M Chen

Authors
  1. L S Weinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Qasem
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L S Weinstein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weinstein, L., Xie, T., Qasem, A. et al. The role of GNAS and other imprinted genes in the development of obesity. Int J Obes 34, 6–17 (2010). https://doi.org/10.1038/ijo.2009.222

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2009.222

Keywords

This article is cited by

Search

Advanced search

Quick links