Epigenetics in Hyperphagia

  • Minati SinghEmail author
Reference work entry


The central dogma states that the genetic information, which is contained in the DNA, is transcribed and translated into proteins. We now know that a recently identified novel phenomenon, known as epigenetics, alters gene expression without altering DNA sequences. Thus, this phenomenon alters the central dogma hypothesis. Some of these epigenetic changes are reversible, while some of these changes are heritable; both have the potential to influence every aspect of biology. Furthermore, epigenetic changes happen naturally during environmental changes, during aging, and during disease states. Consequently, epigenetics impacts our daily lives. One such biological process that is impacted by epigenetics is the feeding behavior. Epigenetics supports the theory that life experience can alter your feeding behavior irrespective of one’s genetic makeup. This is because some life experience leaves physical marks on DNA, or epitranscriptome changes alter biological functions of proteins that are involved in feeding behavior. To date, at least five systems have been identified to be involved in epigenetic processes: DNA methylation, histone modification, noncoding RNA (ncRNA) regulation, RNA methylation, and RNA editing. All these processes initiate and sustain epigenetic changes independently. This chapter highlights various epigenetic changes known to regulate and alter gene expressions and how some of these epigenetic changes can directly or indirectly affect an overeating behavior known as hyperphagia, which leads to obesity.


Hyperphagia Epigenetics DNA methylation RNA methylation Histones RNA editing Epitranscriptome Noncoding RNA microRNA Obesity 

List of Abbreviations


Serotonin 2C receptor

A to I

Adenosine to inosine RNA editing


Adenosine deaminase that acts on RNA


DNA methyltransferase


Fat mass and obesity-associated gene


Hypocretin (orexin)




Melanocortin receptor




Noncoding RNA


Oxytocin receptor




Prader-Willi Syndrome


Ribosomal RNA


Small nucleolar RNA


Small nuclear RNA


Small nuclear ribonucleoprotein


Transfer RNA


  1. Akubuiro A, Bridget Zimmerman M, Boles Ponto LL, Walsh SA, Sunderland J, McCormick L, Singh M (2013) Hyperactive hypothalamus, motivated and non-distractible chronic overeating in ADAR2 transgenic mice. Genes Brain Behav 12:311–322PubMedPubMedCentralCrossRefGoogle Scholar
  2. Alarcon CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF (2015) N6-methyladenosine marks primary microRNAs for processing. Nature 519(7544):482–485PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bali P, Im HI, Kenny PJ (2011) Methylation, memory and addiction. Epigenetics 6(6):671–674PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bass BL (2002) RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 71:817–846PubMedCrossRefGoogle Scholar
  5. Bentley DL (2014) Coupling mRNA processing with transcription in time and space. Nat Rev Genet 15(3):163–175PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128(4):669–681PubMedCrossRefGoogle Scholar
  7. Berthoud HR, Morrison C (2008) The brain, appetite, and obesity. Annu Rev Psychol 59:55–92PubMedCrossRefGoogle Scholar
  8. Berthoud HR, Lenard NR, Shin AC (2011) Food reward, hyperphagia, and obesity. Am J Physiol Regul Integr Comp Physiol 300(6):R1266–R1277PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bittel DC, Butler MG (2005) Prader-Willi syndrome: clinical genetics, cytogenetics and molecular biology. Expert Rev Mol Med 7(14):1–20PubMedPubMedCentralCrossRefGoogle Scholar
  10. Burggren W (2016) Epigenetic inheritance and its role in evolutionary biology: re-evaluation and new perspectives. Biology (Basel) 5(2):24Google Scholar
  11. Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387(6630):303–308PubMedCrossRefGoogle Scholar
  12. Butler MG (2011) Prader-Willi syndrome: obesity due to genomic imprinting. Curr Genomics 12(3):204–215PubMedPubMedCentralCrossRefGoogle Scholar
  13. Cassidy SB, Driscoll DJ (2009) Prader-Willi syndrome. Eur J Hum Genet 17(1):3–13PubMedCrossRefGoogle Scholar
  14. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ (2011) Prader-Willi syndrome. Genet Med 14:10–26PubMedCrossRefGoogle Scholar
  15. Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L, Wells S, Bruning JC, Nolan PM, Ashcroft FM, Cox RD (2010) Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 42(12):1086–1092PubMedPubMedCentralCrossRefGoogle Scholar
  16. Day JJ, Sweatt JD (2011) Cognitive neuroepigenetics: a role for epigenetic mechanisms in learning and memory. Neurobiol Learn Mem 96(1):2–12PubMedCrossRefGoogle Scholar
  17. de Smith AJ, Purmann C, Walters RG, Ellis RJ, Holder SE, Van Haelst MM, Brady AF, Fairbrother UL, Dattani M, Keogh JM, Henning E, Yeo GS, O'Rahilly S, Froguel P, Farooqi IS, Blakemore AI (2009) A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. Hum Mol Genet 18(17):3257–3265PubMedPubMedCentralCrossRefGoogle Scholar
  18. Dimitropoulos A, Feurer ID, Roof E, Stone W, Butler MG, Sutcliffe J, Thompson T (2000) Appetitive behavior, compulsivity, and neurochemistry in Prader-Willi syndrome. Ment Retard Dev Disabil Res Rev 6(2):125–130PubMedPubMedCentralCrossRefGoogle Scholar
  19. Doe CM, Relkovic D, Garfield AS, Dalley JW, Theobald DE, Humby T, Wilkinson LS, Isles AR (2009) Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour. Hum Mol Genet 18(12):2140–2148PubMedPubMedCentralCrossRefGoogle Scholar
  20. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485(7397):201–206PubMedCrossRefGoogle Scholar
  21. Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429(6990):457–463PubMedCrossRefGoogle Scholar
  22. Emeson RB, Singh M (2001) Adenosine to inosine RNA editing: substrates and consequences. RNA editing: frontiers in molecular biology. B. L. Bass. Oxford University Press, London, pp 109–138Google Scholar
  23. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, Volinia S, Guler G, Morrison CD, Chan KK, Marcucci G, Calin GA, Huebner K, Croce CM (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 104(40):15805–15810PubMedPubMedCentralCrossRefGoogle Scholar
  24. Feigerlova E, Diene G, Conte-Auriol F, Molinas C, Gennero I, Salles JP, Arnaud C, Tauber M (2008) Hyperghrelinemia precedes obesity in Prader-Willi syndrome. J Clin Endocrinol Metab 93(7):2800–2805PubMedCrossRefGoogle Scholar
  25. Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M, Isagawa T, Morioka MS, Kakeya H, Manabe I, Okamura H (2013) RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell 155(4):793–806PubMedPubMedCentralCrossRefGoogle Scholar
  26. Glatt-Deeley H, Bancescu DL, Lalande M (2010) Prader-Willi syndrome, Snord115, and Htr2c editing. Neurogenetics 11(1):143–144PubMedCrossRefGoogle Scholar
  27. Gluckman PD, Hanson MA (2008) Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective. Int J Obes 32(Suppl 7):S62–S71CrossRefGoogle Scholar
  28. Gluckman PD, Beedle AS, Hanson MA, Yap EP (2008) Developmental perspectives on individual variation: implications for understanding nutritional needs. Nestle Nutr Work Ser Pediatr Prog 62:1–9; disucssion 9–12CrossRefGoogle Scholar
  29. Goldberg AD, Allis CD, Bernstein E (2007) Epigenetics: a landscape takes shape. Cell 128(4):635–638PubMedCrossRefGoogle Scholar
  30. Heymsfield SB, Avena NM, Baier L, Brantley P, Bray GA, Burnett LC, Butler MG, Driscoll DJ, Egli D, Elmquist J, Forster JL, Goldstone AP, Gourash LM, Greenway FL, Han JC, Kane JG, Leibel RL, Loos RJ, Scheimann AO, Roth CL, Seeley RJ, Sheffield V, Tauber M, Vaisse C, Wang L, Waterland RA, Wevrick R, Yanovski JA, Zinn AR (2014) Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia. Obesity (Silver Spring) 22(Suppl 1):S1–S17CrossRefGoogle Scholar
  31. Holliday R (2002) Epigenetics comes of age in the twenty first century. J Genet 81(1):1–4PubMedCrossRefGoogle Scholar
  32. Holliday R (2006) Epigenetics: a historical overview. Epigenetics 1(2):76–80PubMedCrossRefGoogle Scholar
  33. Ivanova E, Kelsey G (2011) Imprinted genes and hypothalamic function. J Mol Endocrinol 47(2):R67–R74PubMedCrossRefGoogle Scholar
  34. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7(12):885–887PubMedPubMedCentralCrossRefGoogle Scholar
  35. Karra E, O’Daly OG, Choudhury AI, Yousseif A, Millership S, Neary MT, Scott WR, Chandarana K, Manning S, Hess ME, Iwakura H, Akamizu T, Millet Q, Gelegen C, Drew ME, Rahman S, Emmanuel JJ, Williams SC, Ruther UU, Bruning JC, Withers DJ, Zelaya FO, Batterham RL (2013) A link between FTO, ghrelin, and impaired brain food-cue responsivity. J Clin Invest 123(8):3539–3551PubMedPubMedCentralCrossRefGoogle Scholar
  36. Kawahara Y, Grimberg A, Teegarden S, Mombereau C, Liu S, Bale TL, Blendy JA, Nishikura K (2008) Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass. J Neurosci 28(48):12834–12844PubMedPubMedCentralCrossRefGoogle Scholar
  37. Kishore S, Khanna A, Zhang Z, Hui J, Balwierz PJ, Stefan M, Beach C, Nicholls RD, Zavolan M, Stamm S (2010) The snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing. Hum Mol Genet 19(7):1153–1164PubMedPubMedCentralCrossRefGoogle Scholar
  38. Kuroda A, Rauch TA, Todorov I, Ku HT, Al-Abdullah IH, Kandeel F, Mullen Y, Pfeifer GP, Ferreri K (2009) Insulin gene expression is regulated by DNA methylation. PLoS One 4(9):e6953PubMedPubMedCentralCrossRefGoogle Scholar
  39. Li S, Mason CE (2014) The pivotal regulatory landscape of RNA modifications. Annu Rev Genomics Hum Genet 15:127–150PubMedCrossRefGoogle Scholar
  40. Liu F, Clark W, Luo G, Wang X, Fu Y, Wei J, Wang X, Hao Z, Dai Q, Zheng G, Ma H, Han D, Evans M, Klungland A, Pan T, He C (2016) ALKBH1-mediated tRNA demethylation regulates translation. Cell 167(7):1897PubMedCrossRefGoogle Scholar
  41. Marion S, Weiner DM, Caron MG (2004) RNA editing induces variation in desensitization and trafficking of 5-hydroxytryptamine 2c receptor isoforms. J Biol Chem 279(4):2945–2954PubMedCrossRefGoogle Scholar
  42. Melnik BC (2015) Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for western diseases. J Transl Med 13:385PubMedPubMedCentralCrossRefGoogle Scholar
  43. Merkestein M, McTaggart JS, Lee S, Kramer HB, McMurray F, Lafond M, Boutens L, Cox R, Ashcroft FM (2014) Changes in gene expression associated with FTO overexpression in mice. PLoS One 9(5):e97162PubMedPubMedCentralCrossRefGoogle Scholar
  44. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149(7):1635–1646PubMedPubMedCentralCrossRefGoogle Scholar
  45. Mirch MC, McDuffie JR, Yanovski SZ, Schollnberger M, Tanofsky-Kraff M, Theim KR, Krakoff J, Yanovski JA (2006) Effects of binge eating on satiation, satiety, and energy intake of overweight children. Am J Clin Nutr 84(4):732–738PubMedPubMedCentralCrossRefGoogle Scholar
  46. Morabito MV, Abbas AI, Hood JL, Kesterson RA, Jacobs MM, Kump DS, Hachey DL, Roth BL, Emeson RB (2010) Mice with altered serotonin 2C receptor RNA editing display characteristics of Prader-Willi syndrome. Neurobiol Dis 39(2):169–180PubMedPubMedCentralCrossRefGoogle Scholar
  47. Nishikura K (2016) A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol 17(2):83–96PubMedCrossRefGoogle Scholar
  48. Palou M, Pico C, McKay JA, Sanchez J, Priego T, Mathers JC, Palou A (2011) Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro-opiomelanocortin gene. Br J Nutr 106(5):769–778PubMedCrossRefGoogle Scholar
  49. Peters J (2014) The role of genomic imprinting in biology and disease: an expanding view. Nat Rev Genet 15(8):517–530PubMedCrossRefGoogle Scholar
  50. Prohaska KM, Bennett RP, Salter JD, Smith HC (2014) The multifaceted roles of RNA binding in APOBEC cytidine deaminase functions. Wiley Interdiscip Rev RNA 5(4):493–508PubMedPubMedCentralCrossRefGoogle Scholar
  51. Roseboom T, de Rooij S, Painter R (2006) The Dutch famine and its long-term consequences for adult health. Early Hum Dev 82(8):485–491PubMedCrossRefGoogle Scholar
  52. Rosenberg BR, Hamilton CE, Mwangi MM, Dewell S, Papavasiliou FN (2011) Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3′ UTRs. Nat Struct Mol Biol 18(2):230–236PubMedPubMedCentralCrossRefGoogle Scholar
  53. Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, Garnica A, Cheung SW, Beaudet AL (2008) Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet 40(6):719–721PubMedPubMedCentralCrossRefGoogle Scholar
  54. Saletore Y, Meyer K, Korlach J, Vilfan ID, Jaffrey S, Mason CE (2012) The birth of the Epitranscriptome: deciphering the function of RNA modifications. Genome Biol 13(10):175PubMedPubMedCentralCrossRefGoogle Scholar
  55. Schellekens H, Finger BC, Dinan TG, Cryan JF (2012) Ghrelin signalling and obesity: at the interface of stress, mood and food reward. Pharmacol Ther 135:316–326PubMedCrossRefGoogle Scholar
  56. Schellekens H, Dinan TG, Cryan JF (2013a) Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward. Front Neurosci 7:148PubMedPubMedCentralCrossRefGoogle Scholar
  57. Schellekens H, van Oeffelen WE, Dinan TG, Cryan JF (2013b) Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling. J Biol Chem 288(1):181–191PubMedCrossRefGoogle Scholar
  58. Schellekens H, De Francesco PN, Kandil D, Theeuwes WF, McCarthy T, van Oeffelen WE, Perello M, Giblin L, Dinan TG, Cryan JF (2015) Ghrelin’s Orexigenic effect is modulated via a serotonin 2C receptor interaction. ACS Chem Neurosci 6(7):1186–1197PubMedCrossRefGoogle Scholar
  59. Scott MS, Ono M (2011) From snoRNA to miRNA: dual function regulatory non-coding RNAs. Biochimie 93(11):1987–1992PubMedPubMedCentralCrossRefGoogle Scholar
  60. Singh M (2014) Mood, food, and obesity. Front Psychol 5:925PubMedPubMedCentralCrossRefGoogle Scholar
  61. Singh M, Kesterson RA, Jacobs MM, Joers JM, Gore JC, Emeson RB (2007) Hyperphagia-mediated obesity in transgenic mice misexpressing the RNA-editing enzyme ADAR2. J Biol Chem 282(31):22448–22459PubMedCrossRefGoogle Scholar
  62. Singh M, Zimmerman MB, Beltz TG, Johnson AK (2009) Affect-related behaviors in mice misexpressing the RNA editing enzyme ADAR2. Physiol Behav 97(3–4):446–454PubMedPubMedCentralCrossRefGoogle Scholar
  63. Singh M, Singh MM, Na E, Agassandian K, Zimmerman MB, Johnson AK (2011) Altered ADAR 2 equilibrium and 5HT(2C) R editing in the prefrontal cortex of ADAR 2 transgenic mice. Genes Brain Behav 10(6):637–647PubMedPubMedCentralCrossRefGoogle Scholar
  64. Skibicka KP, Hansson C, Egecioglu E, Dickson SL (2012) Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addict Biol 17(1):95–107PubMedPubMedCentralCrossRefGoogle Scholar
  65. Steiger H, Thaler L (2016) Eating disorders, gene-environment interactions and the epigenome: roles of stress exposures and nutritional status. Physiol Behav 162:181–185PubMedCrossRefGoogle Scholar
  66. Tajaddod M, Jantsch MF, Licht K (2016) The dynamic epitranscriptome: a to I editing modulates genetic information. Chromosoma 125(1):51–63PubMedCrossRefGoogle Scholar
  67. Theodoro MF, Talebizadeh Z, Butler MG (2006) Body composition and fatness patterns in Prader-Willi syndrome: comparison with simple obesity. Obesity (Silver Spring) 14(10):1685–1690CrossRefGoogle Scholar
  68. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J (2005) Obesity and metabolic syndrome in circadian clock mutant mice. Science 308(5724):1043–1045PubMedPubMedCentralCrossRefGoogle Scholar
  69. Veenendaal MV, Painter RC, de Rooij SR, Bossuyt PM, van der Post JA, Gluckman PD, Hanson MA, Roseboom TJ (2013) Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine. BJOG 120(5):548–553PubMedCrossRefGoogle Scholar
  70. Wallin MS, Rissanen AM (1994) Food and mood: relationship between food, serotonin and affective disorders. Acta Psychiatr Scand Suppl 377:36–40PubMedCrossRefGoogle Scholar
  71. Werry TD, Loiacono R, Sexton PM, Christopoulos A (2008) RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function. Pharmacol Ther 119(1):7–23PubMedCrossRefGoogle Scholar
  72. Witkin KL, Hanlon SE, Strasburger JA, Coffin JM, Jaffrey SR, Howcroft TK, Dedon PC, Steitz JA, Daschner PJ, Read-Connole E (2015) RNA editing, epitranscriptomics, and processing in cancer progression. Cancer Biol Ther 16(1):21–27PubMedCrossRefGoogle Scholar
  73. Xu Y, Jones JE, Kohno D, Williams KW, Lee CE, Choi MJ, Anderson JG, Heisler LK, Zigman JM, Lowell BB, Elmquist JK (2008) 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60(4):582–589PubMedPubMedCentralCrossRefGoogle Scholar
  74. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vagbo CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49(1):18–29PubMedCrossRefGoogle Scholar
  75. Zheng J, Xiao X, Zhang Q, Yu M, Xu J, Wang Z, Qi C, Wang T (2015) Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic POMC promoter methylation in mouse offspring. Metab Brain Dis 30(5):1129–1137PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PediatricsThe University of IowaIowa CityUSA

Personalised recommendations