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DNA methylation regulates hypothalamic gene expression linking parental diet during pregnancy to the offspring’s risk of obesity in Psammomys obesus

Abstract

Background/Objective:

The rising incidence of obesity is a major public health issue worldwide. Recent human and animal studies suggest that parental diet can influence fetal development and is implicated with risk of obesity and type 2 diabetes in offspring. The hypothalamus is central to body energy homoeostasis and appetite by controlling endocrine signals. We hypothesise that offspring susceptibility to obesity is programmed in the hypothalamus in utero and mediated by changes to DNA methylation, which persist to adulthood. We investigated hypothalamic genome-wide DNA methylation in Psammomys obesus diet during pregnancy to the offspring’s risk of obesity.

Methods:

Using methyl-CpG binding domain capture and deep sequencing (MBD-seq), we examined the hypothalamus of offspring exposed to a low-fat diet and standard chow diet during the gestation and lactation period.

Results:

Offspring exposed to a low-fat parental diet were more obese and had increased circulating insulin and glucose levels. Methylome profiling identified 1447 genomic regions of differential methylation between offspring of parents fed a low-fat diet compared with parents on standard chow diet. Pathway analysis shows novel DNA methylation changes of hypothalamic genes associated with neurological function, nutrient sensing, appetite and energy balance. Differential DNA methylation corresponded to changes in hypothalamic gene expression of Tas1r1 and Abcc8 in the offspring exposed to low-fat parental diet.

Conclusion:

Subject to parental low-fat diet, we observe DNA methylation changes of genes associated with obesity in offspring.

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Gene Expression Omnibus

References

  1. Barker DJ . The fetal and infant origins of adult disease. BMJ 1990; 301: 1111.

    Article  CAS  Google Scholar 

  2. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991; 303: 1019–1022.

    Article  CAS  Google Scholar 

  3. Li Y, Jaddoe VW, Qi L, He Y, Lai J, Wang J . Exposure to the Chinese famine in early life and the risk of hypertension in adulthood. J Hypertens 2011; 29: 1085–1092.

    Article  CAS  Google Scholar 

  4. Stöger R . The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes? Bioessays 2008; 30: 156–166.

    Article  Google Scholar 

  5. Dominguez-Salas P, Moore SE, Baker MS, Bergen AW, Cox SE, Dyer RA et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat Commun 2014; 5: 3746.

    Article  CAS  Google Scholar 

  6. Mozhui K, Smith AK, Tylavsky FA . Ancestry dependent DNA methylation and influence of maternal nutrition. PLoS One 2015; 10: e0118466.

    Article  Google Scholar 

  7. Schroeder JW, Conneely KN, Cubells JC, Kilaru V, Newport DJ, Knight BT et al. Neonatal DNA methylation patterns associate with gestational age. Epigenetics 2011; 6: 1498–1504.

    Article  CAS  Google Scholar 

  8. Schulz LC . The Dutch Hunger Winter and the developmental origins of health and disease. Proc Natl Acad Sci USA 2010; 107: 16757–16758.

    Article  CAS  Google Scholar 

  9. Thurner S, Klimek P, Szell M, Duftschmid G, Endel G, Kautzky-Willer et al. Quantification of excess risk for diabetes for those born in times of hunger, in an entire population of a nation, across a century. Proc Natl Acad Sci USA 2013; 110: 4703–4707.

    Article  CAS  Google Scholar 

  10. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 2008; 105: 17046–17049.

    Article  CAS  Google Scholar 

  11. Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009; 18: 4046–4053.

    Article  CAS  Google Scholar 

  12. Keating ST, El-Osta A . Epigenetics and metabolism. Circ Res 2015; 116: 715–736.

    Article  CAS  Google Scholar 

  13. King BM . The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol Behav 2006; 87: 221–244.

    Article  CAS  Google Scholar 

  14. Dearden L, Ozanne SE . Early life origins of metabolic disease: developmental programming of hypothalamic pathways controlling energy homeostasis. Front Neuroendocrinol 2015; 39: 3–16.

    Article  Google Scholar 

  15. Gali Ramamoorthy T, Begum G, Harno E, White A . Developmental programming of hypothalamic neuronal circuits: impact on energy balance control. Front Neurosci 2015; 9: 126.

    Article  Google Scholar 

  16. Schneeberger M, Gomis R, Claret M . Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J Endocrinol 2014; 220: T25–T46.

    Article  CAS  Google Scholar 

  17. Hallschmid M, Benedict C, Schultes B, Born J, Kern W . Obese men respond to cognitive but not to catabolic brain insulin signaling. Int J Obes (Lond) 2008; 32: 275–282.

    Article  CAS  Google Scholar 

  18. Ross MG, Desai M . Developmental programming of appetite/satiety. Ann Nutr Metab 2014; 64: 36–44.

    Article  CAS  Google Scholar 

  19. Remacle C, Bieswal F, Bol V, Reusens B . Developmental programming of adult obesity and cardiovascular disease in rodents by maternal nutrition imbalance. Am J Clin Nutr 2011; 94: 1846S–1852S.

    Article  CAS  Google Scholar 

  20. Orozco-Solís R, Matos RJB, Guzmán-Quevedo O, Lopes de Souza S, Bihouée A, Houlgatte R et al. Nutritional programming in the rat is linked to long-lasting changes in nutrient sensing and energy homeostasis in the hypothalamus. PLoS One 2010; 5: e13537.

    Article  Google Scholar 

  21. Painter RC, Osmond C, Gluckman P, Hanson M, Phillips DIW, Roseboom TJ . Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG 2008; 115: 1243–1249.

    Article  CAS  Google Scholar 

  22. van Dijk SJ, Molloy PL, Varinli H, Morrison JL, Muhlhausler BS, Members of EpiSCOPE. Epigenetics and human obesity. Int J Obes (Lond) 2015; 39: 85–97.

    Article  CAS  Google Scholar 

  23. Desai M, Jellyman JK, Ross MG . Epigenomics, gestational programming and risk of metabolic syndrome. Int J Obes (Lond) 2015; 39: 633–641.

    Article  CAS  Google Scholar 

  24. King AJF . The use of animal models in diabetes research. Br J Pharmacol 2012; 166: 877–894.

    Article  CAS  Google Scholar 

  25. Lavine RL, Voyles N, Perrino PV, Recant L . Functional abnormalities of islets of Langerhans of obese hyperglycemic mouse. Am J Physiol 1977; 233: E86–E90.

    Article  CAS  Google Scholar 

  26. Schmidt-Nielsen K, Haines HB, Hackel DB . Diabetes mellitus in the sand rat induced by standard laboratory diets. Science 1964; 143: 689–690.

    Article  CAS  Google Scholar 

  27. Marquie G, Duhault J, Hadjiisky P, Petkov P, Bouissou H . Diabetes mellitus in sand rats (Psammomys obesus): microangiopathy during development of the diabetic syndrome. Cell Mol Biol 1991; 37: 651–667.

    CAS  PubMed  Google Scholar 

  28. Walder KR, Fahey RP, Morton GJ, Zimmet PZ, Collier GR . Characterization of obesity phenotypes in Psammomys obesus (Israeli sand rats). Int J Exp Diabetes Res 2000; 1: 177–184.

    Article  CAS  Google Scholar 

  29. Kalderon B, Gutman A, Levy E, Shafrir E, Adler JH . Characterization of stages in development of obesity-diabetes syndrome in sand rat (Psammomys obesus). Diabetes 1986; 35: 717–724.

    Article  CAS  Google Scholar 

  30. Collier GR, McMillan JS, Windmill K, Walder K, Tenne-Brown J, de Silva et al. Beacon: a novel gene involved in the regulation of energy balance. Diabetes 2000; 49: 1766–1771.

    Article  CAS  Google Scholar 

  31. Jowett JB, Elliott KS, Curran JE, Hunt N, Walder KR, Collier GR et al. Genetic variation in BEACON influences quantitative variation in metabolic syndrome-related phenotypes. Diabetes 2004; 53: 2467–2472.

    Article  CAS  Google Scholar 

  32. Kaspi A, Ziemann M, Keating ST, Khurana I, Connor T, Spolding B et al. Non-referenced genome assembly from epigenomic short-read data. Epigenetics 2014; 9: 1329–1338.

    Article  Google Scholar 

  33. Simpson JT, Wong K, Jackman SD, Schein JE, Jones SJM, Birol I . ABySS: a parallel assembler for short read sequence data. Genome Res 2009; 19: 1117–1123.

    Article  CAS  Google Scholar 

  34. Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009; 25: 1754–1760.

    Article  CAS  Google Scholar 

  35. Robinson MD, McCarthy DJ, Smyth GK . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010; 26: 139–140.

    Article  CAS  Google Scholar 

  36. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ . Basic local alignment search tool. J Mol Biol 1990; 215: 403–410.

    Article  CAS  Google Scholar 

  37. Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E . The genotype-tissue expression (GTEx) project. Nature 2013; 45: 580–585.

    CAS  Google Scholar 

  38. Vilella AJ, Severin J, Ureta-Vidal A, Heng L, Durbin R, Birney E . EnsemblCompara GeneTrees: Complete, duplication-aware phylogenetic trees in vertebrates. Genome Res 2009; 19: 327–335.

    Article  CAS  Google Scholar 

  39. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  Google Scholar 

  40. Rakyan VK, Chong S, Champ ME, Cuthbert PC, Morgan HD, Luu KVK et al. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA 2003; 100: 2538–2543.

    Article  CAS  Google Scholar 

  41. McMillen IC, Adam CL, Mühlhäusler BS . Early origins of obesity: programming the appetite regulatory system. J Physiol (Lond) 2005; 565: 9–17.

    Article  CAS  Google Scholar 

  42. Vimaleswaran KS, Tachmazidou I, Zhao JH, Hirschhorn JN, Dudbridge F, Loos RJF . Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI. Hum Mol Genet 2012; 21: 4537–4542.

    Article  CAS  Google Scholar 

  43. Dean M, Hamon Y, Chimini G . The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 2001; 42: 1007–1017.

    CAS  PubMed  Google Scholar 

  44. Quan Y, Barszczyk A, Feng Z-P, Sun H-S . Current understanding of K ATP channels in neonatal diseases: focus on insulin secretion disorders. Acta Pharmacol Sin 2011; 32: 765–780.

    Article  CAS  Google Scholar 

  45. Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 2001; 4: 507–512.

    Article  CAS  Google Scholar 

  46. Pocai A, Lam TKT, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 2005; 434: 1026–1031.

    Article  CAS  Google Scholar 

  47. Cook DL, Satin LS, Ashford ML, Hales CN . ATP-sensitive K+ channels in pancreatic beta- cells. Spare-channel hypothesis. Diabetes 1988; 37: 495–498.

    Article  CAS  Google Scholar 

  48. Seino S . ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu Rev Physiol 1999; 61: 337–362.

    Article  CAS  Google Scholar 

  49. Tarasov A, Dusonchet J, Ashcroft F . Metabolic regulation of the pancreatic beta-cell ATP- sensitive K+ channel: a pas de deux. Diabetes 2004; 53: S113–S122.

    Article  CAS  Google Scholar 

  50. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG, Schwartz MW . Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 2001; 413: 794–795.

    Article  CAS  Google Scholar 

  51. Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature 2002; 420: 629–635.

    Article  CAS  Google Scholar 

  52. Burridge K, Wennerberg K . Rho and Rac take center stage. Cell 2004; 116: 167–179.

    Article  CAS  Google Scholar 

  53. Huang H, Kong D, Byun KH, Ye C, Koda S, Lee DH et al. Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nat Neurosci 2012; 15: 1391–1398.

    Article  CAS  Google Scholar 

  54. Pistocchi A, Gaudenzi G, Carra S, Bresciani E, Del Giacco L, Cotelli F . Crucial role of zebrafish prox1 in hypothalamic catecholaminergic neurons development. BMC. Dev Biol 2008; 8: 27.

    Google Scholar 

  55. Takeda Y, Jetten AM . Prospero-related homeobox 1 (Prox1) functions as a novel modulator of retinoic acid-related orphan receptors α- and γ-mediated transactivation. Nucleic Acids Res 2013; 41: 6992–7008.

    Article  CAS  Google Scholar 

  56. Millington GW . The role of proopiomelanocortin (POMC) neurones in feeding behaviour. Nutr Metab (Lond) 2007; 4: 18.

    Article  Google Scholar 

  57. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A . Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19: 155–157.

    Article  CAS  Google Scholar 

  58. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 1994; 371: 799–802.

    Article  CAS  Google Scholar 

  59. Hoon MA, Adler E, Lindemeier J, Battey JF, Ryba NJ, Zuker CS . Putative mammalian taste receptors: a class of taste-specific GPCRs with distinct topographic selectivity. Cell 1999; 96: 541–551.

    Article  CAS  Google Scholar 

  60. Nelson G, Chandrashekar J, Hoon MA, Feng L, Zhao G, Ryba NJP et al. An amino-acid taste receptor. Nature 2002; 416: 199–202.

    Article  CAS  Google Scholar 

  61. Zhao GQ, Zhang Y, Hoon MA, Chandrashekar J, Erlenbach I, Ryba NJP et al. The receptors for mammalian sweet and umami taste. Cell 2003; 115: 255–266.

    Article  CAS  Google Scholar 

  62. Ren X, Zhou L, Terwilliger R, Newton SS, de Araujo IE . Sweet taste signaling functions as a hypothalamic glucose sensor. Front Integr Neurosci 2009; 3: 12.

    Article  Google Scholar 

  63. Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010; 466: 253–257.

    Article  CAS  Google Scholar 

  64. Jjingo D, Conley AB, Yi SV, Lunyak VV, Jordan IK . On the presence and role of human gene- body DNA methylation. Oncotarget 2012; 3: 462–474.

    Article  Google Scholar 

  65. Shukla S, Kavak E, Gregory M, Imashimizu M . CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 2011; 479: 74–79.

    Article  CAS  Google Scholar 

  66. Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G . Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 2014; 26: 577–590.

    Article  CAS  Google Scholar 

  67. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001; 411: 480–484.

    Article  CAS  Google Scholar 

  68. Guerra-Crespo M, Pérez-Monter C, Janga SC, Castillo-Ramírez S, Gutiérrez-Rios RM, Joseph- Bravo P et al. Transcriptional profiling of fetal hypothalamic TRH neurons. BMC Genomics 2010; 12: 222–222.

    Article  Google Scholar 

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Acknowledgements

We thank Ross Lazarus and Haloom Rafehi for bioinformatics support. This work was supported in part by Gandel Philanthropy and the Royal College of Pathologists of Australasia Scholarships in Pathology for Medical Schools. We acknowledge grant and fellowship support from the National Health and Medical Research Council (NHMRC) as well as the support from the Moshe Meydan Donation. Supported in part by the Victorian Government's Operational Infrastructure Support Program.

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Correspondence to A El-Osta.

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Khurana, I., Kaspi, A., Ziemann, M. et al. DNA methylation regulates hypothalamic gene expression linking parental diet during pregnancy to the offspring’s risk of obesity in Psammomys obesus. Int J Obes 40, 1079–1088 (2016). https://doi.org/10.1038/ijo.2016.64

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