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Genetics and Epigenetics

DNA methylation and gene expression patterns in adipose tissue differ significantly within young adult monozygotic BMI-discordant twin pairs

International Journal of Obesity volume 40, pages 654–661 (2016)Cite this article

Subjects

Abstract

Background:

Little is known about epigenetic alterations associated with subcutaneous adipose tissue (SAT) in obesity. Our aim was to study genome-wide DNA methylation and gene expression differences in SAT in monozygotic (MZ) twin pairs who are discordant for body mass index (BMI). This design completely matches lean and obese groups for genetic background, age, gender and shared environment.

Methods:

14We analyzed DNA methylome and gene expression from SAT, together with body composition (magnetic resonance imaging/spectroscopy) and glucose tolerance test, lipids and C-reactive protein from 26 rare BMI-discordant (intrapair difference in BMI ⩾3 kg m−2) MZ twin pairs identified from 10 birth cohorts of young adult Finnish twins.

Results:

We found 17 novel obesity-associated genes that were differentially methylated across the genome between heavy and lean co-twins. Nine of them were also differentially expressed. Pathway analyses indicated that dysregulation of SAT in obesity includes a paradoxical downregulation of lipo/adipogenesis and upregulation of inflammation and extracellular matrix remodeling. Furthermore, CpG sites whose methylation correlated with metabolically harmful fat depots (intra-abdominal and liver fat) also correlated with measures of insulin resistance, dyslipidemia and low-grade inflammation, thus suggesting that epigenetic alterations in SAT are associated with the development of unhealthy obesity.

Conclusion:

This is the first study in BMI-discordant MZ twin pairs reporting genome-wide DNA methylation and expression profiles in SAT. We found a number of novel genes and pathways whose methylation and expression patterns differ within the twin pairs, suggesting that the pathological adaptation of SAT to obesity is, at least in part, epigenetically regulated.

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References

  1. Heinonen S, Saarinen L, Naukkarinen J, Rodriguez A, Fruhbeck G, Hakkarainen A et al. Adipocyte morphology and implications for metabolic derangements in acquired obesity. Int J Obes (Lond) 2014; 38: 1423–1431.

    Article  CAS  Google Scholar 

  2. Gustafson B, Hammarstedt A, Hedjazifar S, Smith U . Restricted adipogenesis in hypertrophic obesity: the role of WISP2, WNT, and BMP4. Diabetes 2013; 62: 2997–3004.

    Article  CAS  Google Scholar 

  3. Bolton K, Segal D, McMillan J, Jowett J, Heilbronn L, Abberton K et al. Decorin is a secreted protein associated with obesity and type 2 diabetes. Int J Obes (Lond) 2008; 32: 1113–1121.

    Article  CAS  Google Scholar 

  4. Lemoine AY, Ledoux S, Larger E . Adipose tissue angiogenesis in obesity. Thromb Haemost 2013; 110: 661–668.

    Article  CAS  Google Scholar 

  5. Naukkarinen J, Heinonen S, Hakkarainen A, Lundbom J, Vuolteenaho K, Saarinen L et al. Characterising metabolically healthy obesity in weight-discordant monozygotic twins. Diabetologia 2014; 57: 167–176.

    Article  CAS  Google Scholar 

  6. Dick KJ, Nelson CP, Tsaprouni L, Sandling JK, Aissi D, Wahl S et al. DNA methylation and body-mass index: a genome-wide analysis. Lancet 2014; 383: 1990–1998.

    Article  CAS  Google Scholar 

  7. Ronn T, Volkov P, Gillberg L, Kokosar M, Perfilyev A, Jacobsen AL et al. Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood. Hum Mol Genet 2015; 24: 3792–3813.

    PubMed  Google Scholar 

  8. Ribel-Madsen R, Fraga MF, Jacobsen S, Bork-Jensen J, Lara E, Calvanese V et al. Genome-wide analysis of DNA methylation differences in muscle and fat from monozygotic twins discordant for type 2 diabetes. PLoS One 2012; 7: e51302.

    Article  CAS  Google Scholar 

  9. Nilsson E, Jansson PA, Perfilyev A, Volkov P, Pedersen M, Svensson MK et al. Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes 2014; 63: 2962–2976.

    Article  Google Scholar 

  10. Guenard F, Tchernof A, Deshaies Y, Perusse L, Biron S, Lescelleur O et al. Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances. Physiol Genomics 2014; 46: 216–222.

    Article  Google Scholar 

  11. Grundberg E, Meduri E, Sandling JK, Hedman AK, Keildson S, Buil A et al. Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements. Am J Hum Genet 2013; 93: 876–890.

    Article  CAS  Google Scholar 

  12. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518: 197–206.

    Article  CAS  Google Scholar 

  13. Kaprio J . The Finnish Twin Cohort Study: an update. Twin Res Hum Genet 2013; 16: 157–162.

    Article  Google Scholar 

  14. R Core Team R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2013. Available from https://www.R-project.org/.

  15. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004; 5: R80.

    Article  Google Scholar 

  16. Ollikainen M, Ismail K, Gervin K, Kyllonen A, Hakkarainen A, Lundbom J et al. Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fat. Clin Epigenetics 2015; 7 39, eCollection 2015.

  17. Teschendorff AE, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics 2013; 29: 189–196.

    Article  CAS  Google Scholar 

  18. Mikkelsen TS, Xu Z, Zhang X, Wang L, Gimble JM, Lander ES et al. Comparative epigenomic analysis of murine and human adipogenesis. Cell 2010; 143: 156–169.

    Article  CAS  Google Scholar 

  19. Schmitz G, Kaminski WE . ABC transporters and cholesterol metabolism. Front Biosci 2001; 6: D505–D514.

    Article  CAS  Google Scholar 

  20. Henegar C, Tordjman J, Achard V, Lacasa D, Cremer I, Guerre-Millo M et al. Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity. Genome Biol 2008; 9: R14–2008-9-1-r14.

    Article  Google Scholar 

  21. Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A . Adipogenesis and WNT signalling. Trends Endocrinol Metab 2009; 20: 16–24.

    Article  CAS  Google Scholar 

  22. Lodhi IJ, Yin L, Jensen-Urstad AP, Funai K, Coleman T, Baird JH et al. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARgamma activation to decrease diet-induced obesity. Cell Metab 2012; 16: 189–201.

    Article  CAS  Google Scholar 

  23. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2009; 458: 514–518.

    Article  CAS  Google Scholar 

  24. Catalan V, Gomez-Ambrosi J, Rodriguez A, Fruhbeck G . Role of extracellular matrix remodelling in adipose tissue pathophysiology: relevance in the development of obesity. Histol Histopathol 2012; 27: 1515–1528.

    CAS  PubMed  Google Scholar 

  25. Kruger RP, Aurandt J, Guan KL . Semaphorins command cells to move. Nat Rev Mol Cell Biol 2005; 6: 789–800.

    Article  CAS  Google Scholar 

  26. Elks CE, den Hoed M, Zhao JH, Sharp SJ, Wareham NJ, Loos RJ et al. Variability in the heritability of body mass index: a systematic review and meta-regression. Front Endocrinol (Lausanne) 2012; 3: 29.

    Article  Google Scholar 

  27. Lehtovirta M, Pietilainen KH, Levalahti E, Heikkila K, Groop L, Silventoinen K et al. Evidence that BMI and type 2 diabetes share only a minor fraction of genetic variance: a follow-up study of 23,585 monozygotic and dizygotic twins from the Finnish Twin Cohort Study. Diabetologia 2010; 53: 1314–1321.

    Article  CAS  Google Scholar 

  28. van Dongen J, Ehli EA, Slieker RC, Bartels M, Weber ZM, Davies GE et al. Epigenetic variation in monozygotic twins: a genome-wide analysis of DNA methylation in buccal cells. Genes (Basel) 2014; 5: 347–365.

    Article  Google Scholar 

  29. Gordon L, Joo JE, Powell JE, Ollikainen M, Novakovic B, Li X et al. Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence. Genome Res 2012; 22: 1395–1406.

    Article  CAS  Google Scholar 

  30. Bell JT, Tsai PC, Yang TP, Pidsley R, Nisbet J, Glass D et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet 2012; 8: e1002629.

    Article  CAS  Google Scholar 

  31. Wong CC, Caspi A, Williams B, Craig IW, Houts R, Ambler A et al. A longitudinal study of epigenetic variation in twins. Epigenetics 2010; 5: 516–526.

    Article  CAS  Google Scholar 

  32. Keller M, Kralisch S, Rohde K, Schleinitz D, Dietrich A, Schon MR et al. Global DNA methylation levels in human adipose tissue are related to fat distribution and glucose homeostasis. Diabetologia 2014; 57: 2374–2383.

    Article  CAS  Google Scholar 

  33. Wagner JR, Busche S, Ge B, Kwan T, Pastinen T, Blanchette M . The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts. Genome Biol 2014; 15: R37.

    Article  Google Scholar 

  34. Widberg CH, Newell FS, Bachmann AW, Ramnoruth SN, Spelta MC, Whitehead JP et al. Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes. Am J Physiol Endocrinol Metab 2009; 296: E121–E131.

    Article  CAS  Google Scholar 

  35. Amann R, Trueb B . Evidence that the novel receptor FGFRL1 signals indirectly via FGFR1. Int J Mol Med 2013; 32: 983–988.

    Article  CAS  Google Scholar 

  36. Vidal-Puig A . Adipose tissue expandability, lipotoxicity and the metabolic syndrome. Endocrinol Nutr 2013; 60 (Suppl 1): 39–43.

    Article  Google Scholar 

  37. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005; 46: 2347–2355.

    Article  CAS  Google Scholar 

  38. Sun K, Kusminski CM, Scherer PE . Adipose tissue remodeling and obesity. J Clin Invest 2011; 121: 2094–2101.

    Article  CAS  Google Scholar 

  39. Salmenniemi U, Ruotsalainen E, Pihlajamaki J, Vauhkonen I, Kainulainen S, Punnonen K et al. Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines, and adhesion molecules in subjects with metabolic syndrome. Circulation 2004; 110: 3842–3848.

    Article  CAS  Google Scholar 

  40. Gehrke S, Brueckner B, Schepky A, Klein J, Iwen A, Bosch TC et al. Epigenetic regulation of depot-specific gene expression in adipose tissue. PLoS One 2013; 8: e82516.

    Article  Google Scholar 

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Acknowledgements

We thank the participants for their invaluable contributions to the study. The Obesity Research Unit team and the staff at the Finnish Twin Cohort Study are acknowledged for their help in the collection of the data. We also thank Barbara Every, BioMedical Editor, for English language editing. This study was supported by the Academy of Finland (Grants 251316, 100499, 205585, 118555, 141054, 266286 and 272376), The Sigrid Juselius Foundation, The University of Helsinki Research Funds, Helsinki University Hospital Research Funds, grants from Novo Nordisk, the Finnish Diabetes Research Foundation, the Jalmari and Rauha Ahokas Foundation, Orion Pharmos Foundation and Emil Aaltonen Foundation, the Academy of Finland Center of Excellence in Complex Disease Genetics (Grants 213506 and 129680), the Academy of Finland Center of Excellence in Research on Mitochondria, Metabolism and Disease (272376), EPITRAIN - Innovative techniques and models to understand epigenetic regulation in the pathogenesis of common diseases (EPITRAIN - FP7-PEOPLE-2012-ITN, Grant Agreement 316758) and BioSHaRE-EU (Grant Agreement HEALTH-F4-2010-261433) funded by the European Union’s Seventh Framework Programme (FP7/2007-2013).

Author contributions

KHP, JK, AR and MO conceived and designed the study. JK was responsible for the twin cohort data collection from which the study pairs were recruited. KHP collected the biological samples and performed the clinical investigations of the twins. KHP and MO coordinated the study. KHP, KI, EJ and MO wrote the manuscript. JK helped in drafting the manuscript and critically commented on it. KI performed the bioinformatics and the statistical analysis of the methylation and expression data and the clinical measurements. EJ performed the immunohistochemical staining together with MT, as well as imaging and real-time quantitative PCR validation of the array results. MM performed the gene expression data analysis. SH helped in collecting the samples, extracted the adipocytes and their RNA and determined the adipocyte cell diameters. SB analyzed the public data sets and data on unrelated individuals. RL was responsible for the generation of the methylation data. NL, JL and AH performed MR imaging and spectroscopy and analyzed the images. All authors participated in discussions related to analysis and interpretation and have read and approved the final manuscript. MO is the guarantor of this work and as such had full access to the data and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Author notes

  1. K H Pietiläinen and K Ismail: These two authors shared first authorship.

Authors and Affiliations

  1. Obesity Research Unit, Research Programs Unit, University of Helsinki, Helsinki, Finland

    K H Pietiläinen, E Järvinen, S Heinonen, M Tummers, M Muniandy & A Rissanen

  2. Endocrinology, Abdominal Center, Helsinki University Central Hospital, and University of Helsinki, Helsinki, Finland

    K H Pietiläinen

  3. Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland

    K H Pietiläinen & J Kaprio

  4. Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    K Ismail, S Bollepalli, M Muniandy, J Kaprio & M Ollikainen

  5. Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway

    R Lyle

  6. The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland

    E Moilanen

  7. HUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    A Hakkarainen, J Lundbom & N Lundbom

  8. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany

    J Lundbom

  9. German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany

    J Lundbom

  10. National Institute for Health and Welfare, Helsinki, Finland

    J Kaprio

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Correspondence to M Ollikainen.

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Pietiläinen, K., Ismail, K., Järvinen, E. et al. DNA methylation and gene expression patterns in adipose tissue differ significantly within young adult monozygotic BMI-discordant twin pairs. Int J Obes 40, 654–661 (2016). https://doi.org/10.1038/ijo.2015.221

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