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.

  • Article
  • Published:

Nutrigenomics and molecular nutrition

DNA methylation pattern changes following a short-term hypocaloric diet in women with obesity

European Journal of Clinical Nutrition volume 74, pages 1345–1353 (2020)Cite this article

Subjects

Abstract

Background/Objectives

We aimed to investigate the effects of short-term hypocaloric diet-induced weight loss on DNA methylation profile in leukocytes from women with severe obesity.

Methods

Eleven women with morbid obesity (age: 36.9 ± 10.3 years; BMI: 58.5 ± 10.5 kg/m2) were assessed before and after 6 weeks of a hypocaloric dietary intervention. The participants were compared with women of average weight and the same age (age: 36.9 ± 11.8 years; BMI: 22.5 ± 1.6 kg/m2). Genome-wide DNA methylation analysis was performed in DNA extracted from peripheral blood leukocytes using the Infinium Human Methylation 450 BeadChip assay. Changes (Δβ) in the methylation level of each CpGs were calculated. A threshold with a minimum value of 10%, p < 0.001, for the significant CpG sites based on Δβ and a false discovery rate of <0.05 was set.

Results

Dietary intervention changed the methylation levels at 16,064 CpG sites. These CpGs sites were related to cancer, cell cycle-related, MAPK, Rap1, and Ras signaling pathways. However, regardless of hypocaloric intervention, a group of 878 CpGs (related to 649 genes) remained significantly altered in obese women when compared with normal-weight women. Pathway enrichment analysis identified genes related to the cadherin and Wnt pathway, angiogenesis signaling, and p53 pathways by glucose deprivation.

Conclusion

A short-term hypocaloric intervention in patients with severe obesity partially restored the obesity-related DNA methylation pattern. Thus, the full change of obesity-related DNA methylation patterns could be proportional to the weight-loss rate in these patients after dietary interventions.

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

Fig. 1: Clustering analysis of the differentially methylated CpG sites between severely obese versus normal-weight women.
Fig. 2: Clustering analysis of the differentially methylated CpG sites pre versus post intervention.
Fig. 3: Clustering analysis of the differentially methylated CpG sites between obese women versus women of average weight after the intervention.
Fig. 4: Integrated methylation data analysis.

Similar content being viewed by others

References

  1. Dyaczynski M, Scanes CG, Koziec H, Koziec H, Pierzchala-Koziec K. Endocrine implications of obesity and bariatric surgery. Endokrynol Pol. 2018;69:574–97.

    Article  CAS  Google Scholar 

  2. 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 

  3. Mansego ML, Milagro FI, Zulet MA, Moreno-Aliaga MJ, Martinez JA. Differential DNA methylation in relation to age and health risks of obesity. Int J Mol Sci. 2015;16:16816–32.

    Article  CAS  Google Scholar 

  4. Demerath EW, Guan W, Grove ML, Aslibekyan S, Mendelson M, Zhou YH, et al. Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. Hum Mol Genet. 2015;24:4464–79.

    Article  CAS  Google Scholar 

  5. Huang RC, Garratt ES, Pan H, Wu Y, Davis EA, Barton SJ, et al. Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood. Epigenetics. 2015;10:995–1005.

    Article  CAS  Google Scholar 

  6. Sayols-Baixeras S, Subirana I, Fernandez-Sanles A, Senti M, Lluis-Ganella C, Marrugat J, et al. DNA methylation and obesity traits: An epigenome-wide association study. The REGICOR study. Epigenetics. 2017;12:909–16.

    Article  Google Scholar 

  7. Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2017;541:81–86.

    Article  CAS  Google Scholar 

  8. Crujeiras AB, Diaz-Lagares A, Sandoval J, Milagro FI, Navas-Carretero S, Carreira MC, et al. DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern: a genome-wide analysis from non-obese and obese patients. Sci Rep. 2017;7:41903.

    Article  CAS  Google Scholar 

  9. Barres R, Kirchner H, Rasmussen M, Yan J, Kantor FR, Krook A, et al. Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. Cell Rep. 2013;3:1020–7.

    Article  CAS  Google Scholar 

  10. Nicoletti CF, Nonino CB, de Oliveira BA, Pinhel MA, Mansego ML, Milagro FI, et al. DNA methylation and hydroxymethylation levels in relation to two weight loss strategies: energy-restricted diet or bariatric surgery. Obes Surg. 2016;26:603–11.

    Article  Google Scholar 

  11. Nicoletti CF, Pinhel MAS, Diaz-Lagares A, Casanueva FF, Jacome A, Pinhanelli VC, et al. DNA methylation screening after roux-en Y gastric bypass reveals the epigenetic signature stems from genes related to the surgery per se. BMC Med Genomics. 2019;12:72.

    Article  CAS  Google Scholar 

  12. Ronn T, Volkov P, Davegardh C, Dayeh T, Hall E, Olsson AH, et al. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet. 2013;9:e1003572.

    Article  Google Scholar 

  13. Morcillo S, Macias-Gonzalez M, Tinahones FJ. The effect of metabolic and bariatric surgery on DNA methylation patterns. Curr Atheroscler Rep. 2017;19:40.

    Article  Google Scholar 

  14. Samblas M, Mansego ML, Zulet MA, Milagro FI, Martinez JA. An integrated transcriptomic and epigenomic analysis identifies CD44 gene as a potential biomarker for weight loss within an energy-restricted program. Eur J Nutr. 2019;58:1971–80.

    Article  CAS  Google Scholar 

  15. Li R, Grimm SA, Mav D, Gu H, Djukovic D, Shah R, et al. Transcriptome and DNA methylome analysis in a mouse model of diet-induced obesity predicts increased risk of colorectal cancer. Cell Rep. 2018;22:624–37.

    Article  CAS  Google Scholar 

  16. Cortes-Oliveira C, Nicoletti CF, de Souza Pinhel MA, de Oliveira BA, Quinhoneiro DC, Noronha NY, et al. UCP2 expression is associated with weight loss after hypocaloric diet intervention. Eur J Clin Nutr. 2017;71:402–6.

    Article  CAS  Google Scholar 

  17. Bibikova M, Barnes B, Tsan C, Ho V, Klotzle B, Le JM, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011;98:288–95.

    Article  CAS  Google Scholar 

  18. Dedeurwaerder S, Defrance M, Calonne E, Denis H, Sotiriou C, Fuks F. Evaluation of the infinium methylation 450K technology. Epigenomics. 2011;3:771–84.

    Article  CAS  Google Scholar 

  19. ElGendy K, Malcomson FC, Lara JG, Bradburn DM, Mathers JC. Effects of dietary interventions on DNA methylation in adult humans: systematic review and meta-analysis. Br J Nutr. 2018;120:961–76.

    Article  CAS  Google Scholar 

  20. Abete I, Gomez-Uriz AM, Mansego ML, De Arce A, Goyenechea E, Blazquez V, et al. Epigenetic changes in the methylation patterns of KCNQ1 and WT1 after a weight loss intervention program in obese stroke patients. Curr Neurovasc Res. 2015;12:321–33.

    Article  CAS  Google Scholar 

  21. Delgado-Cruzata L, Zhang W, McDonald JA, Tsai WY, Valdovinos C, Falci L, et al. Dietary modifications, weight loss, and changes in metabolic markers affect global DNA methylation in Hispanic, African American, and Afro-Caribbean breast cancer survivors. J Nutr. 2015;145:783–90.

    Article  CAS  Google Scholar 

  22. Martin-Nunez GM, Cabrera-Mulero R, Rubio-Martin E, Rojo-Martinez G, Olveira G, Valdes S, et al. Methylation levels of the SCD1 gene promoter and LINE-1 repeat region are associated with weight change: an intervention study. Mol Nutr Food Res. 2014;58:1528–36.

    Article  CAS  Google Scholar 

  23. Cordero P, Campion J, Milagro FI, Goyenechea E, Steemburgo T, Javierre BM, et al. Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet. J Physiol Biochem. 2011;67:463–70.

    Article  CAS  Google Scholar 

  24. Nilsson EK, Ernst B, Voisin S, Almen MS, Benedict C, Mwinyi J, et al. Roux-en Y gastric bypass surgery induces genome-wide promoter-specific changes in DNA methylation in whole blood of obese patients. PLoS ONE. 2015;10:e0115186.

    Article  Google Scholar 

  25. Bostrom AE, Mwinyi J, Voisin S, Wu W, Schultes B, Zhang K, et al. Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension. BMC Med Genomics. 2016;9:20.

    Article  Google Scholar 

  26. Zhang N. Epigenetic modulation of DNA methylation by nutrition and its mechanisms in animals. Anim Nutr. 2015;1:144–51.

    Article  Google Scholar 

  27. Kadayifci FZ, Zheng S, Pan YX. Molecular mechanisms underlying the link between diet and DNA methylation. Int J Mol Sci. 2018;19:4055.

    Article  Google Scholar 

  28. Li Y, Daniel M, Tollefsbol TO. Epigenetic regulation of caloric restriction in aging. BMC Med. 2011;9:98.

    Article  CAS  Google Scholar 

  29. Maegawa S, Lu Y, Tahara T, Lee JT, Madzo J, Liang S, et al. Caloric restriction delays age-related methylation drift. Nat Commun. 2017;8:539.

    Article  Google Scholar 

  30. Drong AW, Lindgren CM, McCarthy MI. The genetic and epigenetic basis of type 2 diabetes and obesity. Clin Pharm Ther. 2012;92:707–15.

    Article  CAS  Google Scholar 

  31. 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;24:3792–813.

    PubMed  Google Scholar 

  32. Aronica L, Levine AJ, Brennan K, Mi J, Gardner C, Haile RW, et al. A systematic review of studies of DNA methylation in the context of a weight loss intervention. Epigenomics. 2017;9:769–87.

    Article  CAS  Google Scholar 

  33. Crujeiras AB, Casanueva FF. Obesity and the reproductive system disorders: epigenetics as a potential bridge. Hum Reprod Update. 2015;21:249–61.

    Article  CAS  Google Scholar 

  34. Crujeiras AB, Diaz-Lagares A, Stefansson OA, Macias-Gonzalez M, Sandoval J, Cueva J, et al. Obesity and menopause modify the epigenomic profile of breast cancer. Endocr Relat Cancer. 2017;24:351–63.

    Article  CAS  Google Scholar 

  35. Crujeiras AB, Morcillo S, Diaz-Lagares A, Sandoval J, Castellano-Castillo D, Torres E, et al. Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis. Int J Obes. 2019;43:176–88.

    Article  CAS  Google Scholar 

  36. Parrillo L, Spinelli R, Nicolo A, Longo M, Mirra P, Raciti GA, et al. Nutritional factors, DNA methylation, and risk of type 2 diabetes and obesity: perspectives and challenges. Int J Mol Sci. 2019;20.

  37. Gillberg L, Perfilyev A, Brons C, Thomasen M, Grunnet LG, Volkov P, et al. Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding. Diabetologia. 2016;59:799–812.

    Article  CAS  Google Scholar 

  38. Jacobsen SC, Brons C, Bork-Jensen J, Ribel-Madsen R, Yang B, Lara E, et al. Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men. Diabetologia. 2012;55:3341–9.

    Article  CAS  Google Scholar 

  39. Jacobsen SC, Gillberg L, Bork-Jensen J, Ribel-Madsen R, Lara E, Calvanese V, et al. Young men with low birthweight exhibit decreased plasticity of genome-wide muscle DNA methylation by high-fat overfeeding. Diabetologia. 2014;57:1154–8.

    Article  CAS  Google Scholar 

  40. Sziraki A, Tyshkovskiy A, Gladyshev VN. Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell. 2018;17:e12738.

    Article  Google Scholar 

  41. Simons MJ, Koch W, Verhulst S. Dietary restriction of rodents decreases aging rate without affecting initial mortality rate - a meta-analysis. Aging Cell. 2013;12:410–4.

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by São Paulo Research Foundation (FAPESP) (grants #2016/06470-7, #2016/05638-1, and #2015/18669-0), Centro de Investigacion Biomedica En Red (CIBERobn) and grants (PI17/01287) from the Instituto de Salud Carlos III (ISCIII), Spain, co-financed by the European Regional Development Fund (FEDER). This research/work has also been supported by MINECO grants MTM2014-52876-R and MTM2017-82724-R, and by the Xunta de Galicia (Grupos de Referencia Competitiva ED431C-2016-015 and Centro Singular de Investigación de Galicia ED431G/01), all of them through the ERDF. ABC is funded by a research contract, “Miguel Servet” (CP17/00088), from the ISCIII, co-financed by the European Regional Development Fund.

Author information

Authors and Affiliations

  1. Laboratory of Nutrigenomics Studies, Department of Health Science, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil

    C. F. Nicoletti, C. Cortes-Oliveira, N. Y. Noronha, M. A. S. Pinhel & C. B. Nonino

  2. Applied Physiology & Nutrition Research Group, School of Physical Educaton and Sport, Rheumatology Division, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

    C. F. Nicoletti, W. S. Dantas & B. Gualano

  3. Laboratory of Studies in Biochemistry and Molecular Biology, Department of Molecular Biology, São José do Rio Preto Medical School, Sao Paulo, Brazil

    M. A. S. Pinhel

  4. Department of Mathematics, MODES group, CITIC, Faculty of Science, Universidade da Coruña, A Coruña, Spain

    A. Jácome

  5. Department of Internal Medicine, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil

    J. S. Marchini

  6. Epigenomics in Endocrinology and Nutrition, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela University (USC), Santiago de Compostela, Spain

    A. B. Crujeiras

  7. CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain

    A. B. Crujeiras

Authors
  1. C. F. Nicoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Cortes-Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Y. Noronha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. A. S. Pinhel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. S. Dantas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Jácome
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. S. Marchini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B. Gualano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. B. Crujeiras
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C. B. Nonino
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors’ responsibilities were as follows: CFN, MASP, and CBN contributed to the conception and design of the study. CC-O and JSM carried out the recruitment of the patients in the study. CFN, NYN, and MASP performed the laboratory analyses. CFN, AJ, and ABC analyzed the data, performed the statistical analysis, and drafted the manuscript. CFN and CBN wrote the manuscript. WSD, BG, and ABC critically revised the manuscript. All authors have read and approved the final version of the manuscript.

Corresponding authors

Correspondence to A. B. Crujeiras or C. B. Nonino.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

This study was approved by the Hospital Ethics Committee of the School of Medicine of the University of São Paulo (CAAE:19442213.3.0000.5440) and was conducted in agreement with the Declaration of Helsinki. All participants gave informed written consent before their participation.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nicoletti, C.F., Cortes-Oliveira, C., Noronha, N.Y. et al. DNA methylation pattern changes following a short-term hypocaloric diet in women with obesity. Eur J Clin Nutr 74, 1345–1353 (2020). https://doi.org/10.1038/s41430-020-0660-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41430-020-0660-1

This article is cited by

Search

Advanced search

Quick links