Revista de la Sociedad Española de Cirugía de Obesidad y Metabólica y de la Sociedad Española para el Estudio de la Obesidad
"Bariátrica & Metabólica Ibero-Americana"
Español Inglés

Aplicabilidad clínica de la epigenética en obesidad

Artículos de Revisión

Ana Belén Crujeiras Martínez

Organismos colaboradores:
NA

DOI: 10.53435/funj.00992

Resumen:
Los últimos hallazgos en el campo de la epigenética han puesto de manifiesto que la obesidad, al igual que otras enfermedades metabólicas, está regulada por mecanismos epigenéticos y que determinadas terapias de uso actual en la clínica, como la cirugía bariátrica y las intervenciones nutricionales para la pérdida de peso, son capaces de revertir el epigenoma relacionado con la obesidad. A pesar de las evidencias sobre el papel de la regulación epigenética en obesidad, actualmente no se conoce si los mecanismos epigenéticos asociados a la obesidad son causa o consecuencia del exceso de adiposidad. Sin embargo, existen evidencias suficientes que avalan la utilidad del estudio de estos mecanismos epigenéticos como herramientas en la detección de la predisposición al desarrollo de la obesidad y sus enfermedades asociadas y también pueden actuar como posibles dianas terapéuticas, útiles en el campo de la nutriepigenómica y la farcoepigenómica. En esta revisión se expondrá la evidencia científica más actualizada sobre la implicación de la regulación epigenética en el campo de la obesidad, con un especial énfasis en las marcas de metilación del ADN y su utilidad en la prevención, el diagnóstico y tratamiento de la obesidad y sus enfermedades asociadas.

Palabras Clave:
epigenetica, tejido adiposo, compuestos bioactivos, medicina personalizada

Bibliografía:
  1. Izquierdo AG, Crujeiras AB. Epigenetic biomarkers in metabolic syndrome and obesity. In: Prognostic Epigenetics. Elsevier; 2019:269-287. doi:10.1016/B978-0-12-814259-2.00011-X
  2. Pillon NJ, Loos RJF, Marshall SM, Zierath JR. Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care. Cell. 2021;184(6):1530-1544. doi:10.1016/j.cell.2021.02.012
  3. Carless MA, Kulkarni H, Kos MZ, et al. Genetic Effects on DNA Methylation and Its Potential Relevance for Obesity in Mexican Americans. PLoS One. 2013;8(9):e73950. doi:10.1371/journal.pone.0073950
  4. Xu X, Su S, Barnes VA, et al. A genome-wide methylation study on obesity. Epigenetics. 2013;8(5):522-533. doi:10.4161/epi.24506
  5. Dick KJ, Nelson CP, Tsaprouni L, et al. DNA methylation and body-mass index: a genome-wide analysis. The Lancet. 2014;383(9933):1990-1998. doi:10.1016/S0140-6736(13)62674-4
  6. Milagro FI, Gómez-Abellán P, Campión J, Martínez JA, Ordovás JM, Garaulet M. CLOCK, PER2 and BMAL1 DNA Methylation: Association with Obesity and Metabolic Syndrome Characteristics and Monounsaturated Fat Intake. Chronobiol Int. 2012;29(9):1180-1194. doi:10.3109/07420528.2012.719967
  7. Skinner MK, Manikkam M, Guerrero-Bosagna C. Epigenetic transgenerational actions of environmental factors in disease etiology. Trends in Endocrinology & Metabolism. 2010;21(4):214-222. doi:10.1016/j.tem.2009.12.007
  8. Skinner MK, Manikkam M, Tracey R, Guerrero-Bosagna C, Haque M, Nilsson EE. Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity. BMC Med. 2013;11(1):228. doi:10.1186/1741-7015-11-228
  9. Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations. PLoS One. 2013;8(1):e55387. doi:10.1371/journal.pone.0055387
  10. Tracey R, Manikkam M, Guerrero-Bosagna C, Skinner MK. Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. Reproductive Toxicology. 2013;36:104-116. doi:10.1016/j.reprotox.2012.11.011
  11. Barres R, Kirchner H, Rasmussen M, et al. Weight Loss after Gastric Bypass Surgery in Human Obesity Remodels Promoter Methylation. Cell Rep. 2013;3(4):1020-1027. doi:10.1016/j.celrep.2013.03.018
  12. Rönn T, Volkov P, Davegårdh C, et al. A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue. PLoS Genet. 2013;9(6):e1003572. doi:10.1371/journal.pgen.1003572
  13. Nitert MD, Dayeh T, Volkov P, et al. Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes. Diabetes. 2012;61(12):3322-3332. doi:10.2337/db11-1653
  14. Milagro FI, Campión J, Cordero P, et al. A dual epigenomic approach for the search of obesity biomarkers: DNA methylation in relation to diet‐induced weight loss. The FASEB Journal. 2011;25(4):1378-1389. doi:10.1096/fj.10-170365
  15. Bouchard L, Rabasa-Lhoret R, Faraj M, et al. Differential epigenomic and transcriptomic responses in subcutaneous adipose tissue between low and high responders to caloric restriction. Am J Clin Nutr. 2010;91(2):309-320. doi:10.3945/ajcn.2009.28085
  16. Crujeiras AB, Campion J, Díaz-Lagares A, et al. Association of weight regain with specific methylation levels in the NPY and POMC promoters in leukocytes of obese men: A translational study. Regul Pept. 2013;186:1-6. doi:10.1016/j.regpep.2013.06.012
  17. Contreras RE, Schriever SC, Pfluger PT. Physiological and Epigenetic Features of Yoyo Dieting and Weight Control. Front Genet. 2019;10. doi:10.3389/fgene.2019.01015
  18. Núñez-Sánchez MÁ, Jiménez-Méndez A, Suárez-Cortés M, et al. Inherited Epigenetic Hallmarks of Childhood Obesity Derived from Prenatal Exposure to Obesogens. Int J Environ Res Public Health. 2023;20(6):4711. doi:10.3390/ijerph20064711
  19. Iglesia Altaba I, Larqué E, Mesa MD, et al. Early Nutrition and Later Excess Adiposity during Childhood: A Narrative Review. Horm Res Paediatr. 2022;95(2):112-119. doi:10.1159/000520811
  20. ZOU C, SHAO J. Role of adipocytokines in obesity-associated insulin resistance. J Nutr Biochem. 2008;19(5):277-286. doi:10.1016/j.jnutbio.2007.06.006
  21. Catalán V, Gómez-Ambrosi J, Rodríguez A, Salvador J, Frühbeck G. Adipokines in the treatment of diabetes mellitus and obesity. Expert Opin Pharmacother. 2009;10(2):239-254. doi:10.1517/14656560802618811
  22. Roca-Rivada A, Alonso J, Al-Massadi O, et al. Secretome analysis of rat adipose tissues shows location-specific roles for each depot type. J Proteomics. 2011;74(7):1068-1079. doi:10.1016/j.jprot.2011.03.010
  23. Kershaw EE, Flier JS. Adipose Tissue as an Endocrine Organ. J Clin Endocrinol Metab. 2004;89(6):2548-2556. doi:10.1210/jc.2004-0395
  24. Dizdar Ö, Alyamaç E. Obesity: an endocrine tumor? Med Hypotheses. 2004;63(5):790-792. doi:10.1016/j.mehy.2004.01.046
  25. Crujeiras AB, Parra D, Goyenechea E, Abete I, González-Muniesa P, Martínez JA. Energy restriction in obese subjects impact differently two mitochondrial function markers. J Physiol Biochem. 2008;64(3):211-219. doi:10.1007/BF03178844
  26. Vincent HK, Taylor AG. Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes. 2006;30(3):400-418. doi:10.1038/sj.ijo.0803177
  27. Gut P, Verdin E. The nexus of chromatin regulation and intermediary metabolism. Nature. 2013;502(7472):489-498. doi:10.1038/nature12752
  28. Franco R, Schoneveld O, Georgakilas AG, Panayiotidis MI. Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett. 2008;266(1):6-11. doi:10.1016/j.canlet.2008.02.026
  29. Wachsman JT. DNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 1997;375(1):1-8. doi:10.1016/S0027-5107(97)00003-1
  30. Govindarajan B, Klafter R, Miller MS, et al. Reactive Oxygen-induced Carcinogenesis Causes Hypermethylation of p16Ink4a and Activation of MAP Kinase. Molecular Medicine. 2002;8(1):1-8. doi:10.1007/BF03401997
  31. Lim SO, Gu JM, Kim MS, et al. Epigenetic Changes Induced by Reactive Oxygen Species in Hepatocellular Carcinoma: Methylation of the E-cadherin Promoter. Gastroenterology. 2008;135(6):2128-2140.e8. doi:10.1053/j.gastro.2008.07.027
  32. Simone NL, Soule BP, Ly D, et al. Ionizing Radiation-Induced Oxidative Stress Alters miRNA Expression. PLoS One. 2009;4(7):e6377. doi:10.1371/journal.pone.0006377
  33. Mateescu B, Batista L, Cardon M, et al. miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med. 2011;17(12):1627-1635. doi:10.1038/nm.2512
  34. Rajendran R, Garva R, Krstic-Demonacos M, Demonacos C. Sirtuins: Molecular Traffic Lights in the Crossroad of Oxidative Stress, Chromatin Remodeling, and Transcription. J Biomed Biotechnol. 2011;2011:1-17. doi:10.1155/2011/368276
  35. Milagro FI, Mansego ML, De Miguel C, Martínez JA. Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives. Mol Aspects Med. 2013;34(4):782-812. doi:10.1016/j.mam.2012.06.010
  36. Heard E, Martienssen RA. Transgenerational Epigenetic Inheritance: Myths and Mechanisms. Cell. 2014;157(1):95-109. doi:10.1016/j.cell.2014.02.045
  37. Guerrero-Bosagna C, Savenkova M, Haque MdM, Nilsson E, Skinner MK. Environmentally Induced Epigenetic Transgenerational Inheritance of Altered Sertoli Cell Transcriptome and Epigenome: Molecular Etiology of Male Infertility. PLoS One. 2013;8(3):e59922. doi:10.1371/journal.pone.0059922
  38. Pembrey M, Saffery R, Bygren LO. Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J Med Genet. 2014;51(9):563-572. doi:10.1136/jmedgenet-2014-102577
  39. Skinner MK, Guerrero-Bosagna C. Role of CpG deserts in the epigenetic transgenerational inheritance of differential DNA methylation regions. BMC Genomics. 2014;15(1):692. doi:10.1186/1471-2164-15-692
  40. Fullston T, Palmer NO, Owens JA, Mitchell M, Bakos HW, Lane M. Diet-induced paternal obesity in the absence of diabetes diminishes the reproductive health of two subsequent generations of mice. Human Reproduction. 2012;27(5):1391-1400. doi:10.1093/humrep/des030
  41. Fullston T, Teague EMCO, Palmer NO, et al. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F 2 generation and alters the transcriptional profile of testis and sperm microRNA content. The FASEB Journal. 2013;27(10):4226-4243. doi:10.1096/fj.12-224048
  42. Ge ZJ, Luo SM, Lin F, et al. DNA Methylation in Oocytes and Liver of Female Mice and Their Offspring: Effects of High-Fat-Diet–Induced Obesity. Environ Health Perspect. 2014;122(2):159-164. doi:10.1289/ehp.1307047
  43. Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet. 2012;13(10):679-692. doi:10.1038/nrg3270
  44. Andersen GS, Thybo T, Cederberg H, et al. The DEXLIFE study methods: Identifying novel candidate biomarkers that predict progression to type 2 diabetes in high risk individuals. Diabetes Res Clin Pract. 2014;106(2):383-389. doi:10.1016/j.diabres.2014.07.025
  45. Zaina S, Heyn H, Carmona FJ, et al. DNA Methylation Map of Human Atherosclerosis. Circ Cardiovasc Genet. 2014;7(5):692-700. doi:10.1161/CIRCGENETICS.113.000441
  46. Ordovás JM, Smith CE. Epigenetics and cardiovascular disease. Nat Rev Cardiol. 2010;7(9):510-519. doi:10.1038/nrcardio.2010.104
  47. Sanchez-Mut J V., Aso E, Panayotis N, et al. DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease. Brain. 2013;136(10):3018-3027. doi:10.1093/brain/awt237
  48. Urdinguio RG, Sanchez-Mut J V, Esteller M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 2009;8(11):1056-1072. doi:10.1016/S1474-4422(09)70262-5
  49. Glossop JR, Glossop JR, Emes RD, et al. Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associated methylation changes that are distinct to individual T- and B-lymphocyte populations. Epigenetics. 2014;9(9):1228-1237. doi:10.4161/epi.29718
  50. Hamilton JP. Epigenetics: Principles and Practice. Digestive Diseases. 2011;29(2):130-135. doi:10.1159/000323874
  51. Crujeiras AB, Diaz-Lagares A. DNA Methylation in Obesity and Associated Diseases. In: Epigenetic Biomarkers and Diagnostics. Elsevier; 2016:313-329. doi:10.1016/B978-0-12-801899-6.00016-4
  52. Rodriguez-Casanova A, Costa-Fraga N, Castro-Carballeira C, et al. A genome-wide cell-free DNA methylation analysis identifies an episignature associated with metastatic luminal B breast cancer. Front Cell Dev Biol. 2022;10. doi:10.3389/fcell.2022.1016955
  53. Reiner A, Bakulski KM, Fisher JD, et al. Sex-specific DNA methylation in saliva from the multi-ethnic Future of Families and Child Wellbeing Study. Epigenetics. 2023;18(1). doi:10.1080/15592294.2023.2222244
  54. Rapado‐González Ó, Costa‐Fraga N, Bao‐Caamano A, et al. Genome‐wide <scp>DNA</scp> methylation profiling in tongue squamous cell carcinoma. Oral Dis. Published online December 2, 2022. doi:10.1111/odi.14444
  55. Oberhofer A, Bronkhorst AJ, Uhlig C, Ungerer V, Holdenrieder S. Tracing the Origin of Cell-Free DNA Molecules through Tissue-Specific Epigenetic Signatures. Diagnostics. 2022;12(8):1834. doi:10.3390/diagnostics12081834
  56. Rodriguez-Casanova A, Costa-Fraga N, Bao-Caamano A, López-López R, Muinelo-Romay L, Diaz-Lagares A. Epigenetic Landscape of Liquid Biopsy in Colorectal Cancer. Front Cell Dev Biol. 2021;9. doi:10.3389/fcell.2021.622459
  57. Izquierdo AG, Lorenzo PM, Crujeiras AB. Epigenetics and precision medicine in diabetes and obesity prevention and management. In: Epigenetics in Precision Medicine. Elsevier; 2022:327-346. doi:10.1016/B978-0-12-823008-4.00012-3
  58. Crujeiras AB, Diaz-Lagares A, Moreno-Navarrete JM, et al. Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects. Translational Research. 2016;178:13-24.e5. doi:10.1016/j.trsl.2016.07.002
  59. Arpón A, Milagro FI, Ramos-Lopez O, et al. Epigenome-wide association study in peripheral white blood cells involving insulin resistance. Sci Rep. 2019;9(1):2445. doi:10.1038/s41598-019-38980-2
  60. Akinyemiju T, Do AN, Patki A, et al. Epigenome-wide association study of metabolic syndrome in African-American adults. Clin Epigenetics. 2018;10(1):49. doi:10.1186/s13148-018-0483-2
  61. Kurokawa S, Kobori T, Yoneda M, et al. Identification of differentially methylated regions associated with both liver fibrosis and hepatocellular carcinoma. BMC Gastroenterol. 2024;24(1):57. doi:10.1186/s12876-024-03149-3
  62. Crujeiras AB, Diaz-Lagares A, Stefansson OA, et al. Obesity and menopause modify the epigenomic profile of breast cancer. Endocr Relat Cancer. Published online July 2017:351-363. doi:10.1530/ERC-16-0565
  63. Crujeiras AB, Morcillo S, Diaz-Lagares A, et al. Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis. Int J Obes. 2019;43(1):176-188. doi:10.1038/s41366-018-0065-6
  64. Ramos-Lopez O, Riezu-Boj JI, Milagro FI, Alfredo Martinez J. Association of Methylation Signatures at Hepatocellular Carcinoma Pathway Genes with Adiposity and Insulin Resistance Phenotypes. Nutr Cancer. 2019;71(5):840-851. doi:10.1080/01635581.2018.1531136
  65. Izquierdo AG, Carreira MC, Boughanem H, et al. Adipose tissue and blood leukocytes ACE2 DNA methylation in obesity and after weight loss. Eur J Clin Invest. 2022;52(2). doi:10.1111/eci.13685
  66. Crujeiras AB, Goyenechea E, Abete I, et al. Weight Regain after a Diet-Induced Loss Is Predicted by Higher Baseline Leptin and Lower Ghrelin Plasma Levels. J Clin Endocrinol Metab. 2010;95(11):5037-5044. doi:10.1210/jc.2009-2566
  67. Perez-Cornago A, Mansego M, Zulet M, Martinez J. DNA Hypermethylation of the Serotonin Receptor Type-2A Gene Is Associated with a Worse Response to a Weight Loss Intervention in Subjects with Metabolic Syndrome. Nutrients. 2014;6(6):2387-2403. doi:10.3390/nu6062387
  68. Garcia-Lacarte M, Milagro FI, Zulet MA, Martinez JA, Mansego ML. LINE-1 methylation levels, a biomarker of weight loss in obese subjects, are influenced by dietary antioxidant capacity. Redox Report. 2016;21(2):67-74. doi:10.1179/1351000215Y.0000000029
  69. Crujeiras AB, Campion J, Díaz-Lagares A, et al. Association of weight regain with specific methylation levels in the NPY and POMC promoters in leukocytes of obese men: A translational study. Regul Pept. 2013;186:1-6. doi:10.1016/j.regpep.2013.06.012
  70. Nicoletti CF, Pinhel MS, Noronha NY, Jácome A, Crujeiras AB, Nonino CB. Association of MFSD3 promoter methylation level and weight regain after gastric bypass: Assessment for 3 y after surgery. Nutrition. 2020;70:110499. doi:10.1016/j.nut.2019.04.010
  71. Chen YS, Wu R, Yang X, et al. Inhibiting DNA methylation switches adipogenesis to osteoblastogenesis by activating Wnt10a. Sci Rep. 2016;6(1):25283. doi:10.1038/srep25283
  72. Sakamoto H, Kogo Y, Ohgane J, et al. Sequential changes in genome-wide DNA methylation status during adipocyte differentiation. Biochem Biophys Res Commun. 2008;366(2):360-366. doi:10.1016/j.bbrc.2007.11.137
  73. Shore A, Karamitri A, Kemp P, Speakman JR, Lomax MA. Role of Ucp1 enhancer methylation and chromatin remodelling in the control of Ucp1 expression in murine adipose tissue. Diabetologia. 2010;53(6):1164-1173. doi:10.1007/s00125-010-1701-4
  74. Liang J, Jia Y, Yu H, et al. 5-Aza-2′-Deoxycytidine Regulates White Adipocyte Browning by Modulating miRNA-133a/Prdm16. Metabolites. 2022;12(11):1131. doi:10.3390/metabo12111131
  75. Wu YL, Lin ZJ, Li CC, et al. Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study. Signal Transduct Target Ther. 2023;8(1):98. doi:10.1038/s41392-023-01333-7
  76. Ling C, Rönn T. Epigenetics in Human Obesity and Type 2 Diabetes. Cell Metab. 2019;29(5):1028-1044. doi:10.1016/j.cmet.2019.03.009
  77. Izquierdo AG, Crujeiras AB. Obesity-Related Epigenetic Changes After Bariatric Surgery. Front Endocrinol (Lausanne). 2019;10:232. doi:10.3389/fendo.2019.00232
  78. Crujeiras AB, Malagón MM, Casanueva FF, eds. Metodología en investigación morfofuncional aplicada a la enfermedad metabólica crónica adiposa. In: Valoración Morfofuncional En La Enfermedad Metabólica Crónica Adiposa. ; 2024:135-144.

Texto Completo:
PDF

ISSN

2250-737X

Estamos indexados y adscritos a

Directory Open Journal Acces, Journaltocs.ac.uk, Latindex, Dulcinea, ISSN.org, LIS Cuba.

Artículos más leídos
Licencia creative commons
Licencia creative commons

Atribución-NoComercial 4.0 Internacional (CC BY-NC 4.0)
https://creativecommons.org/ licenses/by-nc/4.0/deed.es

BMI Journal
SECO - SEEDO

Una cookie o galleta informática es un pequeño archivo de información que se guarda en su navegador cada vez que visita nuestra página web. La utilidad de las cookies es guardar el historial de su actividad en nuestra página web, de manera que, cuando la visite nuevamente, ésta pueda identificarle y configurar el contenido de la misma en base a sus hábitos de navegación, identidad y preferencias. Las cookies pueden ser aceptadas, rechazadas, bloqueadas y borradas, según desee. Ello podrá hacerlo mediante las opciones disponibles en la presente ventana o a través de la configuración de su navegador, según el caso. En caso de que rechace las cookies no podremos asegurarle el correcto funcionamiento de las distintas funcionalidades de nuestra página web. Más información en el apartado “POLÍTICA DE COOKIES” de nuestra página web.

Aceptar Rechazar