REVIEW
Understanding Obesity: An Epigenetic Perspective - A Narrative Review
DOI:
https://doi.org/10.5281/zenodo.21500282Keywords:
DNA methylation, Epigenetics, Histone modifications, Non-coding RNAs, ObesityAbstract
Obesity represents a significant global health challenge with profound implications on morbidity, mortality, and healthcare costs. Increasing evidence suggests that epigenetic modifications play an important role in the etiology of obesity. This narrative review aims to provide a comprehensive synthesis of the current literature on the role of epigenetic modifications in obesity susceptibility and pathogenesis.
Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation, play critical roles in modulating gene expression patterns without altering the underlying DNA sequence. Emerging evidence suggests that dysregulation of these epigenetic processes may contribute to adipogenesis, metabolic dysfunction, and the development of obesity-related comorbidities.
This narrative review summarizes findings from epidemiological studies, animal models, and in vitro experiments to examine the complex interplay between epigenetic modifications and obesity. Furthermore, we examine the potential clinical implications of epigenetic research in obesity, including the identification of biomarkers for risk prediction, novel therapeutic targets, and personalized interventions. This review emphasizes the importance of considering epigenetic mechanisms in our understanding of the pathogenesis of obesity. By elucidating the complex interactions between genetic predisposition, environmental factors, and epigenetic regulation, it may pave the way for more targeted and effective strategies for the prevention and management of obesity.
Key words: DNA methylation, Epigenetics, Histone modifications, Non-coding RNAs, Obesity
References
[1] Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766-781. doi:10.1016/S0140-6736(14)60460-8
[2] Keller M, Svensson SIA, Rohde-Zimmermann K, et al. Genetics and epigenetics in obesity: what do we know so far? Curr Obes Rep. 2023;12(4):482-501. doi: 10.1007/s13679-023-00526-z.
[3] Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science. 2010 Oct 29;330(6004):612-6. doi: 10.1126/science.1191078.
[4] Razin A, Kantor B. DNA methylation in epigenetic control of gene expression. Prog Mol Subcell Biol.2005; 38:151-67. doi: 10.1007/3-540-27310-7_6.
[5] Nikolaeva AF, Nemtsova MV, Pustovalova AV, Sigin VO. When Genes Wear Marks: Epigenomic Modulation in the Development and Progression of Obesity. Int J Mol Sci. 2025 Aug 20;26(16):8067. doi: 10.3390/ijms26168067.
[6] Liberman N, Wang SY, Greer EL.Transgenerational epigenetic inheritance: from phenomena to molecular mechanisms. Curr Opin Neurobiol. 2019; 59:189-206. doi: 10.1016/j.conb.2019.09.012
[7] Kareta MS, Botello ZM, Ennis JJ, Chou C, Chédin F. Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L. J Biol Chem. 2006 Sep 8;281(36):25893-902. doi: 10.1074/jbc.M603140200.
[8] Jin B, Robertson KD. DNA methyltransferases, DNA damage repair, and cancer. Adv Exp Med Biol. 2013;754:3-29. doi: 10.1007/978-1-4419-9967-2_1.
[9] Illingworth RS, Bird AP (2009) CpG islands--'a rough guide'. FEBS Lett. 2009;583(11):1713-20. doi: 10.1016/j.febslet.2009.04.012
[10] Levin HL, Moran JV. Dynamic interactions between transposable elements and their hosts. Nat Rev Genet. 2011; 12(9):615-27 doi: 10.1038/nrg3030
[11] Smallwood SA, Tomizawa S, Krueger F, et al. Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet. 2011; 43(8):811-4. doi: 10.1038/ng.864
[12] Messerschmidt DM, Knowles BB, Solter D. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev.2014;28(8):812-28 doi: 10.1101/gad.234294.113
[13] Bakshi A, Herke SW, Batzer MA, Kim J. DNA methylation variation of human-specific Alu repeats. Epigenetics. 2016; 11(2):163-173 doi:10.1080/15592294.2015.1130518
[14] Dolinoy DC. The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev .2008; 66 Suppl 1(Suppl 1):S7-11. doi: 10.1111/j.1753-4887.2008.00056.x
[15] Morgan HD, Sutherland HG, Martin DI, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nat Genet. 1999; 23(3):314-318 doi:10.1038/15490
[16] Wolff GL, Roberts DW, Mountjoy KG. Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome. Physiol Genomics.1999; 1(3):151-63 doi: 10.1152/physiolgenomics.1999.1.3.151
[17] Dick KJ, Nelson CP, Tsaprouni L, Sandling JK, Aïssi D, Wahl S, Samani NJ. DNA methylation and body-mass index: a genome-wide analysis. Lancet. 2014; 383(9933):1990-8 doi: 10.1016/S0140-6736(13)62674-4
[18] Pfeiffer S, Krüger J, Maierhofer A, Böttcher Y, Klöting N, El Hajj N, Kovacs P. Hypoxia-inducible factor 3A gene expression and methylation in adipose tissue is related to adipose tissue dysfunction. Sci Rep. 2016; 6:27969 doi: 10.1038/srep27969
[19] Lesseur C, Armstrong DA, Paquette AG, Koestler DC, Padbury JF, Marsit CJ. Tissue-specific Leptin promoter DNA methylation is associated with maternal and infant perinatal factors. Mol Cell Endocrinol. 2013; 381(1-2):160-167 doi:10.1016/j.mce.2013.07.024
[20] Ács O, Péterfia B, Hollósi P, Luczay A, Török D, Szabó A. Methylation Status of CYP27B1 and IGF2 Correlate to BMI SDS in Children with Obesity Obes Facts. 2017; 10(4):353-362. doi: 10.1159/000477462
[21] Deodati A, Inzaghi E, Liguori A, et al. IGF2 methylation is associated with lipid profile in obese children. Horm Res Paediatr. 2013; 79(6):361-7. doi: 10.1159/000351707
[22] Ling C, Del Guerra S, Lupi R, et al. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia. 2008;51(4):615-22. doi: 10.1007/s00125-007-0916-5
[23] Krämer AI, Handschin C.How Epigenetic Modifications Drive the Expression and Mediate the Action of PGC-1α in the Regulation of Metabolism. Int J Mol Sci. 2019; 20(21):5449 doi: 10.3390/ijms20215449
[24] Kühnen P, Handke D, Waterland RA, et al. Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity. Cell Metab. 2016;24(3):502-509 doi: 10.1016/j.cmet.2016.08.001
[25] Na YK, Hong HS, Lee WK, Kim YH, Kim DS. Increased methylation of interleukin 6 gene is associated with obesity in Korean women. Mol Cells. 2015 May;38(5):452-6. doi: 10.14348/molcells.2015.0005.
[26] Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011; 21(3):381-95 doi: 10.1038/cr.2011.22
[27] Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693-705 doi: 10.1016/j.cell.2007.02.005
[28] Taghizadeh N, Mohammadi S, Yousefi Z, et al. Assessment of global histone acetylation in pediatric and adolescent obesity: Correlations with SIRT1 expression and metabolic-inflammatory profiles. PLoS One. 2023; 18(10):e0293217 doi: 10.1371/journal.pone.0293217
[29] Funato H, Oda S, Yokofujita J, Igarashi H, Kuroda M. Fasting and high-fat diet alter histone deacetylase expression in the medial hypothalamus. PLoS One. 2011;6(4):e18950 doi:10.1371/journal.pone.0018950
[30] Kabra DG, Pfuhlmann K, García-Cáceres C, et al. Hypothalamic leptin action is mediated by histone deacetylase. 5. Nat Commun. 2016; 7(1):10782 doi: 10.1038/ncomms10782
[31] Sun L, Marin de Evsikova C, Bian K, et al (2018) .Programming and Regulation of Metabolic Homeostasis by HDAC11. EBioMedicine. 2018; 33:157-168. doi: 10.1016/j.ebiom.2018.06.025
[32] Chatterjee TK, Basford JE, Knoll E, et al. HDAC9 knockout mice are protected from adipose tissue dysfunction and systemic metabolic disease during high-fat feeding. Diabetes. 2014; 263(1):176-87 doi: 10.2337/db13-1148
[33] Panni S, Lovering RC, Porras P, Orchard S. Non-coding RNA regulatory networks. Biochim Biophys Acta Gene Regul Mech. 2020; 1863(6):194417 doi:10.1016/j.bbagrm.2019.194417
[34] Mourão A, Varrot A, Mackereth CD, Cusack S, Sattler M. Structure and RNA recognition by the snRNA and snoRNA transport factor PHAX. RNA. 2010; 16(6):1205-1216 doi:10.1261/rna.2009910
[35] Keller P, Gburcik V, Petrovic N, et al. Gene-chip studies of adipogenesis-regulated microRNAs in mouse primary adipocytes and human obesity. BMC Endocr Disord. 2011; 11:7 doi: 10.1186/1472-6823-11-7
[36] Kristensen MM, Davidsen PK, Vigelsø A, et al. miRNAs in human subcutaneous adipose tissue: Effects of weight loss induced by hypocaloric diet and exercise. Obesity (Silver Spring). 2017;25(3):572-580 doi: 10.1002/oby.21765
[37] Esau C, Kang X, Peralta E, et al.MicroRNA-143 regulates adipocyte differentiation. J Biol Chem. 2004; 279(50):52361-5 doi: 10.1074/jbc.C400438200
[38] Kim YJ, Hwang SJ, Bae YC, Jung JS. MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue. Stem Cells. 2009; 27(12):3093-3102 doi:10.1002/stem.235
[39] Seeger T, Fischer A, Muhly-Reinholz M, Zeiher AM, Dimmeler S. Long-term inhibition of miR-21 leads to reduction of obesity in db/db mice. Obesity (Silver Spring). 2014; 22(11):2352-2360 doi:10.1002/oby.20852
[40] Huang S, Wang S, Bian C, et al. Upregulation of miR-22 promotes osteogenic differentiation and inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells by repressing HDAC6 protein expression. Stem Cells Dev.2012; 21(13):2531-40 doi: 10.1089/scd.2012.0014
[41] Crépin D, Benomar Y, Riffault L, Amine H, Gertler A, Taouis M. The over-expression of miR-200a in the hypothalamus of ob/ob mice is linked to leptin and insulin signaling impairment. Mol Cell Endocrinol. 2014; 384(1-2):1-11 doi:10.1016/j.mce.2013.12.016
[42] Pan S, Yang X, Jia Y, Li R, Zhao R. Microvesicle-shuttled miR-130b reduces fat deposition in recipient primary cultured porcine adipocytes by inhibiting PPAR-g expression. J Cell Physiol. 2014; 229(5):631-639 doi:10.1002/jcp.24486
[43] Li D, Liu Y, Gao W, et al. Inhibition of miR-324-5p increases PM20D1-mediated white and brown adipose loss and reduces body weight in juvenile mice. Eur J Pharmacol. 2019; 863:172708 doi: 10.1016/j.ejphar.2019.172708
[44] Sun J, Ruan Y, Wang M, et al. Differentially expressed circulating LncRNAs and mRNA identified by microarray analysis in obese subjects. Sci Rep. 2016; 6:35421 doi: 10.1038/srep35421
[45] Huang Y, Zheng Y, Jin C, Li X, Jia L, Li W. Long Non-coding RNA H19 Inhibits Adipocyte Differentiation of Bone Marrow Mesenchymal Stem Cells through Epigenetic Modulation of Histone Deacetylases. Sci Rep. 2016; 6:28897doi:10.1038/srep28897
[46] Schmidt E, Dhaouadi I, Gaziano I, et al. LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat. Nat Commun. 2018; 9(1):3622 doi: 10.1038/s41467-018-05933-8
[47] Divoux A, Karastergiou K, Xie H, et al. Identification of a novel lncRNA in gluteal adipose tissue and evidence for its positive effect on preadipocyte differentiation. Obesity (Silver Spring). 2014; 22(8):1781-5. doi: 10.1002/oby.20793
[48] Saavedra LPJ, Piovan S, Moreira VM, Gonçalves GD, Ferreira ARO, Ribeiro MVG, Peres MNC, Almeida DL, Raposo SR, da Silva MC, Barbosa LF, de Freitas Mathias PC. Epigenetic programming for obesity and noncommunicable disease: From womb to tomb. Rev Endocr Metab Disord. 2024 Apr;25(2):309-324. doi: 10.1007/s11154-023-09854-w.
[49] 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
[50] Hales CN, Barker DJ, Clark PM et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ.1991; 303(6809):1019-22 doi: 10.1136/bmj.303.6809.1019
[51].Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab. 2000; 279(1):E83-E87 doi:10.1152/ajpendo.2000.279.1.E83
[52] Roseboom T, de Rooij S, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev.2006; 82(8):485-91 doi: 10.1016/j.earlhumdev.2006.07.001
[53] Godfrey KM, Sheppard A, Gluckman PD, et al. Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes. 2011; 60(5):1528-34 doi: 10.2337/db10-0979
[54] Vucetic Z, Reyes TM. Central dopaminergic circuitry controlling food intake and reward: implications for the regulation of obesity. Wiley Interdiscip Rev Syst Biol Med. 2010; 2(5):577-593 doi: 10.1002/wsbm.77
[55] Gali Ramamoorthy T, Allen TJ, Davies A, et al. Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats. Int J Obes (Lond). 2018; 42(8):1431-1444 doi: 10.1038/s41366-018-0094-1
[56] Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012; 148(6):1145-59 doi: 10.1016/j.cell.2012.02.035
[57] Stoccoro A, Coppedè F. Mitochondrial DNA Methylation and Human Diseases. Int J Mol Sci. 2021; 22(9):4594 doi: 10.3390/ijms22094594
[58] Gillberg L, Jacobsen SC, Rönn T, Brøns C, Vaag A . PPARGC1A DNA methylation in subcutaneous adipose tissue in low birth weight subjects--impact of 5 days of high-fat overfeeding. Metabolism. 2014; 63(2):263-271 doi:10.1016/j.metabol.2013.10.003
[59] Tung PW, Thaker VV, Gallagher D, Kupsco A. Mitochondrial Health Markers and Obesity-Related Health in Human Population Studies: A Narrative Review of Recent Literature. Curr Obes Rep. 2024 Dec;13(4):724-738. doi: 10.1007/s13679-024-00588-7.
[60] Martínez-Reyes I, Diebold LP, Kong H, et al.TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions. Mol Cell. 2016; 61(2):199-209 doi: 10.1016/j.molcel.2015.12.002
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