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Published in: BMC Medical Genetics 1/2018

Open Access 01-12-2018 | Research article

Altered DNA methylation in liver and adipose tissues derived from individuals with obesity and type 2 diabetes

Authors: Francisco Barajas-Olmos, Federico Centeno-Cruz, Carlos Zerrweck, Iván Imaz-Rosshandler, Angélica Martínez-Hernández, Emilio J. Cordova, Claudia Rangel-Escareño, Faustino Gálvez, Armando Castillo, Hernán Maydón, Francisco Campos, Diana Gabriela Maldonado-Pintado, Lorena Orozco

Published in: BMC Medical Genetics | Issue 1/2018

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Abstract

Background

Obesity is a well-recognized risk factor for insulin resistance and type 2 diabetes (T2D), although the precise mechanisms underlying the relationship remain unknown. In this study we identified alterations of DNA methylation influencing T2D pathogenesis, in subcutaneous and visceral adipose tissues, liver, and blood from individuals with obesity.

Methods

The study included individuals with obesity, with and without T2D. From these patients, we obtained samples of liver tissue (n = 16), visceral and subcutaneous adipose tissues (n = 30), and peripheral blood (n = 38). We analyzed DNA methylation using Illumina Infinium Human Methylation arrays, and gene expression profiles using HumanHT-12 Expression BeadChip Arrays.

Results

Analysis of DNA methylation profiles revealed several loci with differential methylation between individuals with and without T2D, in all tissues. Aberrant DNA methylation was mainly found in the liver and visceral adipose tissue. Gene ontology analysis of genes with altered DNA methylation revealed enriched terms related to glucose metabolism, lipid metabolism, cell cycle regulation, and response to wounding. An inverse correlation between altered methylation and gene expression in the four tissues was found in a subset of genes, which were related to insulin resistance, adipogenesis, fat storage, and inflammation.

Conclusions

Our present findings provide additional evidence that aberrant DNA methylation may be a relevant mechanism involved in T2D pathogenesis among individuals with obesity.
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Literature
6.
go back to reference Stefan N, Häring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1:152–62.CrossRefPubMed Stefan N, Häring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1:152–62.CrossRefPubMed
9.
go back to reference Arner P, Sahlqvist A-S, Sinha I, Xu H, Yao X, Waterworth D, et al. The epigenetic signature of systemic insulin resistance in obese women. Diabetologia. 2016;59:2393–405.CrossRefPubMedPubMedCentral Arner P, Sahlqvist A-S, Sinha I, Xu H, Yao X, Waterworth D, et al. The epigenetic signature of systemic insulin resistance in obese women. Diabetologia. 2016;59:2393–405.CrossRefPubMedPubMedCentral
10.
go back to reference Macartney-coxson D, Benton MC, Blick R, Stubbs RS, Hagan RD, Langston MA, Genome-wide DNA. Methylation analysis reveals loci that distinguish different types of adipose tissue in obese individuals. Clin Epigenetics. 2017:1–21. Macartney-coxson D, Benton MC, Blick R, Stubbs RS, Hagan RD, Langston MA, Genome-wide DNA. Methylation analysis reveals loci that distinguish different types of adipose tissue in obese individuals. Clin Epigenetics. 2017:1–21.
11.
go back to reference Guénard F, Tchernof A, Deshaies Y, Biron S, Lescelleur O, Biertho L, et al. Genetic regulation of differentially methylated genes in visceral adipose tissue of severely obese men discordant for the metabolic syndrome. Transl Res. 2017;184:1–11.e2. Guénard F, Tchernof A, Deshaies Y, Biron S, Lescelleur O, Biertho L, et al. Genetic regulation of differentially methylated genes in visceral adipose tissue of severely obese men discordant for the metabolic syndrome. Transl Res. 2017;184:1–11.e2.
12.
go back to reference Crujeiras AB, Sandoval J, Milagro FI. DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern : a genome-wide analysis from non- obese and obese patients. Nat. Publ. Gr. 2017:1–13. Available from: https://doi.org/10.1038/srep41903 Crujeiras AB, Sandoval J, Milagro FI. DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern : a genome-wide analysis from non- obese and obese patients. Nat. Publ. Gr. 2017:1–13. Available from: https://​doi.​org/​10.​1038/​srep41903
15.
go back to reference Rönn T, Volkov P, Davegårdh 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(6):e1003572. Rönn T, Volkov P, Davegårdh 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(6):e1003572.
17.
go back to reference 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. Available from: http://dx.doi.org/10.1371/journal.pone.0051302%5Cnhttp://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0051302&representation=PDF.CrossRefPubMedPubMedCentral 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. Available from: http://​dx.​doi.​org/​10.​1371/​journal.​pone.​0051302%5Cnhttp://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0051302&representation=PDF.CrossRefPubMedPubMedCentral
18.
20.
go back to reference Crujeiras AB, Diaz-Lagares A, Moreno-Navarrete JM, Sandoval J, Hervas D, Gomez A, et al. Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects. Transl Res. 2016;178:13–24.e5. Available from: https://doi.org/10.1016/j.trsl.2016.07.002. Crujeiras AB, Diaz-Lagares A, Moreno-Navarrete JM, Sandoval J, Hervas D, Gomez A, et al. Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects. Transl Res. 2016;178:13–24.e5. Available from: https://​doi.​org/​10.​1016/​j.​trsl.​2016.​07.​002.
21.
go back to reference Diabetes DOF. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2013;36:67–74.CrossRef Diabetes DOF. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2013;36:67–74.CrossRef
22.
go back to reference Du P, Kibbe WA, Lin SM. lumi: A pipeline for processing Illumina microarray. Bioinformatics. 2008;24:1547–8.CrossRefPubMed Du P, Kibbe WA, Lin SM. lumi: A pipeline for processing Illumina microarray. Bioinformatics. 2008;24:1547–8.CrossRefPubMed
23.
go back to reference Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.CrossRefPubMedPubMedCentral Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.CrossRefPubMedPubMedCentral
30.
go back to reference Benton MC, Johnstone A, Eccles D, Harmon B, Hayes MT, Lea RA, et al. An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss. Genome Biol. 2015;16:8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25651499%5Cn, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4301800. Benton MC, Johnstone A, Eccles D, Harmon B, Hayes MT, Lea RA, et al. An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss. Genome Biol. 2015;16:8. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25651499%5Cn, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4301800.
33.
go back to reference Kuramoto J, Arai E, Tian Y, Funahashi N, Hiramoto M, Nammo T, et al. Genome-wide DNA methylation analysis during non-alcoholic steatohepatitis-related multistage hepatocarcinogenesis: comparison with hepatitis virus-related carcinogenesis. Carcinogenesis. 2017;38:261–70.CrossRefPubMed Kuramoto J, Arai E, Tian Y, Funahashi N, Hiramoto M, Nammo T, et al. Genome-wide DNA methylation analysis during non-alcoholic steatohepatitis-related multistage hepatocarcinogenesis: comparison with hepatitis virus-related carcinogenesis. Carcinogenesis. 2017;38:261–70.CrossRefPubMed
34.
go back to reference de Mello VD, Matte A, Perfilyev A, Männistö V, Rönn T, Nilsson E, et al. Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action. Epigenetics. 2017;12:287–95.CrossRefPubMed de Mello VD, Matte A, Perfilyev A, Männistö V, Rönn T, Nilsson E, et al. Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action. Epigenetics. 2017;12:287–95.CrossRefPubMed
35.
go back to reference Sala P, Susana R, De Miranda M, Fonseca DC, Ravacci GR, Waitzberg DL, et al. Tissue - specific methylation profile in obese patients with type 2 diabetes before and after roux - en - Y gastric bypass. Diabetol Metab Syndr BioMed Central. 2017:1–15. Sala P, Susana R, De Miranda M, Fonseca DC, Ravacci GR, Waitzberg DL, et al. Tissue - specific methylation profile in obese patients with type 2 diabetes before and after roux - en - Y gastric bypass. Diabetol Metab Syndr BioMed Central. 2017:1–15.
42.
go back to reference Baranova A, Collantes R, Gowder SJ, Elariny H, Schlauch K, Younoszai A, et al. Obesity-related differential gene expression in the visceral adipose tissue. Obes Surg. 2005;15:758–65.CrossRefPubMed Baranova A, Collantes R, Gowder SJ, Elariny H, Schlauch K, Younoszai A, et al. Obesity-related differential gene expression in the visceral adipose tissue. Obes Surg. 2005;15:758–65.CrossRefPubMed
43.
go back to reference Elbein SC, Kern PA, Rasouli N, Yao-Borengasser A, Sharma NK, Das SK. Global Gene Expression Profiles of Subcutaneous Adipose and Muscle From Glucose-Tolerant, Insulin-Sensitive, and Insulin-Resistant Individuals Matched for BMI. Diabetes. 2011;60(3):1019–29. doi:https://doi.org/10.2337/db10-1270. Elbein SC, Kern PA, Rasouli N, Yao-Borengasser A, Sharma NK, Das SK. Global Gene Expression Profiles of Subcutaneous Adipose and Muscle From Glucose-Tolerant, Insulin-Sensitive, and Insulin-Resistant Individuals Matched for BMI. Diabetes. 2011;60(3):1019–29. doi:https://​doi.​org/​10.​2337/​db10-1270
44.
go back to reference Wang M, Wang XC, Zhao L, Zhang Y, Yao LL, Lin Y, et al. Oligonucleotide microarray analysis reveals dysregulation of energy-related metabolism in insulin-sensitive tissues of type 2 diabetes patients. Genet Mol Res. 2014;13:4494–504.CrossRefPubMed Wang M, Wang XC, Zhao L, Zhang Y, Yao LL, Lin Y, et al. Oligonucleotide microarray analysis reveals dysregulation of energy-related metabolism in insulin-sensitive tissues of type 2 diabetes patients. Genet Mol Res. 2014;13:4494–504.CrossRefPubMed
46.
go back to reference Chen CZ, Zhu YN, Chai ML, Dai LS, Gao Y, Jiang H, et al. AMFR gene silencing inhibits the differentiation of porcine preadipocytes. Genet Mol Res. 2016;15:1–11. Chen CZ, Zhu YN, Chai ML, Dai LS, Gao Y, Jiang H, et al. AMFR gene silencing inhibits the differentiation of porcine preadipocytes. Genet Mol Res. 2016;15:1–11.
47.
go back to reference Patlaka C, Becker H, Norgård M, Paulie S, Nordvall-Bodell A, Lång P, et al. Caveolae-mediated endocytosis of the glucosaminoglycan-interacting adipokine tartrate resistant acid phosphatase 5a in adipocyte progenitor lineage cells. Biochim Biophys Acta - Mol Cell Res. 2014;1843:495–507. Available from: https://doi.org/10.1016/j.bbamcr.2013.11.020. Patlaka C, Becker H, Norgård M, Paulie S, Nordvall-Bodell A, Lång P, et al. Caveolae-mediated endocytosis of the glucosaminoglycan-interacting adipokine tartrate resistant acid phosphatase 5a in adipocyte progenitor lineage cells. Biochim Biophys Acta - Mol Cell Res. 2014;1843:495–507. Available from: https://​doi.​org/​10.​1016/​j.​bbamcr.​2013.​11.​020.
48.
go back to reference Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, et al. Overexpression of [Delta]FosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med 2000;6:985–990. Available from: https://doi.org/10.1038/79683. Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, et al. Overexpression of [Delta]FosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med 2000;6:985–990. Available from: https://​doi.​org/​10.​1038/​79683.
Metadata
Title
Altered DNA methylation in liver and adipose tissues derived from individuals with obesity and type 2 diabetes
Authors
Francisco Barajas-Olmos
Federico Centeno-Cruz
Carlos Zerrweck
Iván Imaz-Rosshandler
Angélica Martínez-Hernández
Emilio J. Cordova
Claudia Rangel-Escareño
Faustino Gálvez
Armando Castillo
Hernán Maydón
Francisco Campos
Diana Gabriela Maldonado-Pintado
Lorena Orozco
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-018-0542-8

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