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Genetics and Epigenetics

DNA methylation in adipocytes from visceral and subcutaneous adipose tissue influences insulin-signaling gene expression in obese individuals



Both obesity and insulin resistance are characterized by severe long-term changes in the expression of many genes of importance in the regulation of metabolism. Because these changes occur throughout life, as a result of external factors, the disorders of gene expression could be epigenetically regulated.


We analyzed the relationship between obesity and insulin resistance in enrolled patients by means of evaluation of the expression rate of numerous genes involved in the regulation of adipocyte metabolism and energy homeostasis in subcutaneous and visceral adipose tissue depots. We also investigated global and site-specific DNA methylation as one of the main regulators of gene expression. Visceral and subcutaneous adipose tissue biopsies were collected from 45 patients during abdominal surgery in an age range of 40–60 years.


We demonstrated hypermethylation of PPARG, INSR, SLC2A4, and ADIPOQ promoters in obese patients with insulin resistance. Moreover, the methylation rate showed a negative correlation with the expression of the investigated genes. More, we showed a correlation between the expression of PPARG and the expression of numerous genes important for proper insulin action. Given the impact of PPARγ on the regulation of the cell insulin sensitivity through modulation of insulin pathway genes expression, hypermethylation in the PPARG promoter region may constitute one of the epigenetic pathways in the development of insulin resistance in obesity.


Our research shows that epigenetic regulation through excessive methylation may constitute a link between obesity and subsequent insulin resistance.

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Fig. 1: A correlation between BMI and the expression level of genes with a p value.
Fig. 2: The results of the comparative analysis regarding the expression of DNMT1 gene and global DNA methylation level between three groups (LH, OH, and OR).
Fig. 3: The results of the analysis regarding to the site-specific methylation of the promoter region of the selected genes.
Fig. 4: A correlation between the expression of PPARG and the expression of other genes with a p value.

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  1. Aung K, Lorenzo C, Hinojosa MA, Haffner SM. Risk of developing diabetes and cardiovascular disease in metabolically unhealthy normal-weight and metabolically healthy obese individuals. J Clin Endocrinol Metab. 2014;99:462–8.

    Article  CAS  Google Scholar 

  2. Nguyen DM, El-Serag HB. The epidemiology of obesity. Gastroenterol Clin N Am. 2010;39:1.

    Article  CAS  Google Scholar 

  3. Smith CJ, Ryckman KK. Epigenetic and developmental influences on the risk of obesity, diabetes, and metabolic syndrome. Diabetes Metab Syndr Obes. 2015;8:295–302.

    PubMed  PubMed Central  Google Scholar 

  4. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23:781.

    Article  CAS  Google Scholar 

  5. Maor GL, Yearim A, Ast G. The alternative role of DNA methylation in splicing regulation. Trends Genet. 2015;31:274–80.

    Article  Google Scholar 

  6. Zheng LD, Linarelli LE, Liu L, Wall SS, Greenawald MH, Seidel RW, et al. Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans. Clin Epigenetics. 2015;7:60.

    Article  Google Scholar 

  7. Arner P, Sinha I, Thorell A, Rydén M, Dahlman-Wright K, Dahlman I. The epigenetic signature of subcutaneous fat cells is linked to altered expression of genes implicated in lipid metabolism in obese women. Clin Epigenetics. 2015;7:93.

    Article  Google Scholar 

  8. Pietiläinen KH, Ismail K, Järvinen E, Heinonen S, Tummers M, Bollepalli S, et al. DNA methylation and gene expression patterns in adipose tissue differ significantly within young adult monozygotic BMI-discordant twin pairs. Int J Obes. 2016;40:654–61.

    Article  Google Scholar 

  9. Barberio MD, Nadler EP, Sevilla S, Lu R, Harmon B, Hubal MJ. Comparison of visceral adipose tissue DNA methylation and gene expression profiles in female adolescents with obesity. Diabetol Metab Syndr. 2019;11:98.

    Article  Google Scholar 

  10. Simar D, Versteyhe S, Donkin I, Liu J, Hesson L, Nylander V, et al. DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human. Metabolism. 2014;63:1188–97.

    Article  CAS  Google Scholar 

  11. Drogan D, Boeing H, Janke J, Schmitt B, Zhou Y, Walter J, et al. Regional distribution of body fat in relation to DNA methylation within the LPL, ADIPOQ and PPARγ promoters in subcutaneous adipose tissue. Nutr Diabetes. 2015;5:168.

    Article  Google Scholar 

  12. Zhang Q, Xiao X, Zheng J, Li M, Yu M, Ping F, et al. A maternal high-fat diet induces DNA methylation changes that contribute to glucose intolerance in offspring. Front Endocrinol. 2019;10:871.

    Article  Google Scholar 

  13. Choi K, Kim Y-B. Molecular mechanism of insulin resistance in obesity and type 2 diabetes. Korean J Intern Med. 2010;25:119–29.

    Article  CAS  Google Scholar 

  14. Cash HL, McGarvey ST, Houseman EA, Marsit CJ, Hawley NL, Lambert-Messerlian GM, et al. Cardiovascular disease risk factors and DNA methylation at the LINE-1 repeat region in peripheral blood from Samoan Islanders. Epigenetics. 2011;6:1257–64.

    Article  CAS  Google Scholar 

  15. Kim M, Long TI, Arakawa K, Wang R, Yu MC, Laird PW. DNA methylation as a biomarker for cardiovascular disease risk. PLoS ONE. 2010;5:3.

    Google Scholar 

  16. Medina-Gomez G, Gray S, Vidal-Puig A. Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγcoactivator-1 (PGC1). Public Health Nutr. 2007;10:1132–7.

    Article  Google Scholar 

  17. Lehrke M, Lazar MA. The many faces of PPARγ. Cell. 2005;123:993–9.

    Article  CAS  Google Scholar 

  18. Elstner E, Müller C, Koshizuka K, Williamson EA, Park D, Asou H, et al. Ligands for peroxisome proliferator-activated receptorγ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. PNAS. 1998;95:8806–11.

    Article  CAS  Google Scholar 

  19. Deeg MA, Tan MH. Pioglitazone versus Rosiglitazone: effects on lipids, lipoproteins, and apolipoproteins in head-to-head randomized clinical studies. PPAR Res. 2008;2008:520465.

    Article  Google Scholar 

  20. He W, Barak Y, Hevener A, Olson P, Liao D, Le J, et al. Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle. PNAS. 2003;100:15712–7.

    Article  CAS  Google Scholar 

  21. Koutnikova H, Cock T-A, Watanabe M, Houten SM, Champy M-F, Dierich A, et al. Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPARγ hypomorphic mice. PNAS. 2003;100:14457–62.

    Article  CAS  Google Scholar 

  22. Gustafson B, Jack MM, Cushman SW, Smith U. Adiponectin gene activation by thiazolidinediones requires PPARγ2, but not C/EBPα—evidence for differential regulation of the aP2 and adiponectin genes. Biochem Biophys Res Commun. 2003;308:933–9.

    Article  CAS  Google Scholar 

  23. Fischer S, Navarrete Santos A, Thieme R, Ramin N, Fischer B. Adiponectin stimulates glucose uptake in rabbit blastocysts. Biol Reprod. 2010;83:859–65.

    Article  CAS  Google Scholar 

  24. Berendoncks AMV, Stensvold D, Garnier A, Fortin D, Sente T, Vrints CJ, et al. Disturbed adiponectin—AMPK system in skeletal muscle of patients with metabolic syndrome. Eur J Prev Cardiolog. 2015;22:203–5.

    Article  Google Scholar 

  25. Schindler M, Pendzialek M, Grybel KJ, Seeling T, Gürke J, Fischer B, et al. Adiponectin stimulates lipid metabolism via AMPK in rabbit blastocysts. Hum Reprod. 2017;32:1382.

    Article  CAS  Google Scholar 

  26. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2002;290:1084–9.

    Article  CAS  Google Scholar 

  27. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes. 2003;52:1779–85.

    Article  CAS  Google Scholar 

  28. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86:1930–5.

    Article  CAS  Google Scholar 

  29. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 1996;271:10697–703.

    Article  CAS  Google Scholar 

  30. Kim AY, Park YJ, Pan X, Shin KC, Kwak S-H, Bassas AF. et al. Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance. Nat Commun. 2015;6:7585.

    Article  Google Scholar 

  31. Cho YM, Youn B-S, Lee H, Lee N, Min S-S, Kwak SH, et al. Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes. Diabetes Care. 2006;29:2457–61.

    Article  CAS  Google Scholar 

  32. Mohapatra J, Sharma M, Acharya A, Pandya G, Chatterjee A, Balaraman R, et al. Retinol-binding protein 4: a possible role in cardiovascular complications. Br J Pharmacol. 2011;164:1939.

    Article  CAS  Google Scholar 

  33. Öst A, Danielsson A, Lidén M, Eriksson U, Nystrom FH, Strålfors P. Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. FASEB J. 2007;21:3696–704.

    Article  Google Scholar 

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The project was funded by The National Science Centre, Poland. The number of the research project: 2016/21/D/NZ5/00155.

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Correspondence to Aneta Cierzniak.

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Cierzniak, A., Pawelka, D., Kaliszewski, K. et al. DNA methylation in adipocytes from visceral and subcutaneous adipose tissue influences insulin-signaling gene expression in obese individuals. Int J Obes 45, 650–658 (2021).

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