Advances in Clinical and Experimental Medicine
2019, vol. 28, nr 12, December, p. 1599–1607
Publication type: original article
Obesity-induced insulin resistance via changes in the DNA methylation profile of insulin pathway genes
1 Molecular Techniques Unit, Department of Forensic Medicine, Wroclaw Medical University, Poland
2 Department of Angiology, Hypertension and Diabetology, Wroclaw Medical University, Poland
3 1st Department and Clinic of General, Gastroenterological and Endocrinological Surgery, Wroclaw Medical University, Poland
4 1st Department and Clinic of Gynecology and Obstetrics, Wroclaw Medical University, Poland
Background. Obesity has been shown to play a key role in the development of insulin resistance (IR). Abundant data implicate obesity in DNA hypermethylation at global and site-specific levels, including genes regulating insulin sensitivity. Deregulation of epigenetic marks implicates gene expression and changes in cell metabolism.
Objectives. Our previous reports demonstrated that the strongest risk factor in the development of IR is BMI; accordingly, the objective of this study was to investigate the effect of obesity on DNA methylation and insulin sensitivity.
Material and Methods. A study was carried out on lymphocytes (N-34) and visceral adipose tissue (VAT; N-35) of insulin-resistant subjects and healthy controls. Genetic material (DNA and RNA) was extracted from cells. Global and site-specific DNA methylation was analyzed with the use of restriction enzymes followed by real-time polymerase chain reaction (PCR). Gene expression was analyzed as relative mRNA level normalized to a housekeeping gene.
Results. Global DNA methylation increased in both types of tissue in obese and insulin-resistant individuals and correlated positively with IR. Two of the 3 investigated promoters of insulin pathway genes were hypermethylated, which correlated negatively with gene expression and positively with IR. The DNMT3a gene was upregulated in obese insulin-resistant individuals in both types of tissues and correlated positively with global DNA methylation.
Conclusion. DNA methylation profile changed depending on body mass index (BMI) and influenced glucose metabolism and insulin sensitivity in VAT.
obesity, insulin resistance, DNA methylation, insulin signaling pathway
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