Obesity-induced insulin resistance via changes in the DNA methylation profile of insulin pathway genes
Obesity-induced insulin resistance via changes in the DNA methylation profile of insulin pathway genes
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DOI：
10.17219/acem/110321
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发表时间：
2019-12-01
影响因子：
2.1
通讯作者：
Dobosz, Tadeusz
中科院分区：
文献类型：
--
作者：
Malodobra-Mazur, Malgorzata;Alama, Aneta;Dobosz, Tadeusz
背景肥胖已被证明在胰岛素抵抗（IR）的发展中起关键作用。大量数据表明肥胖与DNA甲基化有关，包括调节胰岛素敏感性的基因。表观遗传标记的失调与基因表达和细胞代谢的变化有关。我们以前的报告表明，在IR的发展中最强的危险因素是BMI;因此，本研究的目的是调查肥胖对DNA甲基化和胰岛素敏感性的影响。对胰岛素抵抗受试者和健康对照者的淋巴细胞（N-34）和内脏脂肪组织（VAT; N-35）进行了研究。从细胞中提取遗传物质（DNA和RNA）。使用限制性内切酶，然后通过实时聚合酶链反应（PCR）分析全局和位点特异性DNA甲基化。基因表达作为相对于管家基因标准化的mRNA水平进行分析。在肥胖和胰岛素抵抗个体的两种组织中，DNA甲基化水平均升高，并与IR呈正相关;在所研究的3个胰岛素途径基因启动子中，有2个基因甲基化水平升高，与基因表达呈负相关，与IR呈正相关;在肥胖胰岛素抵抗个体的两种组织中，DNMT 3a基因表达上调，并与DNA甲基化水平呈正相关。DNA甲基化改变依赖于体重指数（BMI），并影响葡萄糖代谢和胰岛素敏感性的VAT。
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.Conclusions. DNA methylation profile changed depending on body mass index (BMI) and influenced glucose metabolism and insulin sensitivity in VAT.