Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood

Obesity can increase the risk of complex metabolic diseases, including insulin resistance. Moreover, obesity can be caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are not well defined. Therefore, the identification of novel epigenetic biomarkers of obesity allows for a more complete understanding of the disease and its underlying insulin resistance. The aim of our study was to identify DNA methylation changes in whole-blood that were strongly associated with obesity and insulin resistance. Whole-blood was obtained from lean (n = 10; BMI = 23.6 ± 0.7 kg/m2) and obese (n = 10; BMI = 34.4 ± 1.3 kg/m2) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing on genomic DNA isolated from the blood. We identified 49 differentially methylated cytosines (DMCs; q < 0.05) that were altered in obese compared with lean participants. We identified 2 sites (Chr.21:46,957,981 and Chr.21:46,957,915) in the 5’ untranslated region of solute carrier family 19 member 1 (SLC19A1) with decreased methylation in obese participants (lean 0.73 ± 0.11 vs. obese 0.09 ± 0.05; lean 0.68 ± 0.10 vs. obese 0.09 ± 0.05, respectively). These 2 DMCs identified by obesity were also significantly predicted by insulin sensitivity (r = 0.68, P = 0.003; r = 0.66; P = 0.004). In addition, we performed a differentially methylated region (DMR) analysis and demonstrated a decrease in methylation of Chr.21:46,957,915–46,958,001 in SLC19A1 of −34.9% (70.4% lean vs. 35.5% obese). The decrease in whole-blood SLC19A1 methylation in our obese participants was similar to the change observed in skeletal muscle (Chr.21:46,957,981, lean 0.70 ± 0.09 vs. obese 0.31 ± 0.11 and Chr.21:46,957,915, lean 0.72 ± 0.11 vs. obese 0.31 ± 0.13). Pyrosequencing analysis further demonstrated a decrease in methylation at Chr.21:46,957,915 in both whole-blood (lean 0.71 ± 0.10 vs. obese 0.18 ± 0.06) and skeletal muscle (lean 0.71 ± 0.10 vs. obese 0.30 ± 0.11). Our findings demonstrate a new potential epigenetic biomarker, SLC19A1, for obesity and its underlying insulin resistance.

肥胖症可显著提升复杂代谢性疾病的风险，其中包括胰岛素抵抗。此外，肥胖症可能由环境及遗传因素所诱发。然而，肥胖症的表观遗传机制尚不明确。因此，识别肥胖症的新型表观遗传生物标志物，有助于更全面地理解该疾病及其潜在的胰岛素抵抗。本研究旨在识别与肥胖症及胰岛素抵抗高度相关的全血DNA甲基化变化。本研究收集了来自体重正常（n = 10；BMI = 23.6 ± 0.7 kg/m2）和肥胖（n = 10；BMI = 34.4 ± 1.3 kg/m2）受试者的全血样本，并结合葡萄糖稳态高胰岛素夹闭技术以评估胰岛素敏感性。我们对血液中分离的基因组DNA进行了降低代表性亚硫酸氢盐测序。我们发现了49个差异甲基化胞嘧啶（DMCs；q < 0.05），在肥胖受试者中与体重正常受试者相比发生了改变。在溶质载体家族19成员1（SLC19A1）的5'非翻译区中，我们识别了2个位点（Chr.21:46,957,981和Chr.21:46,957,915），在肥胖受试者中甲基化程度降低（体重正常组分别为0.73 ± 0.11和0.68 ± 0.10，肥胖组分别为0.09 ± 0.05和0.09 ± 0.05）。这2个由肥胖症引起的DMCs也被胰岛素敏感性显著预测（r = 0.68，P = 0.003；r = 0.66，P = 0.004）。此外，我们进行了差异甲基化区域（DMR）分析，并证明了SLC19A1中Chr.21:46,957,915–46,958,001区域的甲基化降低达到-34.9%（体重正常组为70.4%，肥胖组为35.5%）。我们肥胖受试者全血中SLC19A1甲基化的降低与骨骼肌中观察到的变化相似（骨骼肌中，Chr.21:46,957,981，体重正常组为0.70 ± 0.09，肥胖组为0.31 ± 0.11；Chr.21:46,957,915，体重正常组为0.72 ± 0.11，肥胖组为0.31 ± 0.13）。Pyrosequencing分析进一步证实了在血液（体重正常组为0.71 ± 0.10，肥胖组为0.18 ± 0.06）和骨骼肌（体重正常组为0.71 ± 0.10，肥胖组为0.30 ± 0.11）中Chr.21:46,957,915位点甲基化的降低。我们的研究结果表明，SLC19A1可作为肥胖症及其潜在胰岛素抵抗的新兴表观遗传生物标志物。