Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Mol Metab. 2019 Jul;25:159-167. doi: 10.1016/j.molmet.2019.04.009. Epub 2019 Apr 17.
Hypertrophic white adipose tissue (WAT) morphology is associated with insulin resistance and type 2 diabetes. The mechanisms governing hyperplastic versus hypertrophic WAT expansion are poorly understood. We assessed if epigenetic modifications in adipocytes are associated with hypertrophic adipose morphology. A subset of genes with differentially methylated CpG-sites (DMS) in the promoters was taken forward for functional evaluation.
The study included 126 women who underwent abdominal subcutaneous biopsy to determine adipose morphology. Global transcriptome profiling was performed on WAT from 113 of the women, and CpG methylome profiling on isolated adipocytes from 78 women. Small interfering RNAs (siRNA) knockdown in human mesenchymal stem cells (hMSCs) was used to assess influence of specific genes on lipid storage.
A higher proportion of CpG-sites were methylated in hypertrophic compared to hyperplastic WAT. Methylation at 35,138 CpG-sites was found to correlate to adipose morphology. 2,102 of these CpG-sites were also differentially methylated in T2D; 98% showed directionally consistent change in methylation in WAT hypertrophy and T2D. We identified 2,508 DMS in 638 adipose morphology-associated genes where methylation correlated with gene expression. These genes were over-represented in gene sets relevant to WAT hypertrophy, such as insulin resistance, lipolysis, extracellular matrix organization, and innate immunity. siRNA knockdown of ADH1B, AZGP1, C14orf180, GYG2, HADH, PRKAR2B, PFKFB3, and AQP7 influenced lipid storage and metabolism.
CpG methylation could be influential in determining adipose morphology and thereby constitute a novel antidiabetic target. We identified C14orf180 as a novel regulator of adipocyte lipid storage and possibly differentiation.
肥大的白色脂肪组织（WAT）形态与胰岛素抵抗和 2 型糖尿病有关。控制 WAT 过度增生和肥大的机制尚未完全阐明。我们评估了脂肪细胞中的表观遗传修饰是否与肥大的脂肪形态有关。在启动子中具有差异甲基化 CpG 位点（DMS）的一组基因被进一步用于功能评估。
该研究纳入了 126 名女性，她们接受了腹部皮下活检以确定脂肪形态。对其中 113 名女性的 WAT 进行了全转录组谱分析，对 78 名女性的分离脂肪细胞进行了 CpG 甲基组谱分析。人间充质干细胞（hMSC）中的小干扰 RNA（siRNA）敲低用于评估特定基因对脂质储存的影响。
与增生性 WAT 相比，肥大性 WAT 中有更多的 CpG 位点被甲基化。在脂肪形态相关的 638 个基因中，有 2508 个 DMS 与基因表达相关，其甲基化与脂肪形态相关。在这些基因中，有 35138 个 CpG 位点的甲基化与 T2D 相关；98%的 CpG 位点在 WAT 肥大和 T2D 中表现出方向一致的甲基化变化。在胰岛素抵抗、脂肪分解、细胞外基质组织和固有免疫等与 WAT 肥大相关的基因集合中，这些基因被过度表达。ADH1B、AZGP1、C14orf180、GYG2、HADH、PRKAR2B、PFKFB3 和 AQP7 的 siRNA 敲低影响脂质储存和代谢。
CpG 甲基化可能在决定脂肪形态方面具有影响力，从而构成一种新的抗糖尿病靶点。我们发现 C14orf180 是脂肪细胞脂质储存和可能分化的新调节因子。
