Department of Translation Medicine, Federico II University of Naples, 80131 Naples, Italy.
URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy.
Cells. 2022 Feb 18;11(4):728. doi: 10.3390/cells11040728.
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only partially been clarified. In the present report, we show that silencing of the transcription factor () in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate -signaling activation. Importantly, in preadipocytes from FDR individuals, expression was attenuated, with hypermethylation of the promoter region found responsible for its downregulation, as revealed by luciferase assay. Both gene expression and DNA methylation were significantly correlated with SAT adipose cell hypertrophy in FDR, whose increased adipocyte size marks impaired adipogenesis. In preadipocytes from FDR, the low expression negatively correlated with enhanced transcription of the signaling downstream genes and . In silico evidence indicated that and were directly controlled by . The promoter region also was hypermethylated in peripheral blood leukocytes from these same FDR individuals, which was further revealed in peripheral blood leukocytes from an independent group of obese subjects. Thus, controlled adipogenesis in humans by suppressing signaling. Altered DNA methylation of the promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals.
除了胰岛素抵抗和 2 型糖尿病（T2D）风险增加外，2 型糖尿病患者的瘦直系亲属（FDR）在糖尿病发病前就表现出皮下脂肪组织（SAT）中脂肪生成受损和皮下脂肪细胞肥大。将这些事件联系起来的分子机制仅部分阐明。在本报告中，我们表明在人前脂肪细胞中沉默转录因子（）会损害体外成熟脂肪细胞的分化。脂肪生成减少伴随着不适当的 -信号激活。重要的是，在 FDR 个体的前脂肪细胞中，发现 表达减弱，其启动子区域的高甲基化是其下调的原因，这通过荧光素酶测定得到证实。FDR 中的 SAT 脂肪细胞肥大与 基因表达和 DNA 甲基化均呈显著相关，其脂肪细胞增大标志着脂肪生成受损。在来自 FDR 的前脂肪细胞中，低 表达与增强的 信号下游基因 和 的转录呈负相关。计算机模拟证据表明 和 受 直接控制。这些相同 FDR 个体的外周血白细胞中的 启动子区域也发生了高甲基化，在另一组肥胖个体的外周血白细胞中也进一步证实了这一点。因此，通过抑制 信号来控制人类的脂肪生成。 启动子区域的 DNA 甲基化改变导致 2 型糖尿病 FDR 的瘦受试者的 SAT 中脂肪生成受限，以及肥胖个体中脂肪生成受限。
