Division of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Environmental Health & Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Obesity (Silver Spring). 2023 Sep;31(9):2335-2348. doi: 10.1002/oby.23839. Epub 2023 Aug 13.
Visceral obesity contributes to obesity-related complications; however, the intrinsic mechanism of depot-specific adipose tissue behavior remains unclear. Despite the pro-adipogenesis role of glucocorticoids (GCs) in adipogenesis, the role of GCs in visceral adiposity rather than in subcutaneous adipose tissue is not established. Because adipocyte progenitors display a striking depot-specific pattern, the regulatory pathways of novel progenitor subtypes within different depots remain unclear. This study describes a cell-specific mechanism underlying visceral adiposity.
A diverse panel of novel depot-specific adipose progenitors was screened in mice and human samples. The transcriptome distinction and various responses of novel progenitor subtypes of GCs were further measured using the GC receptor-chromatin immunoprecipitation assay and RNA sequencing. The mechanism of novel subtypes was identified using transposase-accessible chromatin analysis and bisulfite sequencing and further confirmed using precise editing of CpG methylation.
Platelet-derived growth factor receptor α (PDGFRα ) progenitors, which were dominant in the visceral adipose tissue, were GC-sensitive beige adipose progenitors, whereas CD137 progenitors, which were dominant in the subcutaneous adipose tissue, were GC-passive beige adipose progenitors. Expression of miR-27b, an inhibitor of adipocyte browning, was significantly increased in PDGFRα progenitors treated with GCs. Using transposase-accessible chromatin analysis, bisulfite sequencing, and precise editing of CpG methylation, TEA domain transcription factor 1 (TEAD1) was discovered to be uniquely hypomethylated in PDGFRα progenitors.
GCs inhibited the PDGFRα progenitors' browning process via miR-27b, which was transcriptionally activated by the collaboration of TEAD1 with the GC receptor. These data provide insights into the mechanism of depot-specific variations in high-fat diet-induced obesity.
内脏肥胖会导致与肥胖相关的并发症；然而，脂肪组织行为的特定部位内在机制仍不清楚。尽管糖皮质激素（GCs）在脂肪生成中具有促进脂肪生成的作用，但 GCs 在内脏肥胖中的作用，而不是在皮下脂肪组织中的作用尚未确定。由于脂肪细胞祖细胞表现出明显的特定部位特征，不同部位内新型祖细胞亚型的调节途径仍不清楚。本研究描述了内脏肥胖的一种细胞特异性机制。
在小鼠和人类样本中筛选了一系列不同的新型特定部位脂肪祖细胞。使用 GC 受体染色质免疫沉淀检测和 RNA 测序进一步测量了新型祖细胞亚型的转录组差异和各种反应。使用转座酶可及染色质分析和亚硫酸氢盐测序确定了新型亚型的机制，并使用 CpG 甲基化的精确编辑进一步证实了该机制。
在内脏脂肪组织中占主导地位的血小板衍生生长因子受体α（PDGFRα）祖细胞是 GC 敏感的米色脂肪祖细胞，而在皮下脂肪组织中占主导地位的 CD137 祖细胞是 GC 非敏感的米色脂肪祖细胞。用 GCs 处理后，miR-27b 的表达，一种米色脂肪细胞棕色化的抑制剂，在 PDGFRα 祖细胞中显著增加。通过转座酶可及染色质分析、亚硫酸氢盐测序和 CpG 甲基化的精确编辑，发现 TEA 结构域转录因子 1（TEAD1）在 PDGFRα 祖细胞中独特地低甲基化。
GCs 通过 miR-27b 抑制 PDGFRα 祖细胞的棕色化过程，miR-27b 是由 TEAD1 与 GC 受体的合作转录激活的。这些数据为特定部位在高脂肪饮食诱导肥胖中的变化机制提供了深入的了解。
