Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis. SC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two–sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12. In normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.

中文翻译：

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正常体重多囊卵巢综合征 (PCOS) 女性在脂肪生成过程中染色质可及性的动态变化、脂肪生成基因表达改变以及总脂肪酸合成与从头合成脂肪酸的对比：细胞编程的证据

体重正常的多囊卵巢综合征 (PCOS) 女性在体内表现出脂肪抵抗，伴随着皮下 (SC) 腹部脂肪干细胞 (ASC) 向脂肪细胞的发育增强，体外每个细胞的脂质积累加速。本研究检查正常体重 PCOS 与年龄和体重指数匹配的正常雄激素排卵（对照）女性的 SC 腹部 ASC 体外分化为脂肪细胞期间的染色质可及性、RNA 表达和脂肪酸 (FA) 合成，以研究表观遗传/遗传脂肪生成过程中 PCOS 和对照 ASC 的特征以及功能改变。PCOS 女性与对照组的 SC 腹部 ASC 在脂肪生成过程中表现出动态的染色质可及性，从第 0 天的染色质可及性显着降低到第 12 天的染色质可及性更高，在第 0、3 和 12 天富集 AP-1 亚家族转录因子 (TF) 的结合基序。在 PCOS 与对照细胞中，控制脂肪细胞分化 (PPARγ、CEBPα、AGPAT2) 和功能 (ADIPOQ、 FABP4、LPL、PLIN1、SLC2A4）在第 3、7 和 12 天增加了 2-6 倍，而涉及 Wnt 信号（FZD1、SFRP1 和 WNT10B）的信号减少了。在这些时间点，PCOS 细胞中的差异基因表达涉及三酰基甘油合成、脂质氧化、游离脂肪酸 β 氧化和 TCA 循环的氧化磷酸化，其中 TGFB1 作为重要的上游调节因子。染色质可及性增加与参与脂肪细胞分化和功能、Wnt 信号转导、以及在脂肪生成的第 12 天参与三酰基甘油合成功能组的基因。从第 7 天到第 12 天，所有细胞中肉豆蔻酸 (C14:0)、棕榈酸 (C16:0)、棕榈油酸 (C16:1) 和油酸 (C18:1) 的总含量和从头合成增加，总含量在第 12 天，PCOS 中 FA 的从头合成显着高于对照细胞。在正常体重的 PCOS 女性中，脂肪生成过程中 SC 腹部 ASC 的动态染色质重塑可能会增强脂肪基因表达，作为促进更多脂肪储存的程序机制。