Abstract：
Abnormal polarization of adipose tissue macrophages (ATMs) results in low-grade systemic inflammation and insulin resistance (IR), potentially contributing to the development of diabetes. However, the underlying mechanisms that regulate the polarization of ATMs associated with gestational diabetes mellitus (GDM) remain unclear. Thus, we aimed to determine the effects of abnormal fatty acids on macrophage polarization and development of insulin resistance in GDM. Levels of fatty acids and inflammation were assessed in the serum samples and adipose tissues of patients with GDM. An in vitro cell model treated with palmitic acid was established, and the mechanisms of palmitic acid in regulating macrophage polarization was clarified. The effects of excessive palmitic acid on the regulation of histone methylations and IR were also explored in the high-fat diet induced GDM mice model. We found that pregnancies with GDM were associated with increased levels of serum fatty acids, and inflammation and IR in adipose tissues. Increased palmitic acid could induce mitochondrial dysfunction and excessive ROS levels in macrophages, leading to abnormal cytoplasmic and nuclear metabolism of succinate and α-ketoglutarate (αKG). Specifically, a decreased nuclear αKG/succinate ratio could attenuate the enrichment of H3K27me3 at the promoters of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, leading to cytokine secretion. Importantly, GDM mice treated with GSK-J4, an inhibitor of histone lysine demethylase, were protected from abnormal pro-inflammatory macrophage polarization and excessive production of pro-inflammatory cytokines. Our findings highlight the importance of the metabolism of αKG and succinate as transcriptional modulators in regulating the polarization of ATMs and the insulin sensitivity of adipose tissue, ensuring a normal pregnancy. This novel insight sheds new light on gestational fatty acid metabolism and epigenetic alterations associated with GDM.
摘要：
脂肪组织巨噬细胞（ATM）的异常极化导致低度全身炎症和胰岛素抵抗（IR），可能导致糖尿病的发展。然而,调节与妊娠期糖尿病(GDM)相关的ATM极化的潜在机制尚不清楚.因此，我们旨在确定异常脂肪酸对GDM巨噬细胞极化和胰岛素抵抗发展的影响。在GDM患者的血清样品和脂肪组织中评估脂肪酸和炎症水平。建立了棕榈酸处理的体外细胞模型，阐明了棕榈酸调节巨噬细胞极化的机制。在高脂饮食诱导的GDM小鼠模型中还探讨了过量棕榈酸对组蛋白甲基化和IR的调节。我们发现GDM妊娠与血清脂肪酸水平升高有关,脂肪组织中的炎症和IR。棕榈酸的增加可诱导线粒体功能障碍和巨噬细胞中过量的ROS水平,导致琥珀酸和α-酮戊二酸（αKG）的细胞质和核代谢异常。具体来说,降低的核αKG/琥珀酸酯比率可以减弱H3K27me3在促炎细胞因子启动子处的富集，如IL-1β，IL-6和TNF-α,导致细胞因子分泌。重要的是,用组蛋白赖氨酸脱甲基酶抑制剂GSK-J4治疗的GDM小鼠，被保护免受异常的促炎巨噬细胞极化和促炎细胞因子的过度产生。我们的发现强调了αKG和琥珀酸作为转录调节剂的代谢在调节ATM的极化和脂肪组织的胰岛素敏感性中的重要性。确保正常怀孕。这种新颖的见解为妊娠脂肪酸代谢和与GDM相关的表观遗传改变提供了新的思路。
