Abstract：
Gestational diabetes mellitus (GDM) is a pregnancy-specific disease characterized by impaired glucose tolerance during pregnancy. Although diagnosis and clinical management have improved significantly, there are still areas where therapeutic approaches need further improvement. Recent evidence suggests that CCL2, a chemokine involved in immunoregulatory and inflammatory processes, is closely related to GDM. However, the potential value for clinical therapeutic applications and the mechanism of CCL2 in adipose tissue macrophages (ATMs) of GDM remain to be elucidated. Here, we found that CCL2 was enriched in macrophages of the visceral adipose tissue from GDM women and HFD-induced GDM mice. The combination of in vitro and in vivo experiments showed that Ccl2 silencing inhibited the inflammatory response of macrophage by blocking calcium transport between ER and mitochondria and reducing excessive ROS generation. Additionally, the ATS-9R/siCcl2 oligopeptide complex targeting adipose tissue was created. Under the delivery of ATS-9R peptide, Ccl2 siRNA is expressed in ATMs, which reduces inflammation in adipose tissue and, as a result, mitigates insulin resistance. All of these findings point to the possibility that the ATS-9R/siCcl2 complex, which targets adipose tissue, is able to reduce insulin resistance in GDM and the inflammatory response in macrophages. The ATS-9R/siCcl2 oligopeptide complex targeting adipose tissue seems to be a viable treatment for GDM pregnancies.
摘要：
妊娠期糖尿病(GDM)是以妊娠期糖耐量受损为特征的妊娠特异性疾病。尽管诊断和临床管理有了显著改善，仍有治疗方法需要进一步改进的领域。最近的证据表明，CCL2是一种参与免疫调节和炎症过程的趋化因子，与GDM密切相关。然而,临床治疗应用的潜在价值和CCL2在GDM脂肪组织巨噬细胞（ATM）中的作用机制仍有待阐明。这里,我们发现CCL2在GDM女性和HFD诱导的GDM小鼠内脏脂肪组织的巨噬细胞中富集。体外和体内实验相结合表明，Ccl2沉默通过阻断ER和线粒体之间的钙转运和减少过量的ROS生成来抑制巨噬细胞的炎症反应。此外,构建了靶向脂肪组织的ATS-9R/siCcl2寡肽复合物.在ATS-9R肽的递送下，Ccl2siRNA在ATM中表达，减少脂肪组织的炎症，因此,减轻胰岛素抵抗。所有这些发现都表明ATS-9R/siCcl2复合物的可能性，靶向脂肪组织，能够降低GDM的胰岛素抵抗和巨噬细胞的炎症反应。靶向脂肪组织的ATS-9R/siCcl2寡肽复合物似乎是GDM妊娠的可行治疗方法。
