Institute of Cell Biology, Histology and Embryology, Center for Molecular Medicine, Medical University of Graz, Graz, Austria.
Diabetes. 2011 Oct;60(10):2457-64. doi: 10.2337/db10-1434. Epub 2011 Aug 18.
This study addressed the hypothesis that placental endothelial lipase (EL) expression is affected by pregnancies complicated by obesity and gestational diabetes mellitus (GDM).
EL expression in placental tissues from pregnancies complicated by obesity, GDM, or obesity combined with GDM (obese-GDM) was analyzed by quantitative RT-PCR. Moreover, primary placental cells were isolated and treated with insulin, glucose, leptin, or tumor necrosis factor (TNF)-α, and EL expression was measured. Inhibitors of nuclear factor (NF)-κB or mitogen-activated protein kinase (MAPK) signaling were used to detect potential pathways of EL regulation in primary placental endothelial cells (ECs).
In placentas from obese-GDM pregnancies, EL expression was upregulated by 1.9-fold (P < 0.05) compared with lean pregnancies, whereas obesity or GDM alone had no significant effect. Analyses of metabolic parameters in maternal venous and umbilical venous plasma revealed significantly increased insulin and leptin as well as slightly increased glucose and TNF-α values in the obese and obese-GDM groups. Cell culture experiments identified TNF-α and leptin, but not glucose or insulin, as regulators of EL expression in ECs. Induction of EL expression by these mediators occurred in a para/endocrine manner, since only leptin and TNF-α receptors, but not the cytokines themselves, were expressed in ECs. Inhibitor experiments suggested that TNF-α and leptin-mediated upregulation of EL may occur via two different routes. Whereas TNF-α induced EL upregulation in ECs by activation of the NF-κB pathway, leptin did not stimulate NF-κB or MAPK signaling pathways in these cells.
Metabolic inflammation with high leptin and locally increased TNF-α concentrations at the fetal-placental interface regulates placental EL expression.
本研究旨在验证以下假设，即胎盘内皮脂肪酶（EL）的表达受肥胖合并妊娠糖尿病（GDM）及单纯肥胖或 GDM 妊娠所影响。
通过定量 RT-PCR 分析肥胖、GDM 或肥胖合并 GDM（肥胖-GDM）妊娠胎盘组织中 EL 的表达。此外，分离原代胎盘细胞并分别用胰岛素、葡萄糖、瘦素或肿瘤坏死因子（TNF）-α处理，检测 EL 表达。用核因子（NF）-κB 或丝裂原活化蛋白激酶（MAPK）信号通路抑制剂检测 EL 在原代胎盘内皮细胞（ECs）中的潜在调节通路。
与瘦素妊娠相比，肥胖-GDM 妊娠胎盘组织中 EL 表达上调 1.9 倍（P < 0.05），而单纯肥胖或 GDM 对其无显著影响。对母体静脉和脐静脉血浆代谢参数的分析表明，肥胖组和肥胖-GDM 组的胰岛素和瘦素水平显著升高，而葡萄糖和 TNF-α水平略有升高。细胞培养实验表明，TNF-α和瘦素而非葡萄糖或胰岛素是 ECs 中 EL 表达的调节因子。这些介质诱导 EL 表达的作用呈旁/内分泌方式，因为只有瘦素和 TNF-α受体而非细胞因子本身在 ECs 中表达。抑制剂实验表明，TNF-α和瘦素介导的 EL 上调可能通过两条不同的途径发生。虽然 TNF-α通过激活 NF-κB 通路诱导 ECs 中 EL 的上调，但瘦素在这些细胞中并未刺激 NF-κB 或 MAPK 信号通路。
胎儿-胎盘界面处的代谢炎症导致高瘦素和局部增加的 TNF-α浓度，调节胎盘 EL 的表达。
