Placental Mitochondrial Function in Gestational Diabetes

项目摘要 肥胖(BMI&GT；30)和妊娠期糖尿病(GDM)的频率都在增加，导致 妊娠期间的不良事件，包括死产、在晚年发展为2型糖尿病，以及重要的 他们还为胎儿随后发展为肥胖症和糖尿病做好准备。目前这些不利因素 治疗妊娠期糖尿病妇女可以减少但不能预防结局。因为胎盘调节 母体新陈代谢、胎儿生长发育，其功能的改变对母体和胎儿都有影响。 支持胎盘功能的能量是通过糖酵解、β氧化和氧化磷酸化产生的 使用葡萄糖和脂肪酸作为底物。母体高血糖和高脂血症与肥胖和 妊娠期糖尿病改变胎盘可获得的底物类型/数量，从而可能改变胎盘新陈代谢 和能源生产。最近我们发现，脂肪酸转运蛋白和酶的表达参与了 性二型肥胖孕妇胎盘中脂肪酸的β氧化改变 举止。我们还证明了线粒体呼吸、线粒体复合体的表达和 妊娠合并肥胖等患者滋养层细胞中三磷酸腺苷的生成减少 因此，在合并A2型妊娠期糖尿病(需要药物治疗)的孕妇中，与瘦身对照组相比。这是 与氧化应激增加、代谢不灵活(糖酵解时不能使用其他底物)有关 被抑制)，并增加糖酵解与妊娠期糖尿病。我们有令人兴奋的初步数据显示 胎盘还可以利用谷氨酰胺产生能量， 脂肪酸和谷氨酰胺会随着肥胖和妊娠期糖尿病而改变。与许多胎盘有关的线粒体 功能，产生超氧阴离子。在许多病理生理状态中，包括肥胖的胎盘和 GDM有过量的超氧化物生成导致氧化应激，这可以反馈和损害 线粒体处于恶性循环中，因此有针对性的药物方法来改善线粒体 功能正在得到广泛推广。最近，我们展示了氧化应激和 肥胖女性胎盘中的抗氧化物酶，同样是以性别二态的方式出现，并显示出 抗氧化剂褪黑素或代谢调节剂二氯乙酸酯(DCA)将改善线粒体 肥胖女性滋养层细胞的呼吸。使用8个母体和胎儿的血浆和胎盘组织 妇女群体(孕前瘦弱或肥胖，伴或不伴妊娠期糖尿病，胎儿为男性或女性(n=8 每组)我们将测试这样的假设，即改变代谢和脂类以及氧化应激 妊娠期糖尿病合并肥胖的胎盘与脂肪酸摄取和氧化改变一起导致减少 氧化磷酸化和改变线粒体的燃料灵活性支持胎盘功能，这可能是 通过新的特定线粒体靶向改善/正常化以减少氧化应激或重定向细胞 新陈代谢。这项翻译工作可能会为未来肥胖或妊娠期糖尿病的治疗方法奠定基础。

Project Summary Obesity (BMI>30) and gestational diabetes (GDM), which are both increasing in frequency, cause more adverse events in pregnancy, including stillbirth, development of type 2 diabetes in later life and importantly they also program the fetus for subsequent development of obesity and diabetes. Currently these adverse outcomes can be reduced but not prevented by treating women with GDM. As the placenta regulates maternal metabolism, fetal growth and development, alterations in its function affects both mother and fetus. Energy to support placental function is generated via glycolysis, β-oxidation and oxidative phosphorylation using glucose and fatty acids as substrates. Maternal hyperglycemia and hyperlipidemia seen with obesity and GDM alter the type/amount of substrates available to the placenta and hence may alter placental metabolism and energy generation. Recently we found that expression of fatty acid transporters and enzymes involved in β-oxidation of fatty acids was altered in the placenta of pregnancies with obesity in a sexually dimorphic manner. We also demonstrated that mitochondrial respiration, expression of mitochondrial complexes and generation of ATP are reduced in trophoblast from women with pregnancies complicated by obesity and more so in pregnancies complicated by type A2 GDM (requiring medication) compared to lean controls. This is associated with increased oxidative stress, metabolic inflexibility (cannot use other substrates when glycolysis is inhibited) in obesity, and increased glycolysis with GDM. We have exciting preliminary data that the placenta can also use glutamine for energy generation and that placental fuel dependency between glucose, fatty acids and glutamine is altered with obesity and GDM. Mitochondria which are involved in many placental functions, generate superoxide anion. In many pathophysiologic states, including the placenta with obesity and GDM there is excessive superoxide generation leading to oxidative stress, which can feedback and damage mitochondria in a vicious cycle hence targeted pharmacologic approaches to improve mitochondrial function are being widely promoted. Recently we demonstrated differences in oxidative stress and in antioxidant enzymes in the placenta of obese women, again in a sexually dimorphic manner and have shown that the antioxidant melatonin or the metabolic modulator dichloroacetate (DCA) will improve mitochondrial respiration in trophoblast from obese women. Using maternal and fetal plasma and placental tissue from 8 groups of women (prepregnancy lean or obese, with or without GDM with either a male or a female fetus (n=8 each group) we will test the hypothesis that altered metabolomic and lipid profiles and oxidative stress seen in the placenta with obesity GDM together with altered fatty acid uptake and oxidation leads to decreased oxidative phosphorylation and altered fuel flexibility of mitochondria supporting placental function which can be improved/normalized by novel specific mitochondrial targeting to reduce oxidative stress or to redirect cellular metabolism. This translational work may form the basis for future therapeutic approaches in obesity or GDM.