Placental Mitochondrial Function in Gestational Diabetes

妊娠糖尿病中的胎盘线粒体功能

基本信息

批准号：
10396015
负责人：
LESLIE MYATT
金额：
$ 33.41万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396015
关键词：
Address Adverse event Affect Antioxidants Apoptosis Body mass index Cell Cycle Complex Congenital Abnormality Data Dependence Development Diabetes Mellitus Dichloroacetate Drug Targeting Elderly Enzymes Event Fatty Acids Feedback Female Fetal Growth Fetal Growth Retardation Fetus Frequencies Functional disorder Future Generations Gestational Age Gestational Diabetes Glucose Glutamine Glycolysis Goals Growth and Development function Hyperlipidemia In Vitro Infant Lipids Maintenance Melatonin Membrane Potentials Metabolic Metabolism Mitochondria Mothers Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Phosphorylation Oxidative Stress Pathway interactions Pharmaceutical Preparations Pharmacology Placenta Plasma Pre-Eclampsia Predisposition Pregnancy Pregnancy Outcome Pregnancy in Diabetics Prevalence Respiration Signal Transduction Steroids Substrate Specificity Superoxides Testing Therapeutic Thinness Tissues Woman Women&apos s Group Work adverse outcome antioxidant enzyme cell growth regulation fatty acid oxidation fetal fetal programming flexibility generation difference improved improved outcome innovation lipidome lipidomics male maternal hyperglycemia maternal obesity metabolome metabolomics mitochondrial dysfunction novel obesity development offspring oxidation prepregnancy prevent programs sexual dimorphism stillbirth trophoblast uptake

项目摘要

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.

项目概要肥胖（BMI>30）和妊娠糖尿病（GDM）的发生频率均在增加，导致更多怀孕期间的不良事件，包括死产、晚年发展为 2 型糖尿病，重要的是他们还对胎儿随后发生的肥胖和糖尿病进行编程。由于胎盘的调节作用，治疗 GDM 可以减少但不能预防结果。母体新陈代谢、胎儿生长发育、其功能的改变都会影响母亲和胎儿。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，导致肥胖和高脂血症。 GDM 改变胎盘可用底物的类型/数量，因此可能改变胎盘代谢最近我们发现脂肪酸转运蛋白和酶的表达参与。性二态性肥胖孕妇胎盘中脂肪酸的β-氧化发生改变我们还证明了线粒体呼吸、线粒体复合物的表达和。因肥胖等原因怀孕的女性滋养层中 ATP 的生成减少因此，与瘦对照相比，患有 A2 型妊娠糖尿病（需要药物治疗）的妊娠情况是这样的。与氧化应激增加、代谢不灵活有关（糖酵解时不能使用其他底物被抑制）在肥胖中，并增加糖酵解与 GDM 我们有令人兴奋的初步数据表明胎盘还可以利用谷氨酰胺产生能量，并且胎盘对葡萄糖、脂肪酸和谷氨酰胺会因肥胖和妊娠期糖尿病而改变，而线粒体与许多胎盘有关。功能，在许多病理生理状态下产生超氧阴离子，包括肥胖和胎盘。 GDM存在过量的超氧化物生成导致氧化应激，氧化应激可以反馈和损害线粒体处于恶性循环中，因此有针对性的药理学方法可以改善线粒体最近我们证明了氧化应激和功能的差异。肥胖女性胎盘中的抗氧化酶也以性别二态性的方式存在，并且已经表明抗氧化剂褪黑激素或代谢调节剂二氯乙酸 (DCA) 将改善线粒体使用来自 8 名孕妇和胎儿的血浆以及胎盘组织对肥胖妇女的滋养层进行呼吸。女性群体（孕前瘦或肥胖，有或没有 GDM，胎儿为男性或女性 (n=8 每组）我们将测试改变代谢组和脂质谱以及氧化应激的假设肥胖 GDM 的胎盘以及脂肪酸摄取和氧化的改变导致氧化磷酸化和线粒体燃料灵活性的改变支持胎盘功能，这可以通过新颖的特定线粒体靶向来减少氧化应激或重定向细胞，从而改善/正常化这项转化工作可能为未来肥胖症或 GDM 的治疗方法奠定基础。