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.

项目摘要肥胖（BMI> 30）和妊娠糖尿病（GDM）都在增加频率，导致更多怀孕的不良事件，包括死产，后来的2型糖尿病的发展，重要的是他们还为胎儿编写了随后的肥胖和糖尿病的发展。目前这些逆境可以通过治疗GDM的妇女来降低结果，但不能阻止结果。随着plapeta的调节母体代谢，胎儿的生长和发育，其功能的改变会影响母亲和胎儿。通过糖酵解，β-氧化和氧化磷酸化产生支持的精子功能。使用葡萄糖和脂肪酸作为底物。肥胖和肥胖和高脂血症的孕产妇高血糖和高脂血症 GDM更改可用于plopeta的底物的类型/数量，因此可能会改变留念代谢和能量产生。最近，我们发现脂肪酸转运蛋白和酶的表达参与脂肪酸的β-氧化在性二态性的肥胖症的妊娠妊娠中改变了方式。我们还证明了线粒体呼吸，线粒体复合物的表达和肥胖症患者复杂的妊娠女性的滋养细胞中，ATP的产生降低了因此，与精益对照相比，在A2 GDM型（需要药物）的妊娠中复杂化。这是与氧化应激增加，代谢僵化相关（糖酵解时不能使用其他底物被抑制）肥胖，并用GDM增加糖酵解。我们有令人兴奋的初步数据胎盘还可以使用谷氨酰胺进行能量产生，以及谷氨酰胺之间的含量燃料依赖性，肥胖和GDM改变脂肪酸和谷氨酰胺。线粒体在许多地方涉及功能，生成超氧化阴离子。在许多病理生理状态，包括肥胖和 GDM会产生过量的超氧化物，导致氧化应激，这会反馈和损害线粒体在恶性循环中，因此采用了改善线粒体的药物方法功能正在广泛促进。最近，我们证明了氧化应激和肥胖女性的抗氧化剂酶再次以性二态性方式再次显示抗氧化剂褪黑激素或代谢调节剂二氯乙酸（DCA）将改善线粒体肥胖女性滋养细胞的呼吸。使用来自8个一组女性（孕妇瘦或肥胖，有或没有GDM的男性或女性胎儿（n = 8）每组）我们将检验以下假设，即改变了代谢组和脂质谱和氧化应激带有肥胖GDM的斑点以及脂肪酸的摄取和氧化的改变会导致精制氧化磷酸化并改变了线粒体支撑位置功能的燃料灵活性，可以是通过新型特异性线粒体靶向改进/归一化，以减少氧化应激或重定向细胞代谢。这项翻译工作可能是肥胖或GDM未来治疗方法的基础。