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, ?-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 ?-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.

Public Health Relevance

Obesity and gestational diabetes (GDM) are both increasing in occurrence and cause many problems both during pregnancy and beyond, predisposing the mother to development of type 2 diabetes and programming the offspring for obesity and diabetes thus promoting a vicious cycle. Treatment of women with GDM reduces but does not prevent adverse outcomes. We have described reduced mitochondrial respiration and increased oxidative stress in the placenta of women with obesity and GDM which may be due to the altered maternal metabolic milieu of these conditions. The goal of this project is to define the substrates used for placental respiration and energy generation, differences with obesity and GDM and how this is related to the metabolome and lipidome of these women. Finally we will employ novel mitochondrial targeted antioxidants to improve mitochondrial respiration and placental function.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Ilekis, John V
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Oregon Health and Science University
Obstetrics & Gynecology
Schools of Medicine
United States
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