Doctor of Philosophy
Physiology and Pharmacology
Regnault, Timothy RH.
An adverse intrauterine environment high in circulating nutrients in pregnancies complicated by maternal obesity and diabetes mellitus has been well linked with the development of metabolic health disorders in the exposed offspring. Impairments in placental development, mitochondrial respiration, and nutrient processing are thought to specifically underlie the in-utero programming of these metabolic diseases. In these “at-risk” pregnancies a maternal diet high in fat as well as poor glycemic control have been highlighted to be important regulators of placental metabolic functions (including the transport, storage, and oxidation of dietary nutrients), and consequently regulators of offspring metabolic health outcomes. However, the independent impacts of dietary saturated and monounsaturated fatty acid (FA) and glucose exposures on important placental metabolic functions, and their underlying regulation, remains poorly understood. Thus, the purpose of this thesis was to investigate placental metabolic function following independent exposure to increased levels of the dietary FA species palmitate and oleate, and hyperglycemia using an in vitro cell culture system. The impacts of nutrient overabundance on BeWo trophoblasts (an in vitro model of both progenitor cytotrophoblasts and differentiated syncytiotrophoblasts) were specifically examined using functional readouts of cellular metabolism and mitochondrial respiration, measurements of nutrient storage, in conjunction with multi-omic analyses integrating transcriptomics, metabolomics, and lipidomics. Through the work in this thesis, we demonstrated that saturated FA (palmitate) and glucose exposure was associated with alterations in placental metabolic function indicative of an early phenotype of mitochondrial dysfunction. Further, glucose and oleate exposures were demonstrated to increase nutrient stores in placental trophoblasts. Finally, BeWo trophoblast cells displayed differential transcriptomic, metabolomic, and lipidomic profiles following exposure to dietary FA species and hyperglycemia. These works further demonstrated that increased nutrient supply directly modulates important placental nutrient processing functions. More importantly, these investigations provided greater insight into the underlying mechanisms that regulate the responses of placental trophoblast cells following exposure to dietary nutrient overabundance. Overall, these data suggest that the clinical management of obese and diabetic pregnancies should continue to emphasize reducing placental exposures to excessive saturated FA and glucose levels to preserve physiological placental nutrient handling, and ultimately limit risks to the developing fetus.
Summary for Lay Audience
The placenta is the central organ responsible for transferring nutrients and oxygen from mother to developing fetus over the 40-weeks of pregnancy. Normal placental functions ensure healthy fetal growth. In situations of excessive nutrient supply (pregnancies complicated by maternal obesity and diabetes) placental functions change leading to impacted fetal growth. This abnormal placental function has been shown to set the stage for later life metabolic diseases (obesity and type 1 diabetes) in the unborn baby. Recently, a poor maternal diet high in saturated fats in obese pregnancies and inadequate maternal control of blood glucose levels in diabetic pregnancies have been found to be important factors that promote changes in placental function. The objective of this thesis was to examine the independent impacts of different fat and glucose exposures on trophoblast (placental) cells and further characterize how these nutrients directly affect placental function. This thesis utilized a well characterized placental model (BeWo cells) to specifically determine how nutrient storage, and the breakdown of nutrients to produce cellular energy (ATP) are impacted in the placenta following exposure to excess dietary fats and glucose. Additionally transcriptomic profiles (examines the expression of all cellular genes), metabolomic profiles (quantifies all metabolites), and lipidomic profiles (quantifies the abundance of all fat types) were examined in nutrient-exposed placental cells to better understand how underlying placental cell functions are modified following these nutrient exposures. In this thesis, trophoblast cells exposed to elevated levels of saturated fats and glucose were found to have markers that suggested their mitochondria (important producers of ATP) were transitioning towards a state of failure. Additionally, placental cells exposed to excess levels of monounsaturated fats and glucose were found to have increased nutrient stores (triglycerides and glycogen). These nutrient-mediated alterations in placental cell functions may ultimately impact nutrient transfer from mother to baby and could be specifically involved in increasing the child’s risk of developing metabolic diseases. Overall, this thesis further demonstrated that dietary fats and glucose are important regulators of placental metabolism and suggests that reducing placental fat and glucose exposures could help protect the unborn baby from later life disease.
Easton, Zachary JW, "The Impact of Excess Nutrients, Fatty Acids or Glucose, on BeWo Placental Trophoblast Metabolic Function" (2022). Electronic Thesis and Dissertation Repository. 8507.
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