The Impact of Excess Nutrients, Fatty Acids or Glucose, on BeWo Placental Trophoblast Metabolic Function
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.
Placenta, Developmental Origins of Health and Disease, Mitochondrial Dysfunction, Pre-pregnancy Obesity, Gestational Diabetes, Diet
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