Author ORCID Identifier
Document Type
Dissertation
Date of Award
2024
Degree Name
Doctor of Philosophy (PhD)
Department
Basic Biomedical Science
First Advisor
Michelle Baack
Abstract
Gestational diabetes (GDM) is the most common pregnancy complication and adversely affects the parent, placenta, and baby. GDM is associated with hyperglycemia and hyperlipidemia, with evidence suggesting individuals who go on to be diagnosed with GDM tend to have elevated circulating lipids. Circulating triglycerides are more predictive of large for gestational age status than glucose, HbA1C, or pre-pregnancy BMI. In diabetic pregnancies, the placenta and baby experience lipid accumulation alongside long-chain polyunsaturated fatty acid (LCPUFA) deficiency, suggesting impaired LCPUFA-specific uptake despite uninhibited uptake of other lipids. LCPUFA transport, critical in the third trimester for fetal brain growth, is energetically demanding, and regulated by mitochondrial function, which can also impact trophoblast FA uptake and processing. However, the kinetics of long-chain fatty acid uptake into placental trophoblasts, the effect of high glucose and high lipid exposure on mitochondrial function, and how these outcomes interact is still unknown. This dissertation demonstrates that FA uptake in trophoblasts varies by FA chain length, saturation, and cell type (BeWo, cytotrophoblast, syncytiotrophoblast). Cytotrophoblast uptake resembled BeWo cells, enabling further study without confounding parental variables. High glucose and lipid exposure selectively impaired uptake of longer, 20-carbon FAs and disrupted lipid droplet partitioning and dynamics. We also found that diabetic fuels impaired mitochondrial respiration, morphology, and membrane potential despite increased mitochondrial abundance. This poor mitochondrial phenotype also led to more apoptosis in exposed cells. Blocking metabolic pathways like oxidative phosphorylation, glycolysis, and fatty acid oxidation significantly impaired the uptake and storage of the longer-chain FAs without significant effect on the shorter, 16-carbon FA counterpart, suggesting a critical relationship between bioenergetics and active long-chain FA processing in the human trophoblast. Using novel live-cell imaging assays and analytical methods with models of physiologically relevant fuel exposures, this work lays a foundation for a better understanding of placental mitochondrial-mediated mechanisms of FA transport that contributes to developmentally programmed metabolic disease and the role of elevated lipids on the development and function of placentas.
Subject Categories
Cell Biology
Keywords
fatty acids, gestational diabetes mellitus, lipid droplets, mitochondria, trophoblast
Number of Pages
188
Publisher
University of South Dakota
Recommended Citation
Siemers, Kyle McKenna, "DIABETIC FUELS INFLUENCE MITOCHONDRIA FUNCTION AND FATTY ACID PROCESSING IN HUMAN TROPHOBLASTS" (2024). Dissertations and Theses. 333.
https://red.library.usd.edu/diss-thesis/333