Maternal metabolic health and fertility : acute and chronic effects of a western-type diet on oviductal and ovarian cells: a multi-omic approach
Authors:   , Moorkens Kerlijne 
Published: July 2024

Maternal metabolic disorders associated with the consumption of an obesogenic (high fat/high sugar, HF/HS) diet are strongly linked with reduced fertility in women. The impact of obesity and an obesogenic diet on the oviductal microenvironment is much less characterized compared to the impact on the follicular environment and oocyte quality. Furthermore, the onset and duration of changes after the start of an obesogenic diet were unclear. In addition, the sensitivity to obesogenic diet-induced obesity and its influence on the metabolic profile and oocyte quality have been shown to be dependent on the genetic background of the mouse model. Therefore, the impact of feeding an obesogenic diet for different time periods on the transcriptome of oviductal epithelial cells (OECs) in Swiss compared to C57BL/6N mice, specifically focusing on genes involved in oxidative and cellular stress levels and inflammatory responses, was tested. Our findings demonstrated, for the first time, that feeding an obesogenic diet for a short period of only three days resulted in acute systemic changes and acute local oxidative stress or mitochondrial stress effects on OECs, evident already before the development of an obese phenotype. The acute effects in the OECs initiated a cascade of transcriptomic changes to control mitochondrial ROS production and endoplasmic reticulum (ER)-stress. However, prolonged, long-term feeding resulted in a persistent upregulation of (mitochondrial) oxidative stress and ER-stress, with ultimate signs of local and systemic inflammation. Furthermore, different responses to the obesogenic diet were observed between Swiss and C57BL/6N mice. Since fatty acids play an important role as structural membrane components, in cell signalling and cell-to-cell interactions, alterations to the lipid composition of the oviduct may reduce its ability to support early embryo development, which may have long-lasting consequences. Therefore, the dynamics and the nature of changes in the lipidomic profile of the oviductal epithelium upon and during obesogenic diet feeding over time in an outbred Swiss mouse model was studied. It was demonstrated that feeding the obesogenic diet resulted in acute changes in the lipid profile in the oviductal epithelium already after 3 days on the obesogenic diet. The changes in the lipid profile progressively increased and became more persistent after long-term obesogenic diet feeding. Functional annotation revealed a differential abundance of phospholipids, sphingomyelins and lysophospholipids in particular. The different durations of feeding used in this PhD research, allowed a clear distinction of acute responses and later changes after long-term feeding and after the development of the obese phenotype, and the associated unhealthy metabolic phenotype. Our findings in the oviduct illustrate that the mechanism by which the obesogenic diet impacts fertility is not only mediated through reduced oocyte quality but might also directly impact early embryo development in the oviduct, potentially leading to long-term effects on foetal development, pregnancy success and postnatal health through epigenetic alterations. In the ovary, it is known that the impact of lipotoxicity, caused by an obesogenic diet, on oocyte quality is mediated by oxidative stress, ER stress and mitochondrial dysfunction. However, the nature and magnitude of these changes may be dependent on the duration of feeding (and thus the development of the obesogenic phenotype). Therefore the impact of feeding an obesogenic diet for different time periods on the ovary and ovarian cells of outbred Swiss mice was tested, with a focus on dynamic changes in granulosa cell transcriptomics and oocyte quality. The results demonstrated that feeding an obesogenic diet resulted in acute changes in the lipid content of oocytes and impacted endoplasmic reticulum and mitochondrial functions in granulosa cells already after short-term feeding of only 24 hours till 1 week. The effects progressively increased over time after prolonged obesogenic diet feeding, with increased mitochondrial abnormalities in oocytes and different affected pathways, linked to DNA repair, cell signalling, UPRs and many other GO annotation biological terms in the granulosa cells. Exposure to an obesogenic diet thus resulted in cell specific changes in oocytes and granulosa cells, already after 24 hours to 1w, which can directly affect oocyte quality and early embryo development, eventually leading to reduced fertility. The deep analysis and novel insights of this PhD thesis can be useful for many researchers and form an important fundament for further studies that focus on protecting and enhancing oocyte and embryo development during the very early stages under diet-induced metabolic stressed conditions. Understanding the magnitude and nature of reproductive cell dysfunction after different exposure periods to a HF/HS diet is crucial to develop more efficient preconception care intervention strategies to enhance fertility under diet-induced metabolic stress conditions.