An Integrated Multi-OMICS Approach Highlights Elevated Non-Esterified Fatty Acids Impact BeWo Trophoblast Metabolism and Lipid Processing

Abstract

Maternal obesity and gestational diabetes mellitus (GDM) are linked with impaired placental function and early onset of non-communicable cardiometabolic diseases in offspring. Previous studies have highlighted that the dietary non-esterified fatty acids (NEFAs) palmitate (PA) and oleate (OA), key dietary metabolites associated with maternal obesity and GDM, are potential modulators of placental lipid processing. Using the BeWo cell line model, the current study integrated transcriptomic (mRNA microarray), metabolomic, and lipidomic readouts to characterize the underlying impacts of exogenous PA and OA on placental villous trophoblast cell metabolism. Targeted gas chromatography and thin-layer chromatography highlighted that saturated and monounsaturated NEFAs differentially impact BeWo cell lipid profiles. Furthermore, cellular lipid profiles differed when exposed to single and multiple NEFA species. Additional multi-omic analyses suggested that PA exposure is associated with enrichment in β-oxidation pathways, while OA exposure is associated with enrichment in anti-inflammatory and antioxidant pathways. Overall, this study further demonstrated that dietary PA and OA are important regulators of placental lipid metabolism. Encouraging appropriate dietary advice and implementing dietary interventions to maintain appropriate placental function by limiting excessive exposure to saturated NEFAs remain crucial in managing at-risk obese and GDM pregnancies.

Multigenerational diabetes mellitus

“…Maternal serum triglyceride levels are notably the strongest predictor of macrosomia and are positively related to insulin resistance ( 59 ). Palmitate (PA) and oleate (OA) are the most abundant circulating NEFA (non-esterified fatty acids) in the serum of pregnant women, and are increased in GDM, which may contribute to altered placental lipid levels ( 61 ). Lipids, in particular PCs, may disrupt glucoregulatory mechanisms, thereby preceding hyperglycaemia.…”

Lipidomics Profiling of Metformin-Induced Changes in Obesity and Type 2 Diabetes Mellitus: Insights and Biomarker Potential

“…Chromatograms acquired with positive and negative ionization were processed separately with our in-house-developed software, NovaMT LipidScreener V.1 (Nova Medical Testing, Inc., Edmonton, AB, Canada). Nova Medical Testing, Inc. developed the Python-based proprietary software package for tailored use with The Metabolomics Innovation Centre's (TMIC) Global (Untargeted) Lipidomics platform, a solution for untargeted lipidomics of biological samples that has been applied to more than 70 projects between 2020 and 2023 [58][59][60][61]. The package includes automated mass recalibration, peak picking, retention time correction using a set of deuterated standards added to all samples, data alignment (based on m/z, MS/MS fragmentation patterns, and retention time), data cleansing (handling of multiple adducts, in-source fragmentation, and contaminants), polarity merging, lipid annotations, quality control, batch effect correction, normalization based on a set of deuterated internal standards, and biostatistics.…”