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bioRxiv · 10.1101/2025.08.01.668117

MATERNAL OBESITY MODULATES FOXO1 ACTIVATION AND ADIPOGENESIS IN NEONATAL MESENCHYMAL STEM CELLS

Bellalta, S.·Borghuis, T.·Prins, J.·Faas, M.·Plosch, T.·Casanello, P.
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Abstract

Maternal obesity contributes to increase adiposity in the offspring. The fetal environment is crucial in determining the number of progenitor cells available for adipocyte formation and the extent of fat depots. In this context, adipogenesis is regulated by an intricate network of transcription factors, including FOXO1, which are responsive to external stimuli and ultimately result in the expression of the adipogenic marker PPARG. We hypothesized that the adipocyte progenitor cells, mesenchymal stem cells (MSCs), from neonates of women with obesity would exhibit a differential activation of the SIRT2-FOXO1-PPARG pathway, which is crucial in the regulation of early adipogenesis. In this study we isolated Whartons jelly-derived MSCs from neonates of women with obesity (BMI>30 kg/m{superscript 2}, OB-MSCs) and women with normal-weight (BMI <25 kg/m{superscript 2}, NW-MSCS) and induced them towards in vitro adipogenesis. OB-MSCs showed higher levels of FOXO1 and lower levels of acetyl-FOXO1 compared to NW-MSCs (p<0.05) and differential regulation of these proteins during early adipogenesis of OB-MSCs versus NW-MSCs (p<0.05). Further, acetyl-FOXO1 was higher in the cytoplasm as compared to NW-MSCs upon day 2 of adipogenesis (p<0.05). Finally, we found higher PPARG gene expression in OB-MSCs adipocytes compared with NW-MSCs adipocytes at day 21 of differentiation (p<0.05), denoting higher adipogenic potential. Our findings suggest that the maternal obesogenic environment influences the early modulation of FOXO1, which could lead to an increased adipogenic differentiation in MSCs from neonates of women with obesity, potentially increasing adipogenesis from their precursor pool. This could explain the higher adiposity in neonates of woman with obesity compared to normal-weight woman.

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Bellalta, S., Borghuis, T., Prins, J., Faas, M., Plosch, T., Casanello, P.. 2025-08-01. MATERNAL OBESITY MODULATES FOXO1 ACTIVATION AND ADIPOGENESIS IN NEONATAL MESENCHYMAL STEM CELLS. https://doi.org/10.1101/2025.08.01.668117

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