Introduction and Objective: Maternal obesity is increasingly recognized as a determinant of long-term metabolic risk in offspring, yet the cellular mechanisms by which maternal nutritional status primes adipose tissue for coordinated remodeling across generations remain poorly defined. Traditional research has focused on metabolic dysfunction, failing to explain why certain maternal-offspring dietary combinations produce distinct phenotypic outcomes beyond additive metabolic stress. This suggests maternal obesity establishes a latent remodeling state that is developmentally encoded and selectively activated by postnatal metabolic cues.Methods: We performed single-nucleus multiome profiling (RNA + ATAC) of epididymal white adipose tissue from offspring exposed to four maternal-offspring diet combinations. All analyses were restricted to within-compartment contrasts to preserve lineage specificity. We applied compartment-aware differential expression, pathway enrichment, and pseudotime trajectory inference to define primed and activated states. Chromatin accessibility dynamics were integrated with transcriptional trajectories to identify regulatory priming events.Results: Maternal high-fat diet established a primed fibrogenic state in stromal progenitors characterized by accessible chromatin at ECM remodeling loci without transcriptional activation. Postnatal high-fat exposure selectively activated this latent program, driving coordinated stromal-to-myofibroblast differentiation and fibrotic remodeling. This primed-then-activated mechanism was lineage-specific, absent in adipocytes, and validated through histological assessment and in vitro differentiation assays.Conclusion: Maternal obesity programs a latent fibrogenic state in adipose stromal progenitors through chromatin-level regulatory priming. This transgenerational mechanism operates independently of offspring metabolic dysfunction and requires postnatal dietary activation, revealing a distinct pathway through which maternal nutrition determines offspring tissue remodeling capacity.
A. Pavel: Research Support; Current; National Institute of Diabetes and Digestive and Kidney Diseases. N. Unsal: None. H. Badr: None. N. Rabhi: None.
National Institute of Diabetes, Digestive, and Kidney Diseases (U24DK097771)
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