Paternal but not maternal adiposity is associated with reduced insulin-stimulated glucose uptake in neonatal umbilical cord mesenchymal stromal cells

Parental adiposity is linked to offspring cardiometabolic risk, but whether altered insulin responsiveness is measurable at birth is unclear. We examined associations among maternal pre-pregnancy body mass index (BMI, documented in the medical record) and paternal preconception BMI (reported by the mother at enrollment), neonatal insulin-related phenotypes, and microRNA (miRNA) expression in umbilical cord-derived mesenchymal stromal cells (uMSCs) from a prospective birth cohort. uMSC lines were established from 20 term neonates; insulin-stimulated glucose uptake was available for 19, paternal BMI for 17, and undifferentiated uMSC miRNA profiling was performed in a subset of 12. The miRNA analyses are exploratory and hypothesis-generating and were not powered for discovery. Higher paternal, but not maternal, BMI was associated with lower insulin-stimulated glucose uptake (Spearman ρ = −0.52, n = 16), as were higher cord blood insulin and HOMA-IR (ρ = −0.55 each, n = 17). One miRNA (miR-548y) was associated with glucose uptake after false discovery rate (FDR) correction (q = 0.015), and 51 miRNAs were associated with cord blood HOMA-IR at q < 0.10; no miRNA was associated with either parental BMI after correction. Using a triangulation framework across parental BMI, cord blood HOMA-IR, and glucose uptake, we identified 17 miRNAs with convergent, directionally coherent associations, of which ten have prior support in insulin or metabolic biology; their experimentally validated targets, mapped to insulin/IGF-AKT signaling, glucose uptake, adhesion and cytoskeletal remodeling, and myogenic growth. These data suggest that parental adiposity, particularly paternal adiposity, is associated with molecular features present at birth relevant to the developmental origins of insulin resistance, and they nominate candidate miRNAs for future validation.