Maternal Western diet programs persistent transcriptomic signatures in offspring PBMCs that are largely reversible by...

Maternal consumption of a Western diet (WD) during critical developmental periods has been shown to program long-term metabolic dysfunction in offspring. However, it remains unclear whether these early exposures leave a persistent transcriptomic imprint into adulthood and whether this signature can be reshaped by postnatal interventions, limiting insight into underlying mechanisms and opportunities for early intervention. Here, we aimed to identify long-term transcriptomic signatures associated with maternal WD exposure during gestation and lactation using peripheral blood mononuclear cells (PBMCs) from adult male and female offspring. We further evaluated the potential of two early-life interventions - maternal dietary normalization and pup leptin supplementation during lactation - to reverse these alterations. The offspring from dams fed a normal-fat diet during gestation and lactation was used as a control group. Considering all groups, the expression of 90 genes differed between the control and WD offspring. Both interventions normalized the expression of most genes altered by maternal WD exposure (83 and 76 out of 90, respectively), shifting the global transcriptomic profile toward control levels. Multivariate analyses identified the 20 highest-ranked contributors to the PLS-DA model distinguishing offspring of WD-fed dams from controls, with stronger discriminatory capacity in males than in females, suggesting coordinated dysregulation of immunometabolic pathways, primarily involving immune and inflammatory signaling, cell fate regulation, and metabolic homeostasis. In conclusion, interventions during lactation may effectively reverse most transcriptomic alterations associated with adverse maternal conditions, supporting this period as a critical window for postnatal reprogramming. These findings suggest that early nutritional interventions may help mitigate long-term health risks associated with adverse maternal diet and support the use of PBMC transcriptomic signatures as potential minimally invasive biomarkers of developmental programming.