Activation of the heat shock response by human milk-derived extracellular vesicles in neonates with perinatal high-fat diet exposure

Maternal consumption of a high-fat diet (mHFD) during perinatal life influences hypothalamic-pituitary-adrenal (HPA) axis activation and impacts the long-term physiological and metabolic health of offspring. Milk-derived extracellular vesicles (MEVs) are lipid-coated nanovesicles that transfer biological materials from mother to infant and can survive intestinal degradation and cross the blood-brain barrier. MEVs provide cytoprotection in peripheral organs; however, their pro-survival functions remain unknown in the neonatal brain. Further, sex differences resulting from MEV treatment require investigation, as male and female neonates display variable responses to early life nutrient stress. We investigated the interaction between MEVs and the heat shock protein response in the liver, hypothalamus, and prefrontal cortex in male and female neonatal rats exposed to perinatal mHFD at postnatal day 11. MEV treatment robustly modulated the HSR in female neonates with the largest response recorded in the prefrontal cortex. These results suggest that MEVs may influence pro-survival outcomes in the prefrontal cortex by activating HSF1-mediated pro-survival in a sex-specific manner.