Maternal obesity programs offspring metabolic dysfunction via small extracellular vesicle-mediated epigenetic remodeling
TL;DR
It is shown that maternal circulating small extracellular vesicles crossed the placenta and delivered obesity-associated miRNAs to the fetal liver, with lasting consequences for insulin sensitivity in male offspring, and a transplacental sEV-miRNA-epigenetic axis is identified as a mediator of maternal obesity.
Abstract
Maternal obesity is linked to heightened metabolic disease risk in offspring, but the mediators of this intergenerational effect remain unclear. Using a diet-induced obesity (DIO) mouse model, we showed that maternal circulating small extracellular vesicles (sEVs) crossed the placenta and delivered obesity-associated miRNAs to the fetal liver, with lasting consequences for insulin sensitivity in male offspring. Among these miRNAs, miR-29a-3p was pathologically elevated and targeted both DNA methyltransferases and demethylases, thereby reshaping the DNA methylation landscape. This included hypomethylation of the Pgc-1α locus, a key regulator of gluconeogenesis, which resulted in premature activation of hepatic gluconeogenesis that contributed to the persistent metabolic dysfunction in adulthood in male offspring. These findings identify a transplacental sEV-miRNA-epigenetic axis that perturbs fetal metabolic programming and may represent a conserved mechanism underlying the developmental origins of metabolic disease. The study identifies a transplacental sEV–miRNA–epigenetic axis as a mediator of maternal obesity. Maternal plasma sEVs transfer miR-29a-3p to the fetal liver, epigenetically reprogramming glucose metabolism and driving adult insulin resistance.