Maternal obesity programs offspring metabolic dysfunction via small extracellular vesicle-mediated epigenetic remodeling.

Authors

Huichen Song, Dameng Li, Lina Ma, Jin Wang, Nina Zhang, Chao Yan, Ke Zen, Xi Chen, Qipeng Zhang, Xiaohong Jiang, Jing Li, Zhijuan Ge, Yujing Zhang, Chen-Yu Zhang, Liang Li

Published in

Nature communications. Volume 17. Issue 1. Aug 25, 2026. Epub Aug 25, 2026.

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.

PMID:
42778568
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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