Maternal obesity induces activator protein 1-mediated inflammatory response to impair embryonic neurogenesis

Maternal obesity (MO) is a growing global problem, which poses significant risks to fetal neurodevelopment and long-term neurological functions of offspring, but the underlying molecular mechanisms remain to be established. To address this female mice were fed either a control diet or a high-fat diet (HFD) for 2 months to induce obesity, and the same dietary treatments were maintained during pregnancy. Embryos were sampled at E11.5 and E13.5. Single-cell RNA sequencing revealed reduced proportions of neurons and neural progenitors in embryos from obese mothers. The downregulation of neurogenesis, nervous system development and synaptic organization pathways were further confirmed by Gene Ontology analysis. Key neurogenic transcription factors, including Neurod1, Neurog2 and Ascl1, were suppressed in MO embryos, accompanied by increased expression of inflammatory markers, including tumour necrosis factor-α (TNF-α) and Cxcl2, and inflammatory signalling mediators, Fos, Jun and Jund. Single-cell ATAC sequencing revealed the activator protein 1 (AP-1) binding sites in the promoter regions of Tnf and Cd68, with MO-enhancing AP-1 transcription factor motif activity and increased chromatin accessibility in the loci of Tnfa and Cd68 genes. Furthermore, TNF-α treatment of neurogenic cells suppressed Neurod1 and Neurog2 expression, suggesting a direct link between inflammatory signalling and impaired neurogenesis. Our findings suggest that MO creates a pro-inflammatory environment that disrupts neurogenesis during early embryonic development, providing new insights into the neurodevelopmental disorders in offspring born to obese mothers. KEY POINTS: Maternal obesity (MO) suppresses neurogenesis in the early embryos. Single-cell RNA sequencing (scRNA-seq) reveals decreased neurogenic cells and neurogenic factors in MO embryos. MO elevates activator protein 1 (AP-1) transcription factor accessibility to the promoters of inflammatory genes. Inflammation induced by tumour necrosis factor-α (TNF-α) suppresses Neurod1 and Neurog2 expression and neurogenesis in vitro.