Influence of Maternal Obesity on the Development of the Central Nervous System

Obesity is a global health concern with significant intergenerational consequences, particularly for women of reproductive age and their offspring. Maternal obesity increases the risk of neurocognitive impairments in the progeny, partly through the developmental programming of tissue-resident macrophages, which originate from the yolk sac and can be shaped by their environment. Among these, microglia - the resident macrophages of the brain parenchyma, are particularly long lived, capable of self-renewal, and highly susceptible to developmental programming. In this study, we investigated which factors of mice exposed to high-fat diet (HFD) influence the developmental programming of offspring microglia, their overall phenotype, and the resulting consequences for brain development. The exposure to HFD in dams decreased the overall diversity of the gut microbiota. Subsequent analysis revealed a potential involvement of specific bacterial families in nutrient metabolism, with corresponding metabolite changes observed in the sera of mothers and offspring, and within the offspring's brain. Using fluorescence microscopy and flow cytometry, significant changes in microglia morphology and function were identified. Maternal obesity results in a region-, and gender-dependent alteration of microglial volume and branch length. Furthermore, microglial engulfment of synaptic material was significantly reduced, by approximately 25%. This functional deficit was corroborated by snRNA-seq analysis, which showed a lowered expression of genes of the complement system and cathepsins, a family of proteins involved in lysosomal degradation. Overall, our findings indicate that maternal diet in prenatal and perinatal stages influences microglial morphology and function in the offspring. This study presents potential mechanisms linking diet-induced changes to alterations in the maternal gut microbiota and circulating metabolites. Unraveling the impact of microglia, maternal derived factors and their underlying mechanisms could open up possibilities for early interventions in neurocognitive disorders. Furthermore, it potentially proposes maternal biomarkers to predict future neurocognitive susceptibilities in the offspring.