The role of cecal metabolites and DNA methylation in deciphering the effects of maternal genistein intake on white fat browning in adult female offspring

Maternal diets during pregnancy and lactation are critical determinants that regulate the metabolic homeostasis in offspring. Our previous research demonstrated that maternal genistein (GEN) intervention ameliorated the dysregulation of glucolipid metabolism induced by intrauterine overnutrition in adult offspring, accompanied by changes in the composition of gut microbiota; however, the underlying mechanisms remain unclear. Here, we used a maternal overnutrition model induced by excess energy intake before and throughout pregnancy and lactation, with maternal GEN administered during the same period. The female offspring were raised on a standard chow diet until sacrificed at 24 weeks. The mRNA levels of browning markers were quantified in inguinal subcutaneous adipose tissues, followed by methylation analysis <i>via</i> the MassArray method. Cecal contents were collected for untargeted metabolomic analysis and a target quantitative analysis of methionine cycle metabolites. Spearman correlation analyses were used to assess whether cecal metabolites are involved in the methylation of browning-related genes and influence their expression. The results showed that maternal GEN supplementation reversed the downregulation of browning markers caused by perinatal high-fat diets in adult female offspring, consistent with a reduction in their methylation levels. Subsequently, we also found that maternal GEN consumption altered cecal metabolite profiles in offspring, promoting the production of bile acids, potent regulators of glucolipid metabolism, and reducing metabolites involved in the methionine cycle, key methyl donors for the methylation process. Furthermore, the abundances of these metabolites were significantly correlated with the methylation and expression levels of browning markers. Overall, this discovery suggested that maternal GEN intake decreased the methylation level of browning markers and induced browning in white adipose tissue of offspring, which correlated with alterations in cecal metabolites. We provide a novel theoretical basis for GEN as a promising nutritional supplement to break the vicious cycle of maternal metabolic disturbances being transmitted to offspring.