Trimethylamine N-Oxide Derived from a High-Protein Diet Induces Insulin Resistance in Pregnant Mice via Gut Microbiota Remodeling

Insulin resistance (IR) is a significant risk factor for various diseases, particularly during pregnancy. Dietary patterns have been reported to influence IR susceptibility. High-protein (HP) diet has gained popularity for its role in weight management. However, whether trimethylamine N-oxide (TMAO), which is produced in the liver from gut microbiota-derived metabolites of dietary protein, influences IR remains uncertain. In this study, we established a pregnant mouse model to examine the effect of an HP diet on IR, assess its impact on liver function, and investigate associated signaling pathways. The role of gut microbiota was also evaluated. We found that the HP diet induced liver injury in pregnant mice following significantly decreased body weight. The HP diet also elevated plasma TMAO levels and upregulated hepatic FMO3 expression. Transcriptomic analysis revealed enrichment of insulin-related signaling pathways in the HP group, with notable downregulation of the Insrr gene. IR was induced through the IRS-1/PI3K/Akt signal pathway. Gut microbiota composition was disrupted in HP group, characterized by an increased Firmicutes/Bacteroidetes ratio and a higher abundance of the TMA-producing genus Coprococcus, indicating an elevated potential for TMA generation. Furthermore, several amino acid metabolism pathways closely linked to IR were also enriched in the HP group. In conclusion, our study demonstrates that HP diet induces liver injury and increases IR risk during pregnancy. Gut microbiota contributes to this process, in part through an enhanced capacity for TMA production. These findings highlight the need for greater attention to dietary patterns in pregnancy to mitigate metabolic risks.