Distinct and stage-specific effects of pre-pregnancy and gestational high-fat diet on maternal metabolism, placental adaptation and gut microbiota in rats.

BACKGROUND: Maternal high-fat diet (HFD) contributes to developmental programming through placental adaptations; however, the effects of exposure timing before and during pregnancy remain unclear. OBJECTIVE: To investigate the distinct effects of pre-pregnancy and gestational HFD on maternal metabolism, pregnancy outcomes, placental oxidative stress, placental gene-expression adaptations, and gut microbiota in rats. METHODS: Female Sprague-Dawley rats were fed a control diet (V) or HFD (H) before and/or during pregnancy, generating four groups (V/V, V/H, H/V, H/H). Maternal metabolic parameters, placental gene expression, oxidative stress, and gut microbiota composition were analyzed at gestational day 21. RESULTS: Pre-pregnancy high-fat diet increased maternal body and liver weights and elevated placental oxidative stress, whereas gestational high-fat diet increased adiposity and impaired glucose tolerance and insulin sensitivity without affecting pregnancy outcomes. Placental nutrient transporters, including glucose transporter 1 (Glut1) and solute carrier family 38 (Slc38) members, were mainly regulated by pre-pregnancy diet. Insulin-like growth factor 2 (Igf2) was influenced by gestational diet and its interaction with pre-pregnancy diet, while insulin-like growth factor 2 receptor (Igf2R) and insulin 2 (Ins2) expression were primarily influenced by pre-pregnancy diet. Forkhead box O1 (FoxO1) and Forkhead box O3 (FoxO3) exhibited differential responses to maternal dietary exposure. Gestational HFD also altered gut microbiota composition without affecting microbial diversity. CONCLUSION: Pre-pregnancy and gestational HFD exert distinct but complementary effects on maternal metabolism and placental adaptations. These findings highlight the stage-specific impact of maternal nutritional status on developmental programming and placental function.