Sex‐Specific Lasting Metabolome Effects of Adverse Gestational Conditions and Prevention by Myo‐Inositol Supplementation During Suckling

This study examines the protective effects of myo‐inositol supplementation during suckling on long‐term negative outcomes caused by fetal energy restriction, using a metabolomics approach.Offspring of rats from both control and 25% gestational calorie‐restricted dams received either myo‐inositol or the vehicle during suckling and were exposed to a Western diet (WD) between 5 and 7 months of age. Metabolomics analysis of plasma samples at 7 months allowed the identification of 164 metabolites, revealing marked sex differences to gestational restriction. In males, maternal calorie restriction resulted in alterations in 19 metabolites, while only six metabolites showed significant variations in females, consistent with a lower impact of gestational calorie restriction (GCR) on the adult phenotype. Supplementation with myo‐inositol normalized the levels of 16 metabolites in males and all six in females. Functionally, myo‐inositol mostly targeted liver‐associated functions in males and metabolic control functions in females. Mild/moderate GCR leads to significant changes in the metabolomic profiles of adult offspring, with males experiencing higher metabolic alterations. Early postnatal myo‐inositol supplementation may be a promising strategy to alleviate the negative metabolic effect of maternal undernutrition. Sex‐specific differences in the metabolomic response emphasize the necessity of considering both sexes for effective interventions.