Perinatal nutrition influences offspring metabolic phenotype and obesity risk. This study examines how a maternal obesogenic diet and offspring's leptin supplementation during suckling affect the metabolome in offspring adulthood, offering insights into long-term metabolic programming. Offspring of dams fed a standard diet (SD), a Western-style diet (WD) before and during gestation and lactation (WD-dams), or a WD switched to SD during lactation were supplemented throughout suckling with leptin or vehicle and then maintained on an SD post-weaning. Metabolomic analysis of plasma from offspring adult animals revealed sex-specific alterations in the relative abundance of circulating metabolites due to maternal WD. Among these, lower abundance of orotic acid in males and arginine in females emerged as the most discriminating metabolites between experimental groups influenced by maternal WD during gestation and lactation. These changes, indicative of poor metabolic programming, were largely normalized by dietary intervention during lactation. Leptin supplementation during suckling also induced favorable metabolic adaptations, reflected in lower N-acetylneuraminic acid and choline abundance (both sexes), higher 5-amino valeric acid betaine (males), lower TCA cycle intermediates (fumarate, succinate, malate), and elevated γ-glutamyl peptides (γ-glutamylalanine, γ-glutamylglutamine) (females), suggesting potential anti-inflammatory effects. These findings enhance our understanding of how early-life conditions influence long-term metabolism and underscore the potential of circulating metabolites as biomarkers for assessing perinatal interventions.

Artificial Intelligence Research Institute of the Balearic Islands Palma Spain

CIBER Fisiopatología de la Obesidad y Nutrición Madrid Spain

Health Research Institute of the Balearic Islands Palma Spain

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Molecular Biology Nutrition and Biotechnology University of the Balearic Islands Palma Spain

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