Altered Hippocampal Transcriptomic Profile Reveals Cognitive Impairment in Young Metabolically Obese, Normal‐Weight Rats, Prevented by Perinatal Leptin Intake

Early-life metabolic environment significantly impacts long-term cognitive and metabolic health. This study investigates transcriptomic alterations in the hippocampus and peripheral blood mononuclear cells (PBMC) of young rats exposed to an isocaloric high-fat diet (HFD), resulting in the metabolically obese, normal-weight (MONW) phenotype. Rats were pair-fed either a standard (NW group) or HFD (MONW group) for 11 weeks after weaning. Another group (MONW-Lep) received leptin supplementation during lactation and subsequently HFD. Transcriptomic analysis of the hippocampus showed disruption of pathways linked to obesity and cognitive decline in the MONW group, which were attenuated by leptin intake. This was consistent with the results of working memory (T-maze test), impaired in MONW versus NW, but preserved in MONW-Lep animals. PBMC transcriptomics revealed overlapping genes with the hippocampus. Notably, Piwil1, a gene linked to neurodegeneration, metabolic syndrome and obesity, was up-regulated in PBMC of MONW but not of MONW-Lep animals, reflecting early hippocampal changes and leptin's preventive effect. These findings highlight the influence of early nutrition on cognitive health, the protective potential of leptin counteracting the effects of HFD intake and the usefulness of PBMC as a reliable source of biomarkers of brain health.