The Metabolically Obese, Normal-Weight Phenotype in Young Rats Is Associated with Cognitive Impairment and Partially Preventable with Leptin Intake during Lactation

Abstract

The intake of high-fat diets (HFDs) and obesity are linked to cognitive impairment. Here, we aimed to investigate whether an early metabolically obese, normal-weight (MONW) phenotype, induced with an HFD in young rats, also leads to cognitive dysfunction and to evaluate the potential cognitive benefits of neonatal intake of leptin. To achieve this, Wistar rats orally received physiological doses of leptin or its vehicle during lactation, followed by 11 weeks of pair-feeding with an HFD or control diet post-weaning. Working memory was assessed using a T-maze, and gene expression in the hippocampus and peripheral blood mononuclear cells (PBMCs) was assessed with real-time RT-qPCR to identify cognition biomarkers. Young MONW-like rats showed hippocampal gene expression changes and decreased working memory. Animals receiving leptin during lactation presented similar gene expression changes but preserved working memory despite HFD intake, partly due to improved insulin sensitivity. Notably, PBMC Syn1 expression appears as an accessible biomarker of cognitive health, reflecting both the detrimental effect of HFD intake at early ages despite the absence of obesity and the positive effects of neonatal leptin treatment on cognition. Thus, the MONW phenotype developed at a young age is linked to cognitive dysfunction, which is reflected at the transcriptomic level in PBMCs. Neonatal leptin intake can partly counteract this impaired cognition resulting from early HFD consumption.