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.

Keywords: biomarker; cognitive function; leptin; perinatal programming; prevention; visceral obesity.

Figure 1

Impact of different diets on spatial working memory using spontaneous alternation paradigm in a T-maze. Groups are the same as those described in Table 1. Five trials per rat were performed, and the percentage of alternation was computed for each respective group. Results are expressed as mean ± SEM (n = 8 in the control NF and HFD groups; n = 10 in the Lep-HFD group). Statistical analysis: significant differences indicated by values with non-shared letters (a, b) (one-way ANOVA, p < 0.05). The LSD post hoc was used following the ANOVA analysis. Additionally, asterisks (*) indicate a significant difference compared with the control group (Student’s t-test, p < 0.05).

Figure 2

Impact of different diets on the expression of genes associated with cognitive impairment in the hippocampus. Groups are the same as those described in Table 1. Real-time RT-qPCR was used to quantify mRNA expression levels. Results are expressed as mean ± SEM (n = 8 in the NF and HFD groups; n = 10 in the Lep-HFD group) of the ratios of specific mRNA levels normalized against Gdi1, which served as a reference gene. The data for the control group were established as 100%, serving as a reference to the rest of the values. Statistical analysis: same as that described in Figure 1.

Figure 3

Impact of different diets on the expression of genes associated with cognitive impairment in PBMCs. Male Wistar rats of the groups explained in Table 1 at the age of 2 (A) and 3.5 (B) months. Real-time RT-qPCR was used to quantify mRNA expression levels. Results are expressed as mean ± SEM (n = 8 in the NF and HFD groups; n = 10 in the Lep-HFD group) of ratios of specific mRNA levels normalized against Gdi1, which served as a reference gene. The data for the control group were established as 100%, serving as a reference to the rest of the values. Statistical analysis: same as that described in Figure 1.