Learning Deficits Induced by High-Calorie Feeding in the Rat are Associated With Impaired Brain Kynurenine Pathway Metabolism

Abstract

In addition to be a primary risk factor for type 2 diabetes and cardiovascular disease, obesity is associated with learning disabilities. Here we examined whether a dysregulation of the kynurenine pathway (KP) of tryptophan (Trp) metabolism might underlie the learning deficits exhibited by obese individuals. The KP is initiated by the enzymatic conversion of Trp into kynurenine (KYN) by indoleamine 2,3-dioxygenase (IDO). KYN is further converted to several signaling molecules including quinolinic acid (QA) which has a negative impact on learning. Wistar rats were fed either standard chow or made obese by exposure to a free choice high-fat high-sugar (fcHFHS) diet. Their learning capacities were evaluated using a combination of the novel object recognition and the novel object location tasks, and the concentrations of Trp and KYN-derived metabolites in several brain regions determined by ultra-performance liquid chromatography-tandem mass spectrometry. Male, but not female, obese rats exhibited reduced learning capacity characterized by impaired encoding along with increased hippocampal concentrations of QA, Xanthurenic acid (XA), Nicotinamide (Nam), and oxidized Nicotinamide Adenine Dinucleotide (NAD+). In contrast, no differences were detected in the serum levels of Trp or KP metabolites. Moreover, obesity enhanced the expression in the hippocampus and frontal cortex of kynurenine monooxygenase (KMO), an enzyme involved in the production of QA from kynurenine. QA stimulates the glutamatergic system and its increased production leads to cognitive impairment. These results suggest that the deleterious effects of obesity on cognition are sex dependent and that altered KP metabolism might contribute to obesity-associated learning disabilities.

Adult rats sired by obese fathers present learning deficits associated with epigenetic and neurochemical alterations linked to impaired brain glutamatergic signaling

“…Indeed, KA blocks the actions modulated by α7 nicotinic acetylcholine (α7nAChR) and NMDA receptors, whereas excessive activation of NMDA receptors by QA leads to neurotoxicity. In a previous study, we found that obesity‐induced memory deficits are linked to increased concentrations of KA and QA in the brain 34 . Therefore, we sought to determine whether the learning deficits in the offspring of obese parents could be underpinned by impaired production of these two neuroactive compounds.…”

“…In a previous study, we found that obesity-induced memory deficits are linked to increased concentrations of KA and QA in the brain. 34 Therefore, we sought to determine whether the learning deficits in the offspring of obese parents could be T A B L E 1 Statistical differences in the expression levels of genes coding for AMPA and NMDA receptor subunits and markers of glutamate-mediated synaptic plasticity in the brain of adult rats born to obese mothers or sired by obese fathers. underpinned by impaired production of these two neuroactive compounds.…”