Obesity-induced memory deficits in female rats are oestrous cycle-dependent and linked to impaired brain kynurenine pathway metabolism

Introduction: Obesity is associated with impaired learning, but the mechanisms underlying this cognitive dysfunction are poorly understood. Moreover, whether obesity-induced learning deficits show sexual dimorphism remains controversial. Females are believed to be protected from cognitive decline by oestrogens. These hormones enhance the expression of tryptophan hydroxylase-2, the rate-limiting enzyme in the transformation of tryptophan (Trp) into serotonin which plays a significant role in learning and memory. However, several learning-regulating compounds also arise from Trp metabolism through the kynurenine pathway (KP), including kynurenic acid (KA), xanthurenic acid (XA), and NAD+. The present study aimed to determine the involvement of the kynurenine pathway of Trp metabolism in the regulation of learning in control and obese female rats. Methods: The learning capabilities of control and obese rats were evaluated using the Novel Object Recognition test. Tryptophan and Trp-derived metabolites were quantified in the hippocampus and frontal cortex by ultra-performance liquid chromatography-tandem mass spectrometry. Results: Control rats in proestrus/oestrus performed better than their control mates in metestrus/dioestrus. Likewise, while control and obese rats in dioestrus/metestrus did not show differences in learning, obese rats in proestrus/oestrus displayed decreased memory capacity along with decreased Trp concentration and reduced KA, XA, and NAD+ production in the hippocampus. These neurochemical alterations were associated with impaired expression of mRNAs coding for key enzymes of the KP. Discussion/Conclusion: The results presented here indicate that the deleterious effects of obesity on learning are closely related to the oestrous cycle and associated with an impairment of the kynurenine pathway of tryptophan metabolism.