Taurine and N-acetyl-cysteine supplementation prevents memory impairment in high-fat diet-fed female mice

Background: The risk to develop memory impairment in has been widely investigated in type 2 diabetes (T2D). There are several mechanisms proposed for T2D-associated cognitive impairment, such as brain insulin resistance, synaptic dysfunction, inflammation, gliosis, or disruption of neuron-astrocyte interactions (Garcia-Serrano & Duarte, 2020). On the other hand, supplementation with the antioxidants taurine and N-acetylcysteine (NAC) have been suggested to have benefits on reducing T2D phenotype and enhancing memory performance in diabetic mice models (Inam-U-Ilah et al, 2018). We aimed at studying mechanisms by which taurine and NAC improve memory in obesity-associated T2D. Method: Ten-week-old female C57Bl/6J mice were divided in 6 groups (n=10): control diet (CD 10%-fat diet), high-fat diet (HFD; 60% fat diet), CD/HFD supplemented with 3% taurine in drinking water (CD+T or HFD+T) or 3% N-acetylcysteine (CD+NAC or HFD+NAC). After 2 months, hippocampal metabolic profiles were analysed by magnetic resonance spectroscopy (MRS) under isoflurane anaesthesia, memory performance was evaluated by behavioural testing with the novel location recognition (NLR) and novel object recognition (NOR) tasks, and diabetes phenotype was measured by monitoring weight, glucose tolerance test and HOMA insulin resistance. Result: HFD group was overweight compared to CD group (p<0.01), with no effects of taurine or NAC. HFD-fed mice showed glucose intolerance compared to CD mice (p<0.001). Although HFD+T and HFD+NAC groups were glucose intolerant but to a lesser degree than untreated HFD mice (p< 0.05 and p<0.01, respectively). None of the experimental groups displayed insulin resistance, neither memory impairment in the NOR test. The NLR test showed memory impairment in the HFD-fed mice compared to controls (p<0.037), which was prevented by taurine and NAC treatments. The metabolic profile showed decreased concentration of the neuronal marker N-acetylaspartate and lactate in the hippocampus of HFD-fed mice compared to controls (p<0.01). While N-acetylaspartate concentrations were recovered to control levels in both HFD+T and HFD+NAC mice, only HFD+NAC group recovered lactate concentration in the hippocampus. Conclusion: Memory impairment in HFD-fed mice was restored by taurine and NAC treatments, through mechanisms that involve metabolism in mitochondria, which is the organelle responsible for producing N-acetylaspartate in neurons.