Cardiotrophin-1 (CT-1) Improves High Fat Diet-Induced Cognitive Deficits in Mice

Previous studies demonstrated that a high fat diet (HFD) results in a loss of working memory in mice correlated with neuroinflammatory changes as well as synaptodendritic abnormalities and brain insulin resistance. Cardiotrophin-1 (CT-1), a member of the gp130 cytokine family, has been shown to potentially play a critical role in obesity and the metabolic syndrome. Our recent studies have demonstrated that CT-1 attenuates cognitive impairment and glucose-uptake defects induced by amyloid-beta in mouse brain through inhibiting GSK-3 beta activity. In this study, we evaluated the effect of CT-1 on cognitive impairment induced by brain insulin resistance in mice fed a HFD, and explored its potential mechanism. CT-1 (1 mu g/day, intracerebroventricular injection) was given for 14 days to mice that were fed with either a HFD or normal diet for 18 weeks. After 20 weeks of treatment, our results showed that in the HFD group, CT-1 significantly improved learning and memory deficits and alleviated neuroinflammation demonstrated by decreasing brain levels of proinflammatory cytokine tumour necrosis factor-alpha and interleukin-1 beta, and increasing brain levels of anti-inflammatory cytokine IL-10. CT-1 significantly reduced body weight gain, restored normal levels of blood glucose, fatty acids and cholesterol. Furthermore, CT-1 significantly enhanced insulin/IGF signaling pathway as indicated by increasing the expression levels of insulin receptor substrate 1 (IRS-1) and the phosphorylation of Akt/GSK-3 beta, and reducing the phosphorylation of IRS-1 in the hippocampus compared to control. Moreover, CT-1 increased the level of the post-synaptic protein, PSD95, and drebrin, a dendritic spine-specific protein in the hippocampus. These results indicate a previously unrecognized potential of CT-1 in alleviating high-fat diet induced cognitive impairment.