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

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Abstract

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-β in mouse brain through inhibiting GSK-3β 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 μg/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-α and interleukin-1β, 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-3β, 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.

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Abbreviations

CT-1:

Cardiotrophin-1

GSK-3β:

Glycogen synthase kinase-3β

HFD:

High fat diet

IL-10:

Interleukin-10

IL-1β:

Interleukin-1β

IR:

Insulin resistance

IRS-1:

Insulin receptor substrate 1

IIS:

Insulin/IGF signaling

PSD95:

Postsynaptic density protein 95

SYP:

The action of synapsin I

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

The present work was supported by National Natural Science Foundation of China (U1304806 and U1304809) and the Scientific Research Fund of Henan University of Science and Technology (No. 09001664).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathogen Biology, Medical College, Henan University of Science and Technology, Building 6, Anhui, Jianxi District, Luoyang, 471003, People’s Republic of China

    Dongmei Wang, Wenlan Wu, Xiaoying Zhu & Yong Wang

  2. Department of Pharmacy, Medical College, Henan University of Science and Technology, Luoyang, People’s Republic of China

    Ling Liu

  3. Department of Neurology, The First Affiliated Hospital of Henan University of Science and Technology, Jinghua Road 24, Luoyang, People’s Republic of China

    Junqiang Yan

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  1. Dongmei Wang
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Correspondence to Dongmei Wang.

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11064_2015_1535_MOESM1_ESM.tif

Supplementary material Fig. S1 effects of CT-1 on food intake in HFD-induced obese mice. Food intake of mice on a control diet (CD), treated with CT-1 per se (CDC), high-fat diet (HFD), high-fat diet and treated with CT-1 (HFDC) prior to CT-1 treatment (A) and during CT-1 treatment (B) were measured. All data are presented as mean ± S.E.M. (n = 10, # p<0.05 vs. HFD mice). (TIFF 136 kb)

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Wang, D., Liu, L., Yan, J. et al. Cardiotrophin-1 (CT-1) Improves High Fat Diet-Induced Cognitive Deficits in Mice. Neurochem Res 40, 843–853 (2015). https://doi.org/10.1007/s11064-015-1535-z

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