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Role of Bmal1 in Type 2 Diabetes Mellitus-Related Glycolipid Metabolic Disorder and Neuropsychiatric Injury: Involved in the Regulation of Synaptic Plasticity and Circadian Rhythms

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Abstract

Increasing data suggest a crucial role of circadian rhythm in regulating metabolic and neurological diseases, and Bmal1 is regarded as a key regulator of circadian transcription. The aim of this study is to investigate the role of Bmal1 in the disruption of circadian rhythm and neuropsychiatric injuries in type 2 diabetes mellitus (T2DM). A T2DM model was induced by the combination of high-fat-diet (HFD) and streptozotocin (STZ) in vivo or HT-22 cells challenged with palmitic-acid (PA) in vitro. The glucolipid metabolism indicators, behavioral performance, and expression of synaptic plasticity proteins and circadian rhythm-related proteins were detected. These changes were also observed after interference of Bmal1 expression via overexpressed plasmid or small interfering RNAs in vitro. The results showed that HFD/STZ could induce T2DM-like glycolipid metabolic turmoil and abnormal neuropsychiatric behaviors in mice, as indicated by the increased concentrations of fasting blood-glucose (FBG), HbA1c and lipids, the impaired glucose tolerance, and the decreased preference index of novel object or novel arm in the novel object recognition test (NOR) and Y-maze test (Y-maze). Consistently, the protein expression of synaptic plasticity proteins and circadian rhythm-related proteins and the positive fluorescence intensity of MT1B and Bmal1 were decreased in the hippocampus of HFD/STZ-induced mice or PA-challenged HT-22 cells. Furthermore, overexpression of Bmal1 could improve the PA-induced lipid metabolic dysfunction and increase the decreased expressions of synaptic plasticity proteins and circadian rhythm-related proteins, and vice versa. These results suggested a crucial role of Bmal1 in T2DM-related glycolipid metabolic disorder and neuropsychiatric injury, which mechanism might be involved in the regulation of synaptic plasticity and circadian rhythms.

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The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

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Acknowledgements

The authors would like to thank the Center for Scientific Research of Anhui Medical University for valuable help in our experiment and Dr. Qiao Jinping, who assisted in the manuscript revision and polishing.

Funding

This study is funded by the National Natural Science Foundation of China (81870403), Foundation for the Top Talents in the University of Anhui Province (gxbjZD2022013), and Scientific Research Promotion Plan of Anhui Medical University (2022xkjT009).

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Author notes

  1. Xinran Gao and Yadong Wei contribute equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China

    Xinran Gao, Yadong Wei, Huaizhi Sun, Shengwei Hao, Mengdie Ma, Huimin Sun & Jinfang Ge

  2. The Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China

    Xinran Gao, Yadong Wei, Huaizhi Sun, Shengwei Hao, Mengdie Ma, Huimin Sun & Jinfang Ge

  3. Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, China

    Xinran Gao, Yadong Wei, Huaizhi Sun, Shengwei Hao, Mengdie Ma, Huimin Sun & Jinfang Ge

  4. The Center for Scientific Research of Anhui Medical University, Hefei, China

    Dandan Zang

  5. Department of Laboratory Animal Science, Fudan University, Shanghai, China

    Congcong Qi

Authors
  1. Xinran Gao
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  9. Jinfang Ge
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Contributions

Prof. Jinfang Ge designed the experiment and supervised the project. Ms. Xinran Gao and Mr. Yadong Wei conducted the experiment and completed the first manuscript with support from Prof. Jinfang Ge. Prof. Congcong Qi contributed to the animal experiment. Ms. Dandan Zang contributed to the immunofluorescence. Mr. Huaizhi Sun, Mr. Shengwei Hao, Ms. Mengdie Ma, and Ms. Huimin Sun helped preparing and performing behavioral tests.

Corresponding author

Correspondence to Jinfang Ge.

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Ethics Approval

The animal study protocol was approved by the Animal Care and Use Committee of Anhui Medical University in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication No. 85–23, revised 1985).

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Gao, X., Wei, Y., Sun, H. et al. Role of Bmal1 in Type 2 Diabetes Mellitus-Related Glycolipid Metabolic Disorder and Neuropsychiatric Injury: Involved in the Regulation of Synaptic Plasticity and Circadian Rhythms. Mol Neurobiol 60, 4595–4617 (2023). https://doi.org/10.1007/s12035-023-03360-5

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