Abstract
Major depression disorder is a severe mental illness often linked with metabolic disorders. Adiponectin is an adipocyte-secreted circulatory hormone with antidiabetic and glucose/lipid modulation capacities. Studies have demonstrated the pathophysiological roles of adiponectin involved in various neurological disorders, including depression. However, the underlying mechanisms are poorly understood. Here we showed that adiponectin deprivation enhanced antidepressive-like behaviors in the LPS-induced model of depression. APN KO mice displayed increased cytokines (both pro and anti-inflammatory), accompanied by an impaired expression of adiponectin receptors (mRNA/protein level) and decreasing IBA-1 level in the cortex and primary microglia of LPS treated APN KO mice. Further, LPS-treatment significantly reduced p-NFκB expression in the microglia of APN KO mice. However, the Bay11-7082 treatment recovered p-NFκB expression in the cortex of APN KO mice in the presence of LPS. Interestingly, the antidepressant potentials of APN KO mice were abolished by TrkB antagonist K252a, IKK inhibitor Bay11-7082, and AdipoRon suggesting crosstalk between TrkB/BDNF signaling and NFκB in depression. Furthermore, the effects of Bay11-7082 were abolished by a TrkB/BDNF activator (7,8-DHF), indicating a critical role of TrkB/BDNF signaling. Taken together, these findings showed that dysregulated neuroinflammatory status and BDNF signaling might underlie the antidepressive-like behaviors of APN KO mice. NFκB elicited BDNF changes may be accountable for the pathogenesis of LPS induced depression, where APN might present an alternative therapeutic target for depressive disorders.
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Acknowledgements
Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China. This work was supported by Grants Science and Technology Innovation Committee of Shenzhen No: JCYJ20170810163329510; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions No: 2019SHIBS0004; Sanming Project of Medicine in Shenzhen (No. SZSM201911003) Shenzhen Key Medical Discipline Construction Fund (No.SZXK06162); Shenzhen bay laboratory NO:SZBL2019062801003.
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WL designed and performed the experiments, TA data analysis, wrote the manuscript, Chengyou Zheng, Kaiwu He, and Zizhen Liu helped in the experiment; Fawad Ali Shah, Ningning Li, and Zhi-Jian Yu helped in manuscript, experimental tools and supported the study. SL endorsed the study, corresponding authors, reviewed and approved the manuscript, and held all the responsibilities related to this manuscript. All authors reviewed and approved the manuscript.
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Li, W., Ali, T., Zheng, C. et al. Anti-depressive-like behaviors of APN KO mice involve Trkb/BDNF signaling related neuroinflammatory changes. Mol Psychiatry 27, 1047–1058 (2022). https://doi.org/10.1038/s41380-021-01327-3
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DOI: https://doi.org/10.1038/s41380-021-01327-3
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