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C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation

  • Ye, Liu1
  • Jia, Gongwei1
  • Li, Yuejie1
  • Wang, Ying1
  • Chen, Hong2
  • Yu, Lehua1
  • Wu, Dandong1
  • 1 The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010, China , Chongqing (China)
  • 2 The First Affiliated Hospital of Chongqing Medical University, Chongqing, China , Chongqing (China)
Published Article
Journal of Neuroinflammation
Springer (Biomed Central Ltd.)
Publication Date
Jul 18, 2021
DOI: 10.1186/s12974-021-02167-2
Springer Nature
  • Research


ObjectiveC1qTNF-related protein 4 (CTRP4) acts in the hypothalamus to modulate food intake in diet-induced obese mice and has been shown to exert an anti-inflammatory effect on macrophages. Since high-fat diet-induced microglial activation and hypothalamic inflammation impair leptin signaling and increase food intake, we aimed to explore the potential connection between the anorexigenic effect of CTRP4 and the suppression of hypothalamic inflammation in mice with DIO.MethodsUsing an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and the hypothalamic leptin signaling pathway in diet-induced obese mice. Furthermore, central and plasma proinflammatory cytokines, including TNF-α and IL-6, were measured by Western blotting and ELISA. Changes in the hypothalamic NF-κB signaling cascade and microglial activation were also examined in vivo. In addition, NF-κB signaling and proinflammatory factors were investigated in BV-2 cells after CTRP4 intervention.ResultsWe found that food intake was decreased, while leptin signaling was significantly improved in mice with DIO after CTRP4 overexpression. Central and peripheral TNF-α and IL-6 levels were reduced by central Ad-CTRP4 administration. Hypothalamic NF-κB signaling and microglial activation were also significantly suppressed in vivo. In addition, NF-κB signaling was inhibited in BV-2 cells following CTRP4 intervention, which was consistent with the decreased production of TNF-α and IL-6.ConclusionsOur data indicate that CTRP4 reverses leptin resistance by inhibiting NF-κB-dependent microglial activation and hypothalamic inflammation.

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