4.5 Article

Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice

期刊

NEUROCHEMISTRY INTERNATIONAL
卷 131, 期 -, 页码 -

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2019.104563

关键词

AKT; Anorexia; Hypothalamus; Inflammation; PRIP; STAT3

资金

  1. JSPS KAKENHI [15K19731, 17K11670, 17H01595, 17K19766, 16K11503]
  2. Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development (AMED) [16dm0107093h0001]
  3. Grants-in-Aid for Scientific Research [17K11670, 15K19731, 16K11503, 17K19766, 17H01595] Funding Source: KAKEN

向作者/读者索取更多资源

Peripheral lipopolysaccharide (LPS) injection induces systemic inflammation through the activation of the inhibitor of nuclear factor kappa B (NF-kappa B) kinase (IICIC)/NF-kappa B signaling pathway, which promotes brain dysfunction resulting in conditions including anorexia. LPS-mediated reduction of food intake is associated with activation of NF-kappa B signaling and phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. We recently reported phospholipase C-related catalytically inactive protein (PRIP) as a new negative regulator of phosphatidylinositol 3-kinase/AKT signaling. AKT regulates the IKK/NF-kappa B signaling pathway; therefore, this study aimed to investigate the role of PRIP/AKT signaling in LPS-mediated neuroinflammation-induced anorexia. PRIP gene (Pripl and Prip2) knockout (Prip-KO) mice intraperitoneally (ip) administered with LPS exhibited increased anorexia responses compared with wild-type (WT) controls. Although few differences were observed between WT and Prip-KO mice in LPS-elicited plasma pro-inflammatory cytokine elevation, hypothalamic pro-inflammatory cytokines were significantly upregulated in Prip-KO rather than WT mice. Hypothalamic AKT and IKK phosphorylation and I kappa B degradation were significantly increased in Prip-KO rather than WT mice, indicating further promotion of AKT-mediated NF-kappa B signaling. Consistently, hypothalamic STAT3 was further phosphorylated in Prip-KO rather than WT mice. Furthermore, suppressor of cytokine signaling 3 (Socs3), a negative feedback regulator for STAT3 signaling, and cyclooxogenase-2 (Cox2), a candidate molecule in LPS-induced anorexigenic responses, were upregulated in the hypothalamus in Prip-KO rather than WIC mice. Pro-inflammatory cytokines were upregulated in hypothalamic microglia isolated from Prip-KO rather than WT mice. Together, these findings indicate that PRIP negatively regulates LPS-induced anorexia caused by pro-inflammatory cytokine expression in the hypothalamus, which is mediated by AKT-activated NF-kappa B signaling. Importantly, hypothalamic microglia participate in this PRIP-mediated process. Elucidation of PRIP-mediated neuroinflammatory responses may provide novel insights into the pathophysiology of many brain dysfunctions.

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