脂肪激素 Mimecan 抑制食欲的机制研究

In our previous study, Mimecan was found a novel hormone secreted by adipose tissue, exerting anorexic effect. It is proposed that inflammatory factors in the hypothalamus is involved in the anorexic effect of Mimecan. In this project, we will further study the mechanisms by which Mimecan regulating food intake. The main items include: 1. To clarify the effect of Mimecan on activation of microglia and the expression of IL-1β and IL-6. 2. To clarify the anorexic effect elicted by Mimecan is mediated by the inflammatory factors, including IL-1β and IL-6 secreted from microglia. 3 To clarify the anorexic effect elicted by Mimecan is mediated by inflammatory factors influencing the activity of POMC and NAG neurons. 4. To clarify the effect of Mimecan on microglia is mediated via TLR4 pathway.

我们课题组早期发现一种新的脂肪激素Mimecan具有显著抑制食欲的作用，推测可能通过下丘脑小胶质细胞分泌炎症因子发挥抑制食欲的作用。在本项目中，我们将深入研究Mimecan抑制食欲的作用机制。主要的研究内容包括：1.明确Mimecan对下丘脑小胶质细胞的活化，以及对炎症因子IL-1β和IL-6的影响。2.明确Mimecan通过促进下丘脑小胶质细胞分泌的炎症因子IL-1β和IL-6，发挥抑制食欲，降低体重的作用。3.明确Mimecan通过小胶质细胞分泌的炎症因子影响下丘脑食欲调节神经元的活性和神经内分泌功能，抑制食欲。4.明确Mimecan是否通过TLR4途径激活小胶质细胞炎症反应，促进炎症因子的表达。揭示Mimecan抑制食欲的作用机制，为肥胖症的治疗探索新思路和新途径。

脂肪激素Mimecan是申请人所在课题组早期发现的一种新的，通过促进胶质细胞分泌炎症因子抑制食欲作用的脂肪激素。在本项目中，我们在多种细胞模型，以及TLR4基因敲除小鼠腹腔巨噬细胞中进一步研究Mimecan促炎作用的分子机制，明确Mimecan是通过TLR4途径，激活下游IKK/NFκB、P38-MAPK、JNK等炎症信号通路，同时促进il-1β、il-6、tnf-α、mcp-1、p65等炎症因子的高表达。当特异性阻断IKK/NFκB途径时，Mimecan对炎症因子的促进作用被有效抑制，揭示了Mimecan通过TLR4途径激活IKK/NFκB炎症信号通路，促进炎症因子的高表达的作用途径。此外，我们还发现Mimecan敲除后，小鼠胰岛素敏感性改善，胰岛素靶器官肌肉组织炎症反应下降，提示Mimecan可能通过调控炎症反应影响机体食欲和胰岛素敏感性，维持机体的能量代谢稳态