KLF7在肥胖诱发脂肪细胞炎症反应中的作用及机制研究

The fact that obesity induces inflammation which further leads to insulin resistance is the key factor of metabolic syndrome, the mechanism of which is still unclear. Results of our previous research showed that KLF7 was involved in the inflammatory response of adipose tissue. Our preliminary results showed that KLF7 could significantly promote PKCζ of adipose cell, inflammatory factor expression and p65 phosphorylation. It has been reported that PKCζ could promote p65 phosphorylation. With these previous researches in mind we put forward the hypothesis: Under the condition of obesity, KLF7 promotes p65 phosphorylation by transcriptionally activating PKCζ; Meanwhile, KLF7 can act as co-activator of p65 to promote the expression of such inflammatory factors as IL-6, IL-1β and MCP-1.In research we utilized adipose tissue KLF7 specific knockout mouse model and primarily cultured mouse adipocyte to determine that KLF7 promotes p65 phosphorylation and the expression of inflammatory factor by enhancing PKCζ expression; we also cultured 293T cells in vitro to clarify the transcriptionalactivation effect of KLF7 on PKCζ and to clarify KLF7’s acting as co-activator of p65 to promote the expression of inflammatory factors. By elucidating the role and mechanism of KLF7 in the obesity induced inflammatory response of adipocytes,we hope to provide a new target for the treatment of obesity and relevant metabolic diseases.

肥胖诱发炎症，继而导致胰岛素抵抗是代谢综合征发生的关键。但肥胖导致炎症的机制尚不明确。课题组前期结果表明，KLF7参与脂肪组织炎症反应。预试验结果发现：KLF7可显著促进脂肪细胞PKCζ、炎症因子表达及p65磷酸化。已有文献表明，PKCζ可促进p65磷酸化。我们提出假设：肥胖状态下，KLF7通过转录激活PKCζ促进p65磷酸化；同时KLF7可作为p65共激活因子协同促进IL-6、IL-1β和MCP-1等炎症因子表达。本研究利用脂肪组织KLF7特异性敲除肥胖小鼠模型和原代培养的小鼠脂肪细胞，明确KLF7通过上调PKCζ表达，促进p65磷酸化及下游炎症因子表达；体外培养293T细胞，明确KLF7对PKCζ的转录激活作用；明确KLF7作为p65共激活因子协同促进炎症因子表达。阐明KLF7在肥胖诱发脂肪细胞炎症过程中的作用及机制，为治疗肥胖及其相关代谢性疾病提供新的靶点。

肥胖是一种慢性炎症状态，与多种代谢性疾病的发生密切关，包括胰岛素抵抗、2型糖尿病和心血管疾病等，但其具体的分子机制目前尚不完全清楚。本研究在构建动物模型及体外培养细胞的的基础上，明确（1）KLF7是否通过PKCζ/NF-κB信号通路，诱发脂肪细胞炎症反应；（2）棕榈酸是否通过激活GPR40/GPR120-NF-κB信号通路上调KLF7表达，诱发炎症反应、抑制葡萄糖消耗能力及胰岛素敏感性；（3）棕榈酸是否通过上调/激活GPR120/GPR40/p38 MAPK信号通路抑制脂肪细胞KLF15的表达，继而导致脂肪细胞糖代谢紊乱。通过本项目的实施，得到如下结论：（1）KLF7可通过靶向上调PKCζ激活NF-κB信号通路，促进脂肪细胞炎症因子的表达。（2）棕榈酸可通过激活GPR40/GPR120促进p-65磷酸化上调KLF7表达，引发脂肪细胞炎症反应，抑制细胞GLUT4表达及葡萄糖消耗能力。（3）棕榈酸通过GPR120促进p38 MAPK的磷酸化，进而抑制KLF15表达，导致脂肪细胞糖消耗能力的降低。本项目的实施为临床寻找治疗肥胖诱发的炎症及相关代谢疾病新靶点提供实验依据和理论基础。依托本项目，共发表科研论文 6 篇，其中 SCI 收录 5 篇（JCR 1 区），培养硕士研究生3名。