内源性二氧化硫通过次磺酸修饰NF-kappa B p65抑制TNF-alpha诱导的脂肪细胞炎症

Adipose chronic inflammation is closely associated with insulin resistance and obesity. Sulfur dioxide is a newly discovered gaseous signaling molecule which plays an important role in metabolism biology. However, whether endogenous sulfur dioxide generation system exists in adipocytes and how adipocytes-derived sulfur dioxide regulates adipose inflammation have been unclear. Our previous study indicated endogenous sulfur dioxide and its generation system existed in different adipose tissues of rat. The study is designed to investigate the existence of endogenous sulfur dioxide and its generation system in adipose; By using sulfur dioxide donor or endogenous sulfur dioxide production inhibitor or gene manipulation, the study is also designed to elucidate the regulatory effect of endogenous sulfur dioxide on inflammation in adipocytes. Furthermore, targeting on NF-kappa B pathway, the study aims to discover the signaling pathway by which sulfur dioxide improves inflammation in adipocytes. Meanwhile, focusing on the NF-kappa B p65 cysteine 38 thiol group, the study aims to examine the molecular mechanism by which endogenous sulfur dioxide suppresses NF-kappa B signaling pathway during adipocytes inflammation. These findings would deepening the understanding of the regulatory effect of endogenous sulfur dioxide on inflammation in adipocytes and its mechanism .

脂肪组织慢性炎症与胰岛素抵抗及肥胖发生密切相关。二氧化硫是新近发现的内源性气体信号分子，具有重要的代谢生物学作用。然而脂肪细胞是否存在内源性二氧化硫及其生成体系、脂肪细胞来源的二氧化硫调节对脂肪细胞炎症反应的调节作用和机制，目前尚不清楚。本研究预实验结果提示，脂肪组织存在内源性二氧化硫及其生成体系。本研究拟探索脂肪内源性二氧化硫及其生成体系；采用给予二氧化硫供体、二氧化硫生成酶抑制剂或基因干预的方法，研究脂肪内源性二氧化硫对肿瘤坏死因子诱导的脂肪细胞炎症因子表达和分泌的调节作用；以NF-kappa B信号途径为切入点，揭示内源性二氧化硫调节脂肪细胞炎症的信号通路；以NF-kappa B p65第38位半胱氨酸巯基基团次磺酸修饰为靶点，研究二氧化硫抑制脂肪细胞炎症过程中NF-kappa B信号通路的分子机制。以期阐明内源性二氧化硫对脂肪细胞炎症反应的调节作用及具体机制。

脂肪组织慢性炎症与胰岛素抵抗及肥胖发生密切相关。二氧化硫是新近发现的内源性气体信号分子，具有重要的代谢生物学作用。然而脂肪细胞是否存在内源性二氧化硫及其生成体系、脂肪细胞来源的二氧化硫对脂肪细胞炎症反应的调节作用和机制，目前尚不清楚。本项目研究表明，脂肪细胞存在内源性AAT1/AAT2- SO2体系。脂肪细胞中，内源性二氧化硫抑制TNF-α诱导NF-κB信号通路激活，抑制炎症细胞因子MCP-1，IL-8分泌。我们进一步构建了脂肪组织特异性AAT1转基因小鼠和高脂饮食诱导的肥胖小鼠模型，结果表明脂肪组织特异性过表达AAT1，增加脂肪组织二氧化硫水平，改善高脂饮食诱导肥胖小鼠胰岛素抵抗。本研究为肥胖、胰岛素抵抗等疾病发病机制理解与有效治疗提供新思路。