S100A8/A9经NF-κB信号通路调控肥胖儿童糖代谢异常的中枢机制研究

糖代谢异常是儿童青少年肥胖和2型糖尿病（T2DM）的重要病理学改变，但其机制尚未完全阐明。前期研究中，我们通过蛋白质组学技术发现S100A8/A9蛋白差异高表达于肥胖儿童血清中；小鼠脑室内注射S100A8/A9蛋白能显著升高血糖；S100A8/A9能显著降低肥胖小鼠的葡萄糖耐受性，显著抑制下丘脑葡萄糖敏感神经元的放电频率；下丘脑来源的GT1-7细胞过表达S100A8/A9后，上调NF-κB，提示S100A8/A9可能通过调节NF-κB信号通路导致糖代谢异常。本研究拟应用过表达、沉默策略评价S100A8/A9对中枢能量平衡、胰岛素途径信号通路的影响；应用转基因、基因敲除小鼠开展S100A8/A9在肥胖糖代谢异常中的功能与机制研究；并以NF-κB信号通路为切入点，分析S100A8/A9影响肥胖儿童糖代谢异常的分子机制。本课题研究具有源头创新性，若获成功可为肥胖及T2DM的防治提供新的理论依据。

Abnormal glucose metabolism contributes to the pathogenesis of childhood obesity and type 2 diabetes mellitus (T2DM), but the detailed mechanism is still largely unknown. In our preliminary study, we found that serum S100A8/A9 protein levels were higher in obese than in healthy children using a proteomics method. S100A8/A9 proteins were highly expressed in the hypothalamus of the high fat diet (HFD)-induced obese mouse. Intracerebroventricular injection of S100A8/A9 increased plasma glucose concentration in young control mice. Furthermore, the firing frequencies of glucose sensing neurons in the hypothalamus were significantly reduced after treating with exogenous S100A8/A9 proteins in both control and obese mice. In addition, S100A8/A9 significantly up-regulated NF-κB expression in hypothalamic GT1-7 cells. These preliminary results suggest that S100A8/A9 may regulate glucose metabolism and energy balance via NF-κB pathway. In this project we propose to apply overexpressing and silencing strategy to explore the central mechanism of S100A8/A9. We will further investigate the roles of S100A8/A9 using neuronal tissue-specific S100A8/A9 transgenic and conditional knockout mice. We also plan to investigate the function of S100A8/A9 in T2DM by looking at the NF-κB signal pathway. This study is important to childhood obesity and T2DM research and will provide a new avenue for the prevention and treatment of obesity and T2DM in the future.