神经肽Y调控机体脂质代谢影响动脉粥样硬化发生发展作用的机制研究

The vascular endothelial dysfunction caused by peripheral lipid metabolism disorder, foam cell formation, cell proliferation of vascular smooth muscle, local plaque inflammation and activation of platelets will induce atherosclerosis. However, the mechanism that the brain regulates the development and progression of peripheral lipid metabolism and atherosclerosis is still unknown. Previous study has reported that the neurons in amygdala activated by cold stimulation plus high-fat diet are most NPY reactivity neurons with the lower expression of tyrosine hydroxylase mRNA in the ventromedial and paraventricular hypothalamic nucleus and peripheral lipid metabolism disorder. Based on the results, we proposed a hypothesis that the expression of neuropeptide Y increasing abnormally in amygdala could inhibit the activation of the downstream central sympathetic nerve system, which may relate to peripheral lipid metabolism disorder and severe atherosclerosis. Thus, our project expects to use a series of latest specific animal models and cutting-edge test methods to demonstrate the neural regulation pathway. Moreover, by the means of regulating the NPY-Y1 receptor to increase the excitability of the sympathetic nerve system of hypothalamus, we could prove the hypothesis through the relief of peripheral lipid metabolism disorder and severe atherosclerosis. Our research may elucidate a new theory that there is a new central nervous channel that could regulate peripheral lipid metabolism disorder and atherosclerosis, which is of great both theoretical and clinical significance.

周围脂质代谢紊乱可以引起血管内皮功能障碍、泡沫细胞形成、血管平滑肌细胞增殖、斑块局部炎症反应、以及血小板的聚集活化，进而导致动脉粥样硬化。但是, 大脑是如何调控周围脂质代谢与动脉粥样硬化的机理还远不清楚。课题组前期研究发现：冷刺激+高脂饮食可以激活杏仁核区域的神经肽Y（NPY）神经元, 同时伴有下丘脑腹内侧和室旁核区域的酪氨酸羟化酶信使核糖核酸表达下降，以及周围脂质代谢紊乱。进而，我们提出杏仁核NPY异常增高，可导致周围脂质代谢紊乱和动脉粥样硬化的假说。为此，本项目组拟采用国际上最新的一系列特定设计的动物模型和检测方法来证明这一神经调控通路的存在，并通过检测NPY-Y1受体的调控，能否提高下丘脑交感神经兴奋性，能否改善或缓解周围脂质代谢紊乱和动脉粥样硬化来进一步验证该假说。本研究结果将有助于阐明一条中枢神经调控周围脂质代谢和动脉粥样硬化的新通道，具有重要的理论意义及潜在的临床应用价值。

周围脂质代谢紊乱可以引起血管内皮功能障碍、泡沫细胞形成、血管平滑肌细胞增殖、斑块局部炎症反应、以及血小板的聚集活化，进而导致动脉粥样硬化。本研究主要是采用C57BL6、NPY-GFP实验小鼠为研究对象，分为普通饮食组、单纯冷刺激组、高脂饮食组以及冷刺激加高脂饮食组4种干预方式，检测实验小鼠的葡萄糖耐量试验、胰岛素耐量试验、白色脂肪以及棕色脂肪的质量，同时运用原位杂交、免疫荧光等方法研究中枢神经系统中代谢相关神经递质的表达水平。我们研究发现，通过冷刺激和高脂饮食激活杏仁核NPY神经元，抑制VMH的BDNF mRNA表达，诱导PVN的GHRH mRNA表达，参与了外周脂质代谢的调控 。同时我们通过RANKL信号通路验证了NPY参与了外周脂质代谢。阐明慢性冷刺激对能量平衡和葡萄糖稳态的影响以及导致这些影响的潜在中枢机制，具有临床意义。通过本基金支持，先后培养博士研究生2名，硕士研究生2名，发表文章5篇。