抑制NNMT对脂肪棕化的影响以及通过此途径改善动脉粥样硬化的研究

Adipose browning is an effective way to alleviate atherosclerosis; however, there are only few and defective methods for adipose browning. Nicotinamide N-methyltransferase (NNMT) has been lately reported to be a novel target for treating obesity, yet without any knowledge of its effect on adipose browning or atherosclerosis alleviation..We have identified that NNMT inhibition induced massive positive expression of UCP1, which is a marker of brown or brite adipose, in adipose of mice. And NNMT inhibition also alleviated atherosclerosis and reduced macrophage infiltration. With the hint from our preliminary experimental results and the current references, we came up with a hypothesis that inhibition of NNMT is capable of browning adipose through de novo differentiation, and that inhibition of NNMT is capable of alleviating atherosclerosis through adipose browning. .With a theme of “NNMT inhibition, adipose browning and atherosclerosis alleviating”, this project will inhibit NNMT employing both genetic and pharmacological methods, and prove that inhibition of NNMT plays a role in adipose browning and subsequent atherosclerosis alleviation through SIRT1/PPARγ and AMPK/p38/ATF2/PGC-1α pathway. The achievement of this project will provide new option for treating atherosclerosis and meanwhile illustrate the effect of traditional Chinese medicine with a novel target.

脂肪棕化是改善动脉粥样硬化的有效措施，但目前诱导脂肪棕化方法不多，且各有弊端。近年发现尼克酰胺甲基转移酶（NNMT）是改善肥胖的新颖靶点，但其对脂肪棕化和动脉粥样硬化的影响尚未可知。.申请者前期研究发现抑制NNMT能增加脂肪组织中棕色/米色脂肪标志物UCP1阳性表达，也能缩小动脉粥样斑块面积和减少巨噬细胞浸润。结合文献，我们提出假说：抑制NNMT通过促进棕色/米色脂肪细胞从头分化过程，实现脂肪棕化，并由此改善动脉粥样硬化。.本项目拟围绕“抑制NNMT→棕化脂肪→改善动脉粥样硬化”的主线，通过基因敲除和抑制剂两种方法抑制NNMT，针对SIRT1/PPARγ和AMPK/p38/ATF2/PGC-1α通路，在细胞和动物水平上阐明抑制NNMT诱导脂肪棕化的作用及其机制，并明确由此改善动脉粥样硬化的作用。.本项目的完成，不仅为动脉粥样硬化治疗提供新靶点与思路，也为传统中药赋予新靶点阐释。

脂肪棕化是改善肥胖的有效措施之一，但目前诱导脂肪棕化方法不多，且各有弊端。近年发现尼克酰胺甲基转移酶（NNMT）是改善肥胖的新颖靶点，但其对脂肪棕化的影响尚未可知。.本项目研究发现，抑制NNMT能降低肥胖小鼠体重、减小脂肪细胞体积；其改善肥胖的作用是通过促进脂肪棕化、增加能量消耗实现的；并且，抑制NNMT促进脂肪棕化的机制，是通过激活 SIRT1 /AMPK/PPARα通路，从而促进脂肪前体细胞向棕色脂肪分化而实现的。.本项目解决了科学问题“抑制NNMT能否诱导脂肪棕化，以及通过怎样的机制诱导脂肪棕化”，明确了NNMT是诱导脂肪棕化的新颖靶点。由于现有的诱导脂肪棕化的方法不多，且各有弊端， NNMT靶点的确立将有效解决该问题。本项目也为肥胖、以及肥胖相关的动脉粥样硬化、糖尿病等疾病的治疗提供了新靶点和新思路。同时，我们寻找了NNMT的天然产物抑制剂，也为传统中药赋予新靶点阐释。