电针调控SAMs促进肥胖小鼠白色脂肪棕色化的效应与机制研究

The browning of white adipose is a new target for the treatment of obesity, while the drug interventions are still being explored. Sympathetic neuron-associated macrophages (SAMs) are identified as new population of macrophages, which were located between adipose tissue and sympathetic nerve. SAMs are responsible for import norepinephrine which were released from activated sympathetic nerve fibers, and then indirectly inhibits the browning of white adipose. Earlier we have confirmed that the significant effect of electroacupuncture included lose weight, reduce blood lipids and anti-inflammatory on obesity patients. As well as the animal experiments suggested that the acupuncture at abdomen points could excite the sympathetic nerve and inhibit the macrophage-induced inflammatory reaction. Accordingly, we propose that "Electroacupuncture promotes the browning of white adipose obesity via sympathetic nerves, and SAMs are the key neuro-immune factors that mediate the effect of electroacupuncture." We intend to systematically explore the regulation effect of electroacupuncture on the browning of white adipose in obese mice at three levels, which include observing the efficacy, analyzing the sympathetic mechanism and exploring neuro-immunity activities. We will focus on whether electroacupuncture has an inhibitory effect on SAMs to promote the browning of white adipose. The purpose of our study is to provide a theoretical basis of the regulatory effect on neuro-immune-endocrine network of electroacupuncture on obesity, and to provide a new direction for the clinical treatment of obesity.

白色脂肪棕色化是临床治疗肥胖病的靶点，目前相关药物研究仍处于探索阶段。最新研究发现位于脂肪组织中的交感神经相关巨噬细胞（SAMs）通过吞噬去甲肾上腺素，间接性抑制白色脂肪棕色化并最终导致肥胖。前期我们已经初步证实，电针可以诱发肥胖小鼠白色脂肪棕色化，电针腹部穴位可以特异性兴奋脂肪组织交感神经，并且电针对于巨噬细胞引发的炎症反应具有抑制效应。据此，本项目提出“电针可能通过抑制交感神经相关巨噬细胞功能促进白色脂肪棕色化，是电针减肥效应的神经-免疫-内分泌核心靶点之一”。本次研究拟通过观察电针促棕色化的减肥效应、交感神经-SAMs-炎症通路在电针干预下的交互关系、SAMs与电针促棕色化的关系三个层面，系统研究电针促白色脂肪棕色化的效应及机制，聚焦于电针是否可以通过抑制SAMs的功能促进白色脂肪棕色化，以期为电针通过调控神经-免疫-内分泌网络治疗肥胖病提供理论基础，并为肥胖病的临床治疗提供新方向。

背景：白色脂肪棕色化是临床治疗肥胖病的靶点，目前相关药物研究仍处于探索阶段。既往研究表明，电针可以通过兴奋交感神经，促进脂肪分解以及减轻炎症反应促进白色脂肪棕色化，而位于脂肪组织中的交感神经相关巨噬细胞（SAMs）是介导白色脂肪棕色化的神经-内分泌-免疫交互点。因此，SAMs可能是探索电针促进白色脂肪棕色化的神经免疫机制的重要切入点。方法：本研究采用高脂饮食（HFD）诱导的肥胖小鼠模型，以体重、体重变化率、脂质水平、炎症水平等为减肥效应指标，以解偶联蛋白1（UCP1）mRNA和蛋白表达为白色脂肪棕色化的观察指标，采用WB、PCR、免疫荧光等方法探索SAMs的特异性标志物SLC6A2（去甲肾上腺素转运蛋白）、MAOA（单胺氧化酶）的mRNA和蛋白表达的变化，并观察SAMs上游交感神经的放电活动，同时应用交感神经消融术及腺相关病毒体内干扰或过表达SLC6A2以验证交感神经-SAMs通路的重要性。结果：与HFD大鼠相比，电针具有明确的降脂抗炎减重的效应，电针可促进UCP1的表达，降低SAMs和SLC6A2的表达，并兴奋交感神经电活动。而采用交感神经消融术会逆转电针效应，脂肪中注射β拮抗剂会增加SLC6A2蛋白水平。因此，电针可能通过兴奋交感神经电活动、抑制SAMs和去甲肾上腺素转运蛋白SLC6A2、减轻炎症、调节免疫平衡，从而促进白色脂肪棕色化。结论：电针促进白色脂肪棕色化可能与交感神经-SAMs-炎症因子通路密切相关。