延髓中缝苍白核的G蛋白偶联型雌激素受体经交感神经系统调控脂肪组织代谢的研究

Obesity is a high risk factor for a wide range of chronic diseases, such as type 2 diabetes and hypertension. Dysfunction of adipose metabolism is an important cause of obesity. The sympathetic nervous system plays a major role in regulation of adipose tissue metabolism. The nucleus raphe pallidus of the rostral ventromedial medulla (rRPa) is an important center of the adipose tissue sympathetic nerves. We recently detected high expression of the G protein-coupled estrogen receptor (GPER) in the rRPa, and microinjection of 17β-estrodial (E2) into rRPa caused a dramatic increase in BAT sympathetic nerve activity and BAT heat production. Importantly, preliminary observation showed that GPER knockout rats were more sensitive to high fat diet (HFD)-induced obesity with significantly increased white adipose tissue (WAT) content and decreased BAT content than wild type rats. These findings suggest that estrogen acting on GPER in the rRPa has a major impact on the adipose tissue, but the neural circuitry and molecular mechanisms involved remain to be delineated. This project aims to confirm the role of GPER in regulation of adipose tissue sympathetic nerve activity and adipose tissue metabolism using in vivo and brain slice electrophysiology, optogenetics, chemogenetics and other methods. Specifically, we will investigate the neural circuitry in rRPa that mediates the effect of GPER activation on adipose tissue sympathetic nerve activity. In addition, we will explore the relation between GPER and obesity using the GPER knockout rat. This project may offer novel mechanistic insights on the regulation of adipose metabolism and may reveal new potential therapeutic targets for obesity.

肥胖是多种慢性疾病如二型糖尿病、高血压等的高危因素，脂肪代谢紊乱是导致肥胖发生的重要原因。交感神经系统在脂肪组织代谢中发挥重要调节作用，延髓中缝苍白核(rRPa)是脂肪组织交感神经的重要中枢。我们发现rRPa高表达G蛋白偶联型雌激素受体(GPER)，激活GPER可增强棕色脂肪组织(BAT)交感神经活动和促进BAT产热，GPER基因敲除大鼠对高脂饲料诱导的肥胖易感，白色脂肪组织(WAT)含量较野生型大鼠显著增多，而BAT含量减少，提示GPER介导雌激素在脂肪组织交感中枢调节脂肪组织代谢的作用，但其中的神经环路和分子机制仍不清楚。本项目拟采用在体、脑片电生理和光/化学遗传学等方法，进一步探讨rRPa的GPER对脂肪组织交感神经及代谢活动的调控作用与神经环路机制；利用GPER基因敲除大鼠，探讨GPER与肥胖的关系。项目成果有望揭示脂肪代谢调控的新机制，为靶向中枢GPER治疗肥胖提供科学依据。

肥胖是多种慢性疾病如二型糖尿病、高血压等的高危因素，但是目前临床上尚没有治疗肥胖的特效药。脂肪代谢紊乱是导致肥胖发生的重要原因，交感神经系统在脂肪组织代谢中发挥重要调节作用，延髓中缝苍白核(rRPa)是脂肪组织交感神经的关键中枢。因此，阐明交感中枢调控脂肪代谢的具体机制对治疗肥胖具有重要意义。本项目借助Gper基因敲除（Gper-/-）小鼠，探讨了rRPa的GPER对脂肪代谢的调控作用及其潜在机制。. 通过3年的研究我们证实：1、雄性Gper-/-小鼠对高脂饮食诱导的肥胖不敏感。高脂饮食下，与WT小鼠相比，雄性Gper-/-小鼠支配白色和棕色脂肪的交感神经活动增强，白色脂肪发生显著棕色化，能量消耗增多。2、在rRPa区，GPER表达在非5-HT能神经元上，且GPER在rRPa区表达显著高于各部分脂肪组织；高脂饮食下，雄性小鼠rRPa区激活的神经元数目显著增多，且GPER表达升高。3、特异性敲减雄性小鼠rRPa的Gper可通过增强交感神经活动促进白色脂肪棕色化，进而抑制高脂饮食诱导的肥胖。4、在rRPa部位存在GPER阳性神经元至5-HT能神经元的局部神经环路，激活GPER神经元可抑制5-HT能神经元活性。5、高脂饮食下，Gper-/-小鼠rRPa区5-HT能神经元激活的数目增加。这些研究结果表明，特异性敲减rRPa的GPER表达可增强支配白色脂肪的交感神经活动，促进白色脂肪棕色化，增加棕色脂肪代谢产热，进而缓解高脂饮食诱导的肥胖；rRPa存在的GPER神经元至5-HT能神经元的神经投射可能是GPER调控脂肪组织代谢的局部神经环路机制。. 本项目首次阐明了GPER在中枢rRPa对脂肪代谢的调控作用，并揭示了GPER与肥胖发生的关系，极大地补充和完善了雌激素调控脂肪代谢的中枢受体机制，为靶向延髓rRPa的GPER治疗肥胖提供科学依据。