TRPV1缺失加重棕色脂肪线粒体功能障碍致肥胖的机制

The disorder of brown adipose energy metabolism is the important pathophysiological basis of obesity. Mitochondrial function of brown adipose tissue plays a key role in regulating energy metabolism. The uncoupling protein 1(UCP1) of brown fat mitochondria is the key factor to energy metabolism disorder. It consumes energy and reduce lipid deposition through thermogenesis.Recently, we found that mice with cation channel (TRPV1) and UCP1 both knockout mice comparing with UCP1 knockout mice, obesity occurred earlier and was more severe.It is suggested that TRPV1 deletion has a significant effect on obesity induced by UCP1 knockout. The purpose of this study is to explore the mechanism of obesity. In this project, the mouse model of TRPV1/UCP1 double gene knockout was successfully modeled. We will monitor the core temperature, basal metabolic rate, change of mitochondrial Ca2+/H+ transaction, respiratory electron transport chain complex activity and expression of brown adipocytes in TRPV1/UCP1 knockout mice, and explore the mechanism leads to energy metabolism disorder and obesity. This study intends to explain the pathogenesis of obesity from a new perspective and provide scientific basis for the prevention and treatment of obesity.

棕色脂肪能量代谢障碍是导致肥胖的重要病理生理基础，线粒体功能在调控能量代谢中发挥关键作用。棕色脂肪线粒体上解偶联蛋白1(UCP1)是能量代谢调节的关键，通过产热消耗能量、减少脂质沉积。我们近期发现，阳离子通道(TRPV1)和UCP1同时敲除的小鼠与UCP1敲除小鼠比较，肥胖发生更早且程度更重，提示TRPV1缺失对UCP1功能异常所致的肥胖有明显促进作用，本研究旨在探索棕色脂肪线粒体功能在肥胖发生中的作用。通过实验室已建模成功的TRPV1/UCP1双基因敲除小鼠模型，监测其基础代谢率、棕色脂肪线粒体呼吸耗氧功能，以及棕色脂肪细胞线粒体Ca2+/H+交换、呼吸电子传递链复合体活性的改变，研究TRPV1缺失加重UCP1敲除所引起的棕色脂肪线粒体Ca2+/H+交换及呼吸耗氧功能障碍，继而引起能量代谢紊乱及肥胖的机制。本研究拟从整体、细胞和分子水平全新的揭示肥胖的发病机制，为防治肥胖提供科学依据。

背景：肥胖合并高血压具有高发病率和死亡率的特征，而肥胖导致高血压的机制尚不清楚。TRPV1是一种脂肪组织中存在，具有抗高血压作用的钙Ca2+通道，而UCP1是一种基因型自发的肥胖模型。.主要研究内容：在这项研究中，我们通过配种TRPV1和UCP1双基因敲除小鼠，探讨了TRPV1对UCP1缺乏小鼠肥胖和高血压发生的作用。.重要结果与关键数据：与UCP1或TRPV1单基因敲除的小鼠比较，TRPV1/UCP1双敲小鼠肥胖和高血压出现的时间更早，并且更严重。在UCP1敲除小鼠中进一步敲除TRPV1基因，减少了功能性棕色脂肪组织（BAT）的生成，静息耗氧量、热量产生和运动活动减少，并伴有严重的线粒体呼吸功能障碍。在机制上，TRPV1、UCP1和LETM1作为一个复合物来维持适当的线粒体Ca2+水平，TRPV1基因敲除通过激活LETM1代偿性增加线粒体Ca2+摄取。然而，在UCP1-/-小鼠的棕色脂肪线粒体，这种代偿作用被阻断，导致线粒体Ca2+摄取显著减少，ATP产生和氧化应激反应的增加。.科学意义：本研究为棕色脂肪线粒体Ca2+稳态在肥胖相关高血压中的关键作用提供了证据，并表明TRPV1/UCP1/LETM1复合物可能是一种潜在的干预靶点。