血管緊張素II在棕色脂肪裡影響粒線體的產熱是透過粒線體的動態平衡

Abstract

因為過多的能量攝取和久坐生活，代謝症候群在全球已經成為最主要的疫情。在先前的研究證實過度的表現的腎素-血管收縮素系統與代謝症候群之間有很大的關聯。在我們實驗室先前的研究顯示在缺乏腎素的老鼠表現中，胰島素變得更敏感，而且較會因為食物攝取而肥胖。棕色脂肪是主要產生熱量、加速能量代謝的器官，在缺乏腎素老鼠的棕色脂肪中，更多的熱被產生，使更多能量被消耗。 因為沒有腎素，使得血管緊張素II無法產生、被偵測，血管緊張素II已經在很多器官中被發現會導致氧自由基產生，而氧自由基被證實有能力造成細胞中粒線體的損傷，使得粒線體失去功能，降低脂肪酸氧化能力，也會引起粒線體的分裂。因此，我們假設當血管收縮素II不存在，使得粒線體變敏感，抑制食物引起的肥胖，是因為抑制血管緊張素II經由抑制立憲底的分裂而使得在棕色脂肪中更多熱的產生。 在我們細胞的研究中顯示，額外加入血管緊張素II明顯的降低UCP1的基因表現量，再透過氯沙坦鉀加入導致第一型血管緊張素II受體被抑制後，UCP1基因表現顯著的恢復，此外，促進產熱的脂肪酸氧化也因為血管緊張素II的加入後減少，但氧自由基和粒線體的分裂卻因為血管緊張素II加入而明顯增加，而在使用線粒體分裂蛋白抑製劑後脂肪酸氧化、產熱都有顯著了恢復。因此，我們的研究顯示血管緊張素II透過使粒線體分裂造成棕色脂肪的脂肪酸氧化和產熱減少。

The metabolic syndrome has become one of the major worldwide epidemics because of increasing obesity, and sedentary lifestyles. An overaction of renin angiotensin system (RAS) has been implicated in metabolic syndrome. Our previous studies showed that mice lacking renin (Ren1c −/−) are insulin sensitive and resist diet-induced obesity. Moreover, heat generation (thermogenesis), which is predominantly produced by brown adipose tissues (BAT) and has the ability to enhance energy expenditure, is significantly increased in Ren1c −/− mice. Plasma angiotensin II (Ang II) can not be detected in Ren1c −/− mice, and Ang II is known for inducing reactive oxygen species (ROS) which can cause mitochondrial damage, decrease fatty acid oxidation and induce mitochondrial dynamics needed for maintaining mitochondrial quality. Therefore, we hypothesized that inhibition of Ang II resists diet-induced obesity by enhancing thermogenesis in BAT via regulating fatty acid oxidation and mitochondrial dynamics. In vitro, our study indicated that Ang II significantly decreased uncouple protein 1 (UCP1) gene expression. After treating Ang II type 1 blocker losartan, UCP1 gene expression was restored. Furthermore, Ang II reduced fatty acid oxidation and increased mitochondrial fission while we treated mitochondrial fission protein Drp-1 inhibitor mdivi-1 resulting in abolishing Ang II effects, and restored mitochondrial function. Therefore, our data suggested that Ang II regulates BAT thermogenesis and fatty acid oxidation via increased mitochondrial fission.