激活TRPV1调控SIRT1/ RIP140抑制棕色脂肪白色化预防肥胖的机制

Brown-to-white adipose tissue plays an important role in the genesis of obesity. the mechanism of which was of great significance for the prevention of obesity. It was reported SIRT1 deacetylation suppressed the production of white adipose through activating PGC-1α, While RIP140 was a negative regulator of PGC-1α/ UCP-1 and reduce mitochondria biogenesis. Our research found the brown-to-white adipose tissue existed in obese mice by down-regulation of PGC-1α/ UCP-1 in adipose, activation of TRPV1 channel up-regulated the expression of UCP-1 and down-regulated RIP140 in brown adipose, Activation of TRPV1 up-regulated the expression of UCP-1 and down-regulated RIP140,but whether Sirt1/RIP140 participated in the brown-to-white adipose tissue was unclear. Therefore, we hypothesized SIRT1/RIP140 regulating PGC-1α, which induced the dysfunction of mitochondria and energy metabolism, and then enhanced brown-to-white adipose tissue. Activation of TRPV1 channel by dietary capsaicin could prevent obesity by up-regulating the positive effects of SIRT1/PGC-1α and inhibiting brown-to-white adipose tissue. For testing the hypothesize, we will explore the mechanism of SIRT1/ RIP140 on brown-to-white adipose tissue by mitochondria and uncover the mechanism of TRPV1 maintains the structure and function of brown adipose by SIRT1/ RIP140/PGC-1α. Our study will shed light on new approaches for prevention of obesity.

棕色脂肪白色化与肥胖密切相关，阐明其机制对肥胖防治有重要意义。研究表明SIRT1去乙酰化激活PGC-1α抑制白色脂肪生成，RIP140抑制PGC-1α/UCP-1，减少线粒体生成。我们发现肥胖时棕色脂肪白色化与PGC-1α/UCP-1调控线粒体功能有关，激活TRPV1上调棕色脂肪UCP-1/下调RIP140, 但其是否参与PGC-1α调控棕色脂肪白色化尚并不清楚。为此我们假设：肥胖时SIRT1/RIP140轴调节PGC-1α致线粒体功能障碍及能量代谢失衡，促进棕色脂肪白色化；激活TRPV1上调SIRT1/PGC-1α增加棕色脂肪功能，抑制RIP140/PGC-1α阻止棕色脂肪白色化，预防肥胖。 拟从整体和细胞水平阐明SIRT1/ RIP140轴调控PGC-1α抑制棕色脂肪白色化，揭示TRPV1影响SIRT1/RIP140/PGC-1α轴维持棕色脂肪结构与功能正常的机制，为肥胖防治提供新措施

近年研究证实除了白色脂肪重构参与肥胖发生外，棕色脂肪白色化（brown-to-white）在肥胖发生发展过程中至关重要,阐明其机制对肥胖防治有重要意义。TRPV1/SIRT1通路在棕色脂肪中的作用已有报道,因此本研究做出适当调整。研究表明SIRT3能够调控棕色脂肪细胞线粒体功能，改善肥胖相关的氧化应激。因此，我们推测，TRPV1激活后通过作用于SIRT3改善高脂饮食介导的棕色脂肪线粒体功能障碍和ROS生成，促进产热和能量代谢，进而抑制棕色脂肪白色化。为此本课题以高脂饮食、TRPV1基因敲除（TRPV1-/-）、SIRT3基因敲除（SIRT3-/-）小鼠为对象。研究结果表明肥胖和衰老时，能量代谢减低，棕色脂肪线粒体氧化和呼吸功能障碍，表现为白色化，而TRPV1、SIRT3表达低下。辣椒素干预肥胖小鼠可增加能量代谢，但在TRPV1-/-、SIRT3-/-小鼠中该作用消失。进一步研究发现，肥胖和衰老可通过抑制SIRT3增强Mcu启动子组蛋白3乙酰化水平导致线粒体Ca2+超载，线粒体ROS大量产生及代谢功能障碍，引起棕色脂肪白色化；而通过腺病毒载体过表达SIRT3或辣椒素干预可逆转肥胖或衰老引起的上述变化。其机制在于辣椒素通过激活AMPK/SIRT3抑制组蛋白3乙酰化水平改善线粒体Ca2+超载，从而维持棕色脂肪形态与功能，其中SIRT3与AMPK形成正反馈环，通过上述途径进一步改善肥胖和衰老时棕色脂肪白色化。本研究明确辣椒素激活TRPV1抑制棕色脂肪白色化的作用及分子机制，为膳食因子辣椒素改善肥胖提供新证据；同时明确了SIRT3在辣椒素对抗肥胖发生发展中的关键作用，为防治肥胖提供新的干预靶点，具有较好的应用前景。其次，我们对代谢性血管病的诊断和干预进行了研究。应用99mTc-MIBI显像测定糖尿病患者下肢组织灌注，创新性地应用Hill函数对测定的灌注曲线进行模型构建，较好的评价糖尿病患者早期下肢血管微循环障碍的程度，对糖尿病合并下肢动脉病变患者的早期发现及治疗具有重要意义。通过荟萃分析探讨调节脂代谢对外周血管病变介入治疗的远期疗效的影响。明确长期他汀类药物干预可改善外周动脉病变的生存率及通畅率，降低心血管和卒中发生率，为临床干预代谢性血管病提供指导。