靶向调控白色脂肪棕色化治疗肥胖相关性肾病

While studies clearly indicate that the high risk of chronic kidney disease (CKD) is driven by diabetes and hypertension, emerging evidences suggest that obesity can directly lead to the development of CKD independently of either diabetes or hypertension. In contrast to white adipose tissue (WAT), brown adipose tissue (BAT) plays an active role in energy expenditure. Recently, a series of investigations have demonstrated that, under certain conditions, white adipocyte could take on the characteristics of brown adipose cells, thus remodeling the WAT from an energy storage into an energy-disposal site. Further, recent evidences showed that browning of white fat also attenuated adipose inflammation. Therefore, browning of WAT has become a current focus in the ongoing fight against obesity and metabolic syndrome. In our previous study, we found that 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) led to a significant inhibition of the expression of BAT-specific genes in white adipocyte, indicating that 11β-HSD1 acts as a vital regulator that controls the browning of WAT. Moreover, we now observed a significant increase of the expression of UCP1, a specific mitochondrial protein, in WAT and an marked ameliorate of kidney dysfunction in BVT.2733 (a selective inhibitor of 11β-HSD1)-treated obese rats. Therefore, 11β-HSD1 might play a key role in obesity related kidney disease via regulating the browning effect of WAT. In this proposal, we synthesised the specific 11β-HSD1 inhibitor targeted WAT, which was already synthesized, to clarify the role of 11β-HSD1 in regulating the white fat function and provide therapeutic target for obesity related kidney disease.

不仅肥胖相关的糖尿病、高血压是慢性肾病的危险因素，而且肥胖本身更是肾病的高危因素，是慢性肾病形成的基石。白色脂肪棕色化不仅促进能量消耗、减轻肥胖，而且在维持脂肪正常功能（分泌功能、炎症、氧化应激）中起着至关重要的作用，是治疗肥胖的新靶点。我们前期研究发现，作为调控糖皮质激素（GC）活性的关键酶，11β-羟化类固醇脱氢酶1（11β-HSD1）调控白色脂肪棕色化，在肥胖相关性肾病中发挥着重要作用。因此，为了明确11β-HSD1抑制剂治疗肥胖相关性肾病的具体机制，确定白色脂肪棕色化在肥胖相关性肾病中的作用机理，本课题利用特异性白色脂肪组织靶向11β-HSD1抑制剂（已自行合成），研究其对肥胖相关性肾病的影响。并且利用白色脂肪细胞与肾足细胞的共培养模型，从解偶联蛋白1（UCP1）与活性氧簇（ROS）入手，搞清11β-HSD1通过调控脂肪功能影响肾脏的分子机理，为有效干预肥胖相关性肾病提供新手段。

随着肥胖发病率的逐年攀升，肥胖相关性疾病——2型糖尿病、高血压病、脂质代谢紊乱，以及心脑血管疾病等已成为了威胁人类健康的重大问题。目前，肥胖相关的肾损害已受到越来越多的关注。事实上，不仅肥胖相关的糖尿病、高血压会造成慢性肾损害，肥胖本身更是慢性肾病形成的基石。而脂肪组织功能紊乱是肥胖直接导致慢性肾损害发生的基础。白色脂肪棕色化不仅促进能量消耗、减轻肥胖，而且在维持脂肪正常功能（分泌功能、炎症、氧化应激）中起着至关重要的作用，是治疗肥胖的新靶点。通过本项目的实施，我们研究发现，作为调控糖皮质激素（GC）活性的关键酶，11β-羟化类固醇脱氢酶1（11β-HSD1）调控白色脂肪棕色化，促进解偶联蛋白1（UCP1）的表达，改善脂肪组织功能，在肥胖相关性肾病中发挥着重要作用。人体研究还发现，肾周脂肪的棕色化程度与肾脏肿瘤的发生发展密切相关，肾周脂肪组织的UCP1表达升高提示肿瘤的恶性程度越高，肾周脂肪棕色化可能是提示肾癌预后不良的重要指标。此外，在研究肥胖对靶器官的损害时，我们还发现11β-HSD1在高脂饮食诱导的心肌肥大中也发挥着重要作用。肥胖大鼠心肌肥大、室间隔、左室后壁厚度明显增加、心功能下降，使用11β-HSD1抑制剂——BVT.2733后可显著逆转，体外研究也证明了以上结果，并且基因组芯片和生物信息学分析结果显示此作用可能是通过下游糖皮质激素受体和盐皮质激素受体，以及c-AMP介导的信号通路和钙通道介导的信号通路发挥的作用。总之，本课题创新性的从白色脂肪棕色化入手，阐明11β-HSD1调控脂肪组织功能影响肥胖相关的靶器官功能损害的机理，为防治肥胖相关性疾病提供新手段。