原儿茶酸激活棕色脂肪改善肥胖的作用及其机制研究

Brown fat tissue (BAT) plays an important role in resistance to obesity and regulate disorder of glucose and lipid metabolism. Our previous results showed that cyanidin-3-glucoside (C3G) had obvious function to activate BAT. However, the absorption efficiency of C3G in vivo is very low. It is speculated that C3G may activate BAT through its metabolite protocatechuic acid (PCA). Our preliminary experiments also indicate that PCA can up-regulate the expression of Ucp1, the key thermogenic gene in brown adipocytes, and activate BAT in obese mice. However, the mechanism of PCA regulating BAT activity is not yet clear. Based on previous conclusions, PCA, C3H10T1/2 cells and three kinds of obese mice models are used as the test system. Firstly, the energy metabolism indexes of different types of mice, such as body weight, glucose homeostasis, energy metabolism, oxygen consumption, BAT thermogenesis and core temperature, will be detected. Then, the formation of BAT, BAT thermogenesis and fatty acid oxidation relative gene and protein expression level will be investigated, whose purpose is to clarify the effect of PCA on the formation of BAT and the thermogenesis energy expenditure by BAT activation. Lastly, we will explore the BAT activation mechanism from two aspects: mitochondria synthesis and function as well as target identification of UCP1 using RT-PCR, western blot and, gene knockout and gene over expression. This project will provide new perspective for combating obesity and ameliorating dysfunction of glucose and lipid metabolism.

棕色脂肪（BAT）在抵抗肥胖和改善糖脂代谢异常过程中发挥着重要作用。我们前期的研究结果表明，矢车菊素-3-葡萄糖苷（C3G）具有激活BAT的功效，但C3G在体内吸收利用率极低，推测其可能通过代谢产物原儿茶酸（PCA）激活BAT；且我们的预实验也表明PCA可上调棕色脂肪细胞产热关键基因Ucp1的表达和激活肥胖小鼠BAT，然而PCA调控BAT活性的机制尚未明确。基于此，本项目以PCA及C3H10T1/2细胞和三种肥胖模型小鼠为试验体系，通过检测小鼠的体重、血糖稳态、耗氧量、产热和核心体温等能量代谢相关指标，并结合BAT形成、产热及脂肪酸氧化相关的基因和蛋白的表达量，研究PCA激活BAT产热功能的影响；同时采用RT-PCR、免疫印迹、基因敲除和基因过表达等技术，从Ucp1基因调控位点和线粒体合成与功能两方面，研究PCA激活BAT产热耗能的机制。本项目将为抵抗肥胖和改善糖脂代谢异常提供新证据。

棕色脂肪（BAT）是一种燃烧能量促进代谢的器官，在调节糖脂代谢紊乱方面发挥重要作用。我们前期的研究结果表明，矢车菊素-3-葡萄糖苷（C3G）具有激活BAT的功效，但C3G在体内吸收利用率极低，推测其可能通过代谢产物原儿茶酸（PCA）激活BAT。本项目采用PCA处理C3H10T1/2细胞模型、高脂饮食诱导肥胖小鼠模型及UCP1敲除小鼠，通过测定小鼠的体重、血糖稳态、耗氧量、产热和核心体温等能量代谢相关指标，并结合BAT形成、产热、脂肪酸氧化以及线粒体合成相关的基因和蛋白表达量的影响，研究PCA对BAT产热功能的效果及其机制；研究结果表明，PCA可上调棕色脂肪细胞产热关键基因UCP1的表达，并且通过作用于UCP1而激活肥胖小鼠的BAT，进而对肥胖及其相关代谢紊乱疾病具有抑制作用。本项目为PCA抵抗肥胖和改善糖脂代谢异常提供新证据。