胆汁酸受体TGR5天然配体齐墩果酸减肥作用的分子机制研究

The G-protein coupled receptor TGR5 and the Farnesoid X receptor (FXR) are both receptors of bile acids, co-regulating homeostasis and signal transduction of bile acids as well as glucose metabolism. Body fat is stored in white adipose tissue (WAT) and brown adipose tissue (BAT), which play important roles in energy storaga, and body heat generation and energy consumption, respectivey. TGR5 is highly expressed in mitochodrials of BAT, and down-regulates ATP synthesis by bile acids-TGR5-CAMP-D2-T3-UCP pathways, thus regulating energy homeostasis and reduce body weight. Oleic acid (OA) is a natural ligand of TGR5, which was originally used for hepatitis. Thereafter, OA was found to reduce high-fat diet-induced obesity andimprove glucose tolerance. However, its detailed relationship with TGR5 has not been characterized. This study is to explore the mechanisms of the natural compound OA on regulating energy metabolisms by its receptor TGR5 in BAT in spontaneous and diet-induced obesity animal models.

G蛋白偶联受体（TGR5）同法尼酯受体（FXR）同属胆汁酸受体，共同调节胆汁酸的动态平衡和信号通路，都能调节糖代谢。脂肪分为白色脂肪（WAT）和褐色脂肪（ＢＡＴ），WAT是以脂肪的形式贮存能量，BAT是通过生热作用，以产热的形式消耗能量。TGR5在褐色脂肪（BAT）中的线粒体上高表达，通过胆酸－TGR5 - CAMP - D2 - T3- UCP通路导致ATP合成降低，从而调节能量代谢的动态平衡达到减肥效果。齐墩果酸（ＯＡ）是TGR5天然植物配体，原用为治疗肝炎药物,后发现OA可使高脂饮食的动物体重下降，能提高糖耐，但与TGR5关系不清楚。本研究通过建立先天性肥胖及后天性肥胖的动物模型，探索天然植物药齐墩果酸（OA）是否且如何通过褐色脂肪中高表达的TGR5受体调节能量代谢，消耗能量达到减肥效果的作用机制。

G蛋白偶联受体（TGR5）同法尼酯受体（FXR）同属胆汁酸受体，共同调节胆汁酸的动态平衡和信号通路，都能调节糖代谢。脂肪分为白色脂肪（WAT）和褐色脂肪（ＢＡＴ），WAT是以脂肪的形式贮存能量，BAT是通过生热作用，以产热的形式消耗能量。TGR5在褐色脂肪（BAT）中的线粒体上高表达，通过胆酸－TGR5 - CAMP - D2 - T3- UCP通路导致ATP合成降低，从而调节能量代谢的动态平衡达到减肥效果。齐墩果酸（ＯＡ）是TGR5天然植物配体，原用为治疗肝炎药物,后发现OA可使高脂饮食的动物体重下降，能提高糖耐，但与TGR5关系不清楚。本研究通过建立先天性肥胖及后天性肥胖的动物模型，证实OA可明显减少后天性肥胖小鼠体内脂质堆积，减轻肥胖小鼠体重，调节糖代谢，其作用是通过激活胆汁酸膜受体TGR5诱导miR-26a表达以及相关下游信号通路得以实现的。