Obesity and its associated complications are highly related to a current public health crisis around the world. A growing body of evidence has indicated that G-protein coupled bile acid (BA) receptor TGR5 (also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders. We have identified notoginsenoside Ft1 (Ft1) from Panax notoginseng as an agonist of TGR5 in vitro. However, the pharmacological effects of Ft1 on diet-induced obese (DIO) mice and the underlying mechanisms are still elusive. Here we show that Ft1 (100 mg/100 diet) increased adipose lipolysis, promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1 (GLP-1) secretion in the ileum of wild type but not Tgr5^−/− obese mice. In addition, Ft1 elevated serum free and taurine-conjugated bile acids (BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues. The metabolic benefits of Ft1 were abolished in Cyp27a1^−/− mice which have much lower BA levels. These results identify Ft1 as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.

肥胖及其相关并发症与当前世界各地的公共卫生危机密切相关。越来越多的证据表明，G 蛋白偶联胆汁酸 (BA) 受体 TGR5（也称为 Gpbar-1）是治疗肥胖和相关代谢紊乱的潜在药物靶点。我们在体外鉴定了三七中的三七皂苷 Ft1 (Ft1)作为 TGR5 的激动剂。然而，Ft1 对饮食诱导肥胖 (DIO) 小鼠的药理作用及其潜在机制仍不清楚。在这里，我们表明 Ft1（100 mg/100 饮食）增加脂肪分解，促进腹股沟脂肪组织中的脂肪褐变，并诱导野生型回肠中胰高血糖素样肽-1 (GLP-1) 分泌，但 Tgr5 −/ −^肥胖则不然老鼠。此外，Ft1 通过拮抗回肠中的Fxr转录活性来激活脂肪组织中的Tgr5 ，从而升高血清游离胆汁酸和牛磺酸结合胆汁酸 (BA)。Ft1 的代谢益处在BA 水平低得多的Cyp27a1 ^{−/−小鼠中被消除。}这些结果表明，Ft1 是一种对两个关键 BA 受体具有相反活性的单一化合物，可减轻高脂肪饮食引起的小鼠肥胖和胰岛素抵抗。