Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice

Abstract

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 <i>Panax notoginseng</i> as an agonist of TGR5 <i>in vitro</i>. 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 <i>Tgr5</i> ^<i>-/-</i> obese mice. In addition, Ft1 elevated serum free and taurine-conjugated bile acids (BAs) by antagonizing <i>Fxr</i> transcriptional activities in the ileum to activate <i>Tgr5</i> in the adipose tissues. The metabolic benefits of Ft1 were abolished in <i>Cyp27a1</i> ^<i>-/-</i> 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.