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

Lili Ding; Qiaoling Yang; Eryun Zhang; Yangmeng Wang; Siming Sun; Yingbo Yang; Tong Tian; Zhengcai Ju; Linshan Jiang; Xunjiang Wang; Zhengtao Wang; Wendong Huang; Li Yang

doi:10.1016/j.apsb.2021.03.038

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

Acta Pharm Sin B. 2021 Jun;11(6):1541-1554. doi: 10.1016/j.apsb.2021.03.038. Epub 2021 Mar 30.

Authors

Lili Ding^{1

2}, Qiaoling Yang^{1

2

3}, Eryun Zhang^{1

2}, Yangmeng Wang², Siming Sun², Yingbo Yang¹, Tong Tian¹, Zhengcai Ju¹, Linshan Jiang¹, Xunjiang Wang¹, Zhengtao Wang¹, Wendong Huang^{2

4}, Li Yang^{1

5}

Affiliations

¹ Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
² Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
³ Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.
⁴ Graduate School of Biological Science, City of Hope National Medical Center, Duarte, CA 91010, USA.
⁵ Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

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 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.

Keywords: ANOVA, analysis of variance; AUC, area under the curve; BAT, brown adipose tissue; BAs, bile acids; Bile acids; DIO, diet-induced obesity; FGF, fibroblast growth factor; FXR; Ft1, notoginsenoside Ft1; Fxr, nuclear farnesoid X receptor; GLP-1; GLP-1, glucagon-like peptide-1; GTT, glucose tolerance test; HFD, high fat diet; ITT, insulin tolerance test; Insulin resistance; KO, knockout; Metabolic disorders; Notoginsenoside Ft1; Obesity; TGR5; Tgr5, membrane-bound G protein-coupled receptor; Ucp, uncoupling protein; Wt, wild-type; cAMP, adenosine 3′,5′ cyclic monophosphate; eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue.