Ginsenoside Ro Ameliorates High-Fat Diet–Induced Obesity and Insulin Resistance in Mice via Activation of the G Protein–Coupled Bile Acid Receptor 5 Pathway

Abstract

Obesity, a well-known risk factor in multiple metabolic diseases, is dramatically increasing worldwide. Ginsenosides extracted from ginseng have been reported against obesity and the associated metabolic disorders. As a subtype of ginsenoside, ginsenoside Ro is a critical constituent of ginseng. However, its specific effects on obesity remains unknown. G protein-coupled bile acid receptor 5 (TGR5, also known as GPBAR1) is a bile acid membrane receptor, widely expressed in human tissues contributing to various metabolic processes to confer the regulations of glucose and lipid homeostasis. TGR5 has displayed potentials as a therapeutic target for the treatment of metabolic disorders. Here, we explore the anti-obesity effect of ginsenoside Ro with TGR5 activation screened by a library of natural products. Our results showed that the ginsenoside Ro (90mg/kg) treatment ameliorated body weight and lipid accumulation in multiple metabolic organs of high fat diet-induced obese (DIO) mice without affecting food intake, and improved oral glucose tolerance tests (OGTT), intraperitoneal insulin tolerance tests (IPITT), and fasting serum glucose. We also found that triglyceride (TG) and total cholesterol (TC) in serum and liver were significantly decreased after ginsenoside Ro treatment. Then we used Tgr5 knockout mice to explore the role of Tgr5 in the anti-obesity effect of ginsenoside Ro. Our results further demonstrated that ginsenoside Ro promoted glucagon-like peptide-1 (GLP-1) secretion and energy expenditure in wild type DIO mice. However, the stimulation of ginsenoside Ro on GLP-1 secretion and energy expenditure were restrained in the Tgr5 knockout mice.In conclusion, our findings demonstrated that ginsenoside Ro ameliorates obesity and insulin resistance in DIO mice via activating TGR5, indicatinga potential therapeutic role of ginsenoside Ro to treat obesity and its associated metabolic diseases. SIGNIFICANCE STATEMENTObesity is dramatically increasing worldwide and it contributes to multiple metabolic diseases.TGR5 is a potential therapeutic target for the treatment of metabolic disorders. Ginsenoside Ro, as a oleanane-type ginsenoside, ameliorates obesity and insulin resistance, promotes GLP-1 secretion, This article has not been copyedited and formatted. The final version may differ from this version.

Optimized ultra-high-performance liquid chromatography tandem mass spectrometry method for detecting compositional changes in Eucommia ulmoides and Achyranthes bidentata paired decoctions in vitro and in vivo

“…Among them, the contents of ginsenoside Ro, chikusetsusaponin Ⅳa, and achyranthoside C in A. bidentata increased significantly after drug pairing. Ginsenoside Ro is an oleanolic acid-type saponin found in A. bidentata, which has been shown to inhibit apoptosis and inflammation of rat chondrocytes by inhibiting the NF-κB signaling pathway [26], and could improve obesity and insulin resistance induced by a high-fat diet in mice by activating Takeda G-protein-coupled receptor 5 (TGR5) [17]. Another study also found that the ginsenoside Ro content increased when used in a combined ginseng decoction with Trogopteroum feces or Raphani semen, suggesting that the combined decoction promoted the dissolution of ginsenoside Ro [27].…”

“…In this study, 10 representative components were selected through basic research of drug-pair chemicals and a related literature review, including representative compounds with reported pharmacological activity in both E. ulmoides and A. bidentata [17][18][19][20], and unique components of E. ulmoides and A. bidentata with no previously reported quality control (QC) standards. Thus, there is a need to optimize existing methods to develop a suitable method that can detect the above selected components equally sensitive to lower sample concentrations.…”

Bile acids-gut microbiota crosstalk contributes to the improvement of type 2 diabetes mellitus

“…Ginsenosides is the main active components of ginseng, which regulates glucose and lipid metabolism by inducing gluconeogenesis reduction and glucose transport ( Bai et al, 2018 ). Ginsenoside Ro improves IR by activating TGR5 to promote GLP-1 secretion and energy expenditure in adipose tissue in DIO mice, which suggests that ginsenoside Ro is a potential compound for the treatment of T2DM ( Supplementary Table S1 ) ( Jiang et al, 2021 ). Jyoti et al found that Pregnane-Oximino-Alkyl-Amino-Ether (compound 14b), a TGR5 agonist, improved glucose tolerance in sucrose-loaded rats by increasing glucose utilization in skeletal muscle and hepatocytes ( Supplementary Table S1 ).…”

Ginseng in vascular dysfunction: A review of therapeutic potentials and molecular mechanisms

“…In addition, insulin resistance refers to the decreased sensitivity of the body to insulin and is closely related to metabolic syndrome and T2DM. It was reported that ginsenoside Ro ameliorated obesity and insulin resistance induced by high fat diet in mice by activating the TGR5 pathway (Jiang et al, 2021). And ginsenoside Mc1 improved liver steatosis and insulin resistance by reducing endoplasmic reticulum stress (Roh et al, 2020).…”