Red ginseng extracts ameliorate high-fat diet-induced obesity and insulin resistance by activating the intestinal TGR5-mediated bile acids signaling pathway.

BACKGROUND: Obesity has emerged as a worldwide metabolic disease, given its rapid growth in global prevalence. Red ginseng extracts (RGS), one of the traditional processed products of ginseng, show the potential to improve the metabolic phenotype of obesity. However, the RGS mechanism for regulating obesity and late insulin resistance remains to be clarified. PURPOSE: This study aimed to emphasize the potential use of RGS in treatment of obesity and insulin resistance (IR) and explore the underlying mechanism affecting glucose and lipid metabolism improvements. METHODS: The role of RGS was evaluated in a high-fat diet (HFD) rodent model. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to characterize the glucose metabolism level. The expression of lipolysis proteins and uncoupling protein-1 (UCP-1) were investigated by western blot. Glucagon-like peptide-1 (GLP-1) and apical sodium-dependent bile acid transporter (ASBT) protein expression in the intestine were determined via immunofluorescence. UPLC-Q-TOF-MS were used to detect the alterations in bile acids (BAs) levels in serum, ileum, and inguinal white adipose tissue (iWAT). In addition, intestine-specific Tgr5 knockout mice were employed to verify the efficacy of RGS in improving obesity. RESULTS: RGS treatment alleviated dietary-induced dyslipidemia and IR in obese mice in a dose-dependent manner and improved glucose and insulin tolerance, and energy expenditure. RGS treatment significantly reduced lipid deposition and induced GLP-1 secretion in the intestine of wild-type mice but not in Tgr5ΔIN obese mice. Furthermore, RGS intervention increased BA levels in serum, ileum, and iWAT. The increase of circulating BAs in mice was related to the activation of ileal TGR5 and the promotion of ASBT translocation to the plasma membrane, thus affecting BA transport. Next, the increased level of circulating BAs entered the periphery, which might facilitate lipolysis and energy consumption by activating TGR5 in iWAT. CONCLUSION: Our results demonstrated that RGS significantly alleviated HFD-induced obesity and insulin resistance in mice. RGS intervention improved glucose metabolism, promoted lipolysis, and energy metabolism by activating TGR5 in the intestine. In addition, we found that activating intestinal TGR5 facilitated the localization of ASBT to the plasma membrane, which ultimately promoted the transport of BAs to regulate metabolic phenotype.

The Role of Gut Microbiota-Bile Acids Axis in the Progression of Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), an emerging global health problem affecting 25-30% of the total population, refers to excessive lipid accumulation in the liver accompanied by insulin resistance (IR) without significant alcohol intake. The increasing prevalence of NAFLD will lead to an increasing number of cirrhosis patients, as well as hepatocellular carcinoma (HCC) requiring liver transplantation, while the current treatments for NAFLD and its advanced diseases are suboptimal. Accordingly, it is necessary to find signaling pathways and targets related to the pathogenesis of NAFLD for the development of novel drugs. A large number of studies and reviews have described the critical roles of bile acids (BAs) and their receptors in the pathogenesis of NAFLD. The gut microbiota (GM), whose composition varies between healthy and NAFLD patients, promotes the transformation of more than 50 secondary bile acids and is involved in the pathophysiology of NAFLD through the GM-BAs axis. Correspondingly, BAs inhibit the overgrowth of GM and maintain a healthy gut through their antibacterial effects. Here we review the biosynthesis, enterohepatic circulation, and major receptors of BAs, as well as the relationship of GM, BAs, and the pathogenesis of NAFLD in different disease progression. This article also reviews several therapeutic approaches for the management and prevention of NAFLD targeting the GM-BAs axis.

Gut Microbiota: Novel Therapeutic Target of Ginsenosides for the Treatment of Obesity and Its Complications.

Obesity, generally characterized by excessive lipid accumulation, is a metabolic threat worldwide due to its rapid growth in global prevalence. Ginsenosides are crucial components derived from natural plants that can confer metabolic benefits for obese patients. Considering the low bioavailability and degradable properties of ginsenosides in vivo, it should be admitted that the mechanism of ginsenosides on anti-obesity contribution is still obscure. Recently, studies have indicated that ginsenoside intervention has beneficial metabolic effects on obesity and its complications because it allows for the correction of gut microbiota dysbiosis and regulates the secretion of related endogenous metabolites. In this review, we summarize the role of gut microbiota in the pathogenetic process of obesity, and explore the mechanism of ginsenosides for ameliorating obesity, which can modulate the composition of gut microbiota by improving the metabolism of intestinal endogenous substances and alleviating the level of inflammation. Ginsenosides are expected to become a promising anti-obesity medical intervention in the foreseeable clinical settings.

Energy metabolism in major depressive disorder: Recent advances from omics technologies and imaging.

Major depressive disorder (MDD) is a serious psychiatric disorder that associated with high rate of disability and increasing suicide rate, and the pathogenesis is still unclear. Many researches showed that the energy metabolism of patients with depression is impaired, which may be the direction of depression treatment. In this review, we focus on the "omics" technologies such as genomics, proteomics, transcriptomics and metabolomics, as well as imaging, and the progress on energy metabolism of MDD. These findings indicate that abnormal energy metabolism is one of the important mechanisms for the occurrence and development of depression. Although the research on various mechanisms of depression is still ongoing, the rapid development of new technologies and the joint use of various technologies will help to clarify the pathogenesis of depression and explore efficient diagnosis and treatment methods.

Dose-Related Urinary Metabolic Alterations of a Combination of Quercetin and Resveratrol-Treated High-Fat Diet Fed Rats.

Most herbal polyphenols and flavonoids reveals multiple ameliorative benefits for obesity caused by chronic metabolic disorders. Accumulated studies have revealed that preferable therapeutic effects can be obtained through clinical combination of these two kinds of natural compounds for obesity improvement. The typical representative research was the combination of quercetin and resveratrol (CQR), in which the ratio of quercetin and resveratrol is 2:1, demonstrating a synergistic effect in anti-obesity process. Although there exists reports clarifying the mechanism of the combination of two to improve obesity from the perspective of improving adipose tissue inflammation or modulating the composition of intestinal flora, there are few further studies on the mechanism of drug action from the perspective of metabolites transformation. In this research, we mainly focused on the alterations of endogenous metabolites in rats, and analyzed the urine metabolites of obese and intervention model. Therefore, a gas chromatography-mass spectrometry (GC-MS) based metabolomics approach was applied to assess the potential effects and mechanisms of CQR at different dosages (45, 90, and 180 mg/kg) in high fat diet (HFD)-induced obesity rats. Body weight gain and visceral fat weight were reduced by CQR, as well as blood lipid and inflammatory factor levels were increased by CQR in a dose-related manner. Urinary metabolomics revealed 22 differential metabolites related to the HFD-induced obesity, which were reversed in a dose-dependent manner by CQR, of which 8 were reversed in the 45 mg/kg CQR group, 15 were reversed in the 90 mg/kg CQR group, and 18 were reversed in the 180 mg/kg CQR group. Combined with bioinformatics and pattern recognition, the results demonstrated that the key differential metabolites were basically involved in amino acid metabolism, galactose metabolism, pantothenate and CoA biosynthesis, pyruvate metabolism and lysine degradation. In summary, our results showed significant therapeutic action by CQR administration and remarkable metabolomic changes after HFD feeding and CQR intervention. Urinary metabolomic analysis was highlighted on account of providing holistic and comprehensive insights into the pathophysiological mechanisms of the HFD-induced obesity, which also supplied clues for the future mechanism studies of CQR's anti-obesity effects.

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.

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 remain 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 potential as a therapeutic target for the treatment of metabolic disorders. Here, we explore the antiobesity 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, intraperitoneal insulin tolerance tests, and fasting serum glucose. We also found that triglyceride and total cholesterol 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 antiobesity 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, indicating a potential therapeutic role of ginsenoside Ro to treat obesity and its associated metabolic diseases. SIGNIFICANCE STATEMENT: Obesity is dramatically increasing worldwide, and it contributes to multiple metabolic diseases. G protein-coupled bile acid receptor 5 (TGR5) is a potential therapeutic target for the treatment of metabolic disorders. Ginsenoside Ro, as an oleanane-type ginsenoside, ameliorates obesity and insulin resistance, promotes glucagon-like peptide 1 secretion, and increases energy expenditure via activating TGR5. Ginsenoside Ro could be a potential leading compound for treating obesity and its associated metabolic diseases.

Hepatoprotection and hepatotoxicity of Chinese herb Rhubarb (Dahuang): How to properly control the "General (Jiang Jun)" in Chinese medical herb.

Chinese herb Rhubarb (Dahuang), one of the most widely used traditional Chinese medicine in clinical application for over a thousand years and known as the "General (Jiang Jun)" in Chinese medical herb, currently used clinically for long-term treatment of gastrointestinal diseases and chronic liver diseases. Through previous researches, it has been identified that Rhubarb possessed a good hepatoprotective effect, which primarily protected liver from oxidation, fibrosis and cirrhosis, liver failure, hepatocellular carcinoma and various types of hepatitis. Meanwhile, it has been recently reported that long-term administration of Rhubarb preparation may undertake the risk of liver damage, which has aroused worldwide doubts about the safety of Rhubarb. Therefore, how to correctly understand the "two-way" effect of Rhubarb on liver protection and liver toxicity provides a basis for scientific evaluation of Rhubarb's efficacy on liver and side effects, as well as guiding clinical rational drug use. In this review, the mechanisms of Rhubarb how to play a role in hepatoprotection and why it causes hepatotoxic potential will be elaborated in detail and critically. In addition, some positive clinical guidances are also advised on how to reduce its hepatotoxicity in medical treatment.

Gut Microbiota: A Pivotal Hub for Polyphenols as Antidepressants.

Polyphenols, present in a broad range of plants, have been thought to be responsible for many beneficial health effects, such as an antidepressant. Despite that polyphenols can be absorbed in the small intestine directly, most of them have low bioavailability and reach the large intestine without any modifications due to their complex structures. The interaction between microbial communities and polyphenols in the intestine is important for the latter to exert antidepressant effects. Gut microbiota can improve the bioavailability of polyphenols; in turn, polyphenols can maintain the intestinal barrier as well as the community of the gut microbiota in normal status. Furthermore, gut microbita catabolize polyphenols to more active, better-absorbed metabolites, further ameliorating depression through the microbial-gut-brain (MGB) axis. Based on this evidence, the review illustrates the potential role of gut microbiota in the processes of polyphenols or their metabolites acting as antidepressants and further envisions the gut microbiota as therapeutic targets for depression.