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

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      Author(s): a , b , a , b , e , a , b , b , b , a , † , a , † , a , a , a , a , b , c , ∗ , a , d , ∗
      Publication date (Electronic):
      Journal: Acta Pharmaceutica Sinica. B
      Publisher: Elsevier
      Keywords: Notoginsenoside Ft1, Obesity, Insulin resistance, Bile acids, TGR5, FXR, GLP-1, Metabolic disorders, ANOVA, analysis of variance, AUC, area under the curve, BAs, bile acids, BAT, brown adipose tissue, cAMP, adenosine 3′,5′ cyclic monophosphate, DIO, diet-induced obesity, eWAT, epididymal white adipose tissue, FGF, fibroblast growth factor, Fxr, nuclear farnesoid X receptor, GLP-1, glucagon-like peptide-1, Tgr5, membrane-bound G protein-coupled receptor, HFD, high fat diet, GTT, glucose tolerance test, ITT, insulin tolerance test, iWAT, inguinal white adipose tissue, KO, knockout, Ft1, notoginsenoside Ft1, Ucp, uncoupling protein, Wt, wild-type

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          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.

          Graphical abstract

          Notoginsenoside Ft1 activates Tgr5, but antagonizes Fxr in ileum to enhance bile acid synthesis, thereby imparts metabolic improvement in high fat diet induced obese mice.

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          Overweight, Obesity, and Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults

          Eugenia E Calle, Carmen Rodríguez, Kimberly Walker-Thurmond … (2003)
          The influence of excess body weight on the risk of death from cancer has not been fully characterized. In a prospectively studied population of more than 900,000 U.S. adults (404,576 men and 495,477 women) who were free of cancer at enrollment in 1982, there were 57,145 deaths from cancer during 16 years of follow-up. We examined the relation in men and women between the body-mass index in 1982 and the risk of death from all cancers and from cancers at individual sites, while controlling for other risk factors in multivariate proportional-hazards models. We calculated the proportion of all deaths from cancer that was attributable to overweight and obesity in the U.S. population on the basis of risk estimates from the current study and national estimates of the prevalence of overweight and obesity in the U.S. adult population. The heaviest members of this cohort (those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of at least 40) had death rates from all cancers combined that were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight. For men, the relative risk of death was 1.52 (95 percent confidence interval, 1.13 to 2.05); for women, the relative risk was 1.62 (95 percent confidence interval, 1.40 to 1.87). In both men and women, body-mass index was also significantly associated with higher rates of death due to cancer of the esophagus, colon and rectum, liver, gallbladder, pancreas, and kidney; the same was true for death due to non-Hodgkin's lymphoma and multiple myeloma. Significant trends of increasing risk with higher body-mass-index values were observed for death from cancers of the stomach and prostate in men and for death from cancers of the breast, uterus, cervix, and ovary in women. On the basis of associations observed in this study, we estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women. Increased body weight was associated with increased death rates for all cancers combined and for cancers at multiple specific sites. Copyright 2003 Massachusetts Medical Society
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            Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.

            H. Wang, J. Chen, K Hollister … (1999)
            The major metabolic pathway for elimination of cholesterol is via conversion to bile acids. In addition to this metabolic function, bile acids also act as signaling molecules that negatively regulate their own biosynthesis. However, the precise nature of this signaling pathway has been elusive. We have isolated an endogenous biliary component (chenodeoxycholic acid) that selectively activates the orphan nuclear receptor, FXR. Structure-activity analysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. Finally, we show that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We suggest that FXR (BAR) is the endogenous bile acid sensor and thus an important regulator of cholesterol homeostasis.
            Article 0 comments Cited 349 times – based on 0 reviews     Review now
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              Gut microbiota and intestinal FXR mediate the clinical benefits of metformin

              Lulu Sun, Cen Xie, Guang Zhou Wang … (2018)
              The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis –GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.
              Article 0 comments Cited 344 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Wendong Huang
                Li Yang
                Journal
                Journal ID (nlm-ta): Acta Pharm Sin B
                Journal ID (iso-abbrev): Acta Pharm Sin B
                Title: Acta Pharmaceutica Sinica. B
                Publisher: Elsevier
                ISSN (Print): 2211-3835
                ISSN (Electronic): 2211-3843
                Publication date PMC-release: 30 March 2021
                Publication date (Print): June 2021
                Publication date (Electronic): 30 March 2021
                Volume: 11
                Issue: 6
                Pages: 1541-1554
                Affiliations
                [a ]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
                [b ]Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
                [c ]Graduate School of Biological Science, City of Hope National Medical Center, Duarte, CA 91010, USA
                [d ]Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
                [e ]Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China
                Author notes
                [∗ ]Corresponding authors. Tel.: +1 626 258 1203, fax: +1 626 256 8704 (Wendong Huang); Tel.: +86 21 51322506, fax: +86 21 51322519 (Li Yang). whuang@ 123456coh.org yangli7951@ 123456hotmail.com
                [†]

                Current address: Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China.

                Article
                Publisher Item ID: S2211-3835(21)00110-6
                DOI: 10.1016/j.apsb.2021.03.038
                PMC ID: 8245856
                PubMed ID: 34221867
                SO-VID: baa247bf-2c4c-45ca-ae33-702b96d72bd8
                Copyright © © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 8 January 2021
                Date revision received : 7 March 2021
                Date accepted : 10 March 2021
                Categories
                Subject: Original Article

                Keywords: notoginsenoside ft1,obesity,insulin resistance,bile acids,tgr5,fxr,glp-1,metabolic disorders,anova, analysis of variance,auc, area under the curve,bas, bile acids,bat, brown adipose tissue,camp, adenosine 3′,5′ cyclic monophosphate,dio, diet-induced obesity,ewat, epididymal white adipose tissue,fgf, fibroblast growth factor,fxr, nuclear farnesoid x receptor,glp-1, glucagon-like peptide-1,tgr5, membrane-bound g protein-coupled receptor,hfd, high fat diet,gtt, glucose tolerance test,itt, insulin tolerance test,iwat, inguinal white adipose tissue,ko, knockout,ft1, notoginsenoside ft1,ucp, uncoupling protein,wt, wild-type
                Data availability:
                Keywords: notoginsenoside ft1, obesity, insulin resistance, bile acids, tgr5, fxr, glp-1, metabolic disorders, anova, analysis of variance, auc, area under the curve, bas, bile acids, bat, brown adipose tissue, camp, adenosine 3′,5′ cyclic monophosphate, dio, diet-induced obesity, ewat, epididymal white adipose tissue, fgf, fibroblast growth factor, fxr, nuclear farnesoid x receptor, glp-1, glucagon-like peptide-1, tgr5, membrane-bound g protein-coupled receptor, hfd, high fat diet, gtt, glucose tolerance test, itt, insulin tolerance test, iwat, inguinal white adipose tissue, ko, knockout, ft1, notoginsenoside ft1, ucp, uncoupling protein, wt, wild-type

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