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Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice

Aims/hypothesis Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat compli... Full description

Journal Title: Diabetologia 2016-03-16, Vol.59 (6), p.1276-1286
Main Author: Feng, Li
Other Authors: Luo, Huan , Xu, Zhijian , Yang, Zhuo , Du, Guoxin , Zhang, Yu , Yu, Lijing , Hu, Kaifeng , Zhu, Weiliang , Tong, Qingchun , Chen, Kaixian , Guo, Fujiang , Huang, Cheng , Li, Yiming
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
ID: ISSN: 0012-186X
Link: https://www.ncbi.nlm.nih.gov/pubmed/26983922
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recordid: cdi_springer_journals_10_1007_s00125_016_3912_9
title: Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice
format: Article
creator:
  • Feng, Li
  • Luo, Huan
  • Xu, Zhijian
  • Yang, Zhuo
  • Du, Guoxin
  • Zhang, Yu
  • Yu, Lijing
  • Hu, Kaifeng
  • Zhu, Weiliang
  • Tong, Qingchun
  • Chen, Kaixian
  • Guo, Fujiang
  • Huang, Cheng
  • Li, Yiming
subjects:
  • 3T3-L1 Cells
  • Animals
  • Article
  • Binding Sites
  • Blood Glucose - drug effects
  • Drug Synergism
  • Female
  • Flavonoids - administration & dosage
  • Flavonoids - therapeutic use
  • Human Physiology
  • Internal Medicine
  • Lipid Metabolism - drug effects
  • Medicine
  • Medicine & Public Health
  • Metabolic Diseases
  • Mice
  • Obesity - blood
  • Obesity - drug therapy
  • Obesity - metabolism
  • PPAR alpha - agonists
  • PPAR gamma
  • Thiazolidinediones - therapeutic use
  • Triglycerides - blood
ispartof: Diabetologia, 2016-03-16, Vol.59 (6), p.1276-1286
description: Aims/hypothesis Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. Methods Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db / db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. Results BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db / db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. Conclusions/interpretation This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
language: eng
source:
identifier: ISSN: 0012-186X
fulltext: no_fulltext
issn:
  • 0012-186X
  • 1432-0428
url: Link


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titleBavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice
creatorFeng, Li ; Luo, Huan ; Xu, Zhijian ; Yang, Zhuo ; Du, Guoxin ; Zhang, Yu ; Yu, Lijing ; Hu, Kaifeng ; Zhu, Weiliang ; Tong, Qingchun ; Chen, Kaixian ; Guo, Fujiang ; Huang, Cheng ; Li, Yiming
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descriptionAims/hypothesis Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. Methods Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db / db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. Results BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db / db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. Conclusions/interpretation This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
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descriptionAims/hypothesis Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. Methods Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db / db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. Results BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db / db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. Conclusions/interpretation This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
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atitleBavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice
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abstractAims/hypothesis Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. Methods Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db / db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. Results BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db / db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. Conclusions/interpretation This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
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