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

• Published in: Diabetologia 2016-06, Vol.59 (6), p.1276-1286
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Animals; 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
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-016-3912-9

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.