Bavachinin, as a novel natural pan PPAR agonist, exhibits unique synergistic effects with synthetic PPAR g and PPAR a agonists on carbohydrate and lipid metabolism in db/db and diet induced obese mice
Aims/hypothesisPan 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.MethodsNatural 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.ResultsBVC exhibited glucose lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR g agonists, and fibrates, which are PPAR a 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 g agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site.Conclusions/interpretationThis is the first report of a synergistic glucose and lipid lowering effect of BVC and synthetic agonists induced by unique binding with PPAR g or a. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
Diabetologia