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 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-u.This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.