Differential effects of isoflavones, from Astragalus membranaceus and Pueraria thomsonii, on the activation of PPAR[alpha], PPAR[gamma], and adipocyte differentiation in vitro

Compounds that target the peroxisome proliferator-activated receptors PPAR[alpha] and PPAR[gamma] are used to correct dyslipidemia and to restore glycemic balance, respectively. Because the majority of diabetic patients suffer from atherogenic lipid abnormalities, in addition to insulin resistance, ligands are required that can activate both PPAR[alpha] and PPAR[gamma]. In this study, we used chimeric PPAR[alpha]/[gamma], reporter-gene bioassays to screen herbal extracts with purported antidiabetic properties. Extracts of Astragalus membranaceus and Pueraria thomsonii significantly activated PPAR[alpha] and PPAR[gamma]. Bioassay-guided fractionation resulted in the isolation of the isoflavones, formononetin, and calycosin from Astragalus membranaceus, and daidzein from Pueraria thomsonii as the PPAR-activating compounds. We investigated the effects of these and 2 common isoflavones, genistein and biochanin A, using chimeric and full-length PPAR constructs in vitro. Biochanin A and formononectin were potent activators of both PPAR receptors ([EC.sub.50] = 1-4 [micro]mol/L) with PPAR[alpha]/PPAR[gamma] activity ratios of 1:3 in the chimeric and almost 1:1 in the full-length assay, comparable to those observed for synthetic dual PPAR-activating compounds under pharmaceutical development. There was a subtle hierarchy of PPAR[alpha]/[gamma] activities, indicating that biochanin A, formononetin, and genistein were more potent than calycosin and daidzein in chimeric as well as full-length receptor assays. At low doses, only biochanin A and formononetin, but not genistein, calycosin, or daidzein, activated PPAR[gamma]-driven reporter-gene activity and induced differentiation of 3T3-L1 preadipocytes. Our data suggest the potential value of isoflavones, especially biochanin A and their parent botanicals, as antidiabetic agents and for use in regulating lipid metabolism. KEY WORDS: * PPAR[alpha] * PPAR[gamma] * isoflavones * adipocyte differentiation