Background: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.
Methods: We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists.
Results: The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.
Conclusion: We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.
General significance: This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine.
Keywords: 3-isobutyl-1-methylxanthine; AMP-activated kinase; AMPK; ANOVA; ATCC; American type culture collection; BADGE; BMP; BSA; CMCNa; DMEM; DMSO; Dulbecco's modified Eagle's medium; EC(50); EGFP; FCS; GST; HPLC; IBMX; LBD; MEF; Metabolic disease; NADPH-dependent oxidase; NBS; NF-κB; NMR; NOX; Natural product; PBS; PPARγ; Peroxisome proliferator-activated receptor; RXR; SEM; SPF; SREBP; TCM; TLC; TR-FRET; analysis of variance; bisphenol A diglycidyl ether; bone morphogenic protein 4; bovine serum albumin; dimethyl sulfoxide; effective concentration 50%; enhanced green fluorescent protein; fetal calf serum; glutathione-S-transferase; high-performance liquid chromatography; ligand-binding domain; mTOR; mammalian target of rapamycin; mouse embryonic fibroblasts; newborn bovine serum; nuclear factor κB; nuclear magnetic resonance; peroxisome proliferator-activated receptor gamma; phosphate buffered saline; retinoic X receptor; sodium carboxymethyl cellulose; specific pathogen free; standard error of the mean; sterol regulatory element binding protein; thin layer chromatography; time-resolved fluorescence resonance energy transfer; traditional Chinese medicine.
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