Honokiol: A non-adipogenic PPARγ agonist from nature

• Published in: Biochimica et biophysica acta Vol. 1830; no. 10; pp. 4813 - 4819
• Main Authors: Atanasov, Atanas G., Wang, Jian N., Gu, Shi P., Bu, Jing, Kramer, Matthias P., Baumgartner, Lisa, Fakhrudin, Nanang, Ladurner, Angela, Malainer, Clemens, Vuorinen, Anna, Noha, Stefan M., Schwaiger, Stefan, Rollinger, Judith M., Schuster, Daniela, Stuppner, Hermann, Dirsch, Verena M., Heiss, Elke H.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2013; Elsevier Pub. Co
• Subjects: 3T3-L1 Cells; adipocytes; adipogenesis; Adipose Tissue - cytology; Adipose Tissue - drug effects; adverse effects; agonists; Animals; Biological Products - isolation & purification; Biological Products - pharmacology; Biphenyl Compounds - isolation & purification; Biphenyl Compounds - pharmacology; Cell Differentiation - drug effects; Diabetes Mellitus, Experimental - physiopathology; dietary supplements; fibroblasts; glucose; HEK293 Cells; herbal medicines; honokiol; Humans; hyperglycemia; Lignans - isolation & purification; Lignans - pharmacology; luciferase; Magnolia officinalis; Metabolic disease; Mice; Molecular Docking Simulation; Natural product; Peroxisome proliferator-activated receptor; PPAR gamma - agonists; traditional medicine; weight gain; BADGE; DMSO; SPF; TLC; EGFP; ATCC; RXR; LBD; Metabolic disease; BSA; DMEM; NF-κB; Peroxisome proliferator-activated receptor; ANOVA; mTOR; EC50; HPLC; NBS; PBS; SREBP; BMP; IBMX; Natural product; GST; PPARγ; MEF; NMR; NOX; FCS; CMCNa; AMPK; SEM; TR-FRET; TCM; nuclear factor κB; NADPH-dependent oxidase; ligand-binding domain; retinoic X receptor; bisphenol A diglycidyl ether; mouse embryonic fibroblasts; AMP-activated kinase; EC; effective concentration 50; Dulbecco's modified Eagle's medium; sodium carboxymethyl cellulose; specific pathogen free; standard error of the mean; peroxisome proliferator-activated receptor gamma; bovine serum albumin; glutathione-S-transferase; 3-isobutyl-1-methylxanthine; mammalian target of rapamycin; dimethyl sulfoxide; analysis of variance; high-performance liquid chromatography; American type culture collection; fetal calf serum; bone morphogenic protein 4; time-resolved fluorescence resonance energy transfer; thin layer chromatography; sterol regulatory element binding protein; traditional Chinese medicine; nuclear magnetic resonance; newborn bovine serum; enhanced green fluorescent protein; phosphate buffered saline
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.06.021

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. 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. 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. We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. 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. •Honokiol is identified and characterized as novel partial PPARγ agonist from nature.•In cell models honokiol increases glucose uptake but is not adipogenic.•In KKAy diabetic mice it decreases blood glucose and suppresses weight gain.•PPARγ agonism of honokiol may explain the use of Magnolia bark in traditional medicine.