Limei Wang a , 1 , Birgit Waltenberger b , 1 , Eva-Maria Pferschy-Wenzig c , Martina Blunder c , Xin Liu c , Clemens Malainer a , Tina Blazevic a , Stefan Schwaiger b , Judith M. Rollinger b , Elke H. Heiss a , Daniela Schuster d , Brigitte Kopp a , Rudolf Bauer c , Hermann Stuppner b , Verena M. Dirsch a , Atanas G. Atanasov a , *
01 November 2014
PPAR gamma, Nuclear receptor, Natural product, Nutrition, Diabetes, 9-(S)-HODE, (9S,10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid, AF-2, activation function-2, CAP, c-Cbl-associated protein, Cdk5, cyclin-dependent kinase 5, DCM, dichloromethane, DIO, diet-induced obesity, DPP-4, dipeptidylpeptidase 4, EMA, European Medicines Agency, FDA, Food and Drug Administration, Glut4, glucose transporter type 4, HDL, high-density lipoprotein, HUVEC, human umbilical vein endothelial cells, LBD, ligand-binding domain, LDL, low-density lipoprotein, MAPK, mitogen-activated protein kinase, MeOH, methanol, NF-κB, nuclear factor-kappaB, PPAR, peroxisome proliferator-activated receptor, RXR, retinoid X receptor, PDB, protein data bank, PPRE, peroxisome proliferator response element, SPPARMs, selective PPARγ modulators, TCM, traditional Chinese medicine, TNF-α, tumor necrosis factor alpha
Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant.
Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.