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, 92 (1), 73-89

Natural Product Agonists of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ): A Review


Natural Product Agonists of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ): A Review

Limei Wang et al. Biochem Pharmacol.


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.

Keywords: (−)-Catechin (PubChem CID: 73160); Amorfrutin 1 (PubChem CID: 10132170); Diabetes; Falcarindiol (PubChem CID: 5281148); Honokiol (PubChem CID: 72303); Linolenic acid (PubChem CID: 5280934); Magnolol (PubChem CID: 72300); Natural product; Nuclear receptor; Nutrition; PPAR gamma; Pioglitazone (PubChem CID: 4829); Quercetin (PubChem CID: 5280343); Resveratrol (PubChem CID: 445154); Rosiglitazone (PubChem CID: 77999).


Fig. 1
Fig. 1
PPARγ transcriptional activation. (1) Binding of activating ligands to PPARγ and to its dimer partner RXR; (2) following the ligand binding there are conformational changes of the receptors, resulting in re-arrangement of the transcriptional complex and changes in the associated transcriptional cofactors; (3) resulting from this reorganization, the transcriptional complex is activated and initiates changes in the expression of the regulated PPARγ target genes.
Fig. 2
Fig. 2
Binding modes of selected PPARγ ligands co-crystallized with PPARγ. (A) The Y-shaped PPARγ LBD composed of one entrance domain and two arms (arm I is substantially polar, arm II is mainly hydrophobic) . Observed protein-ligand interactions are presented between the human PPARγ LBD and (B) the synthetic agonist rosiglitazone (PDB: 4ema), (C) the endogenous agonist 9-(S)-HODE binding as a homodimer (PDB: 2vsr), the natural ligands (D) amorfrutin B (PDB: 4a4w), (E) magnolol binding as homodimer (PDB: 3r5n), and (F) luteolin binding as a mixed dimer with myristic acid (PDB: 3sz1). The interactions were visualized by means of the software LigandScout with the following color code: hydrogen bond acceptor (red arrow), hydrogen bond donor (green arrow), hydrophobic interaction (yellow sphere), and negative ionizable area (red star). The ligand binding pocket is depicted as surface; its colors are based on the lipo- and hydrophilicity. Contacts with active site water molecules are not shown.

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