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Natural products signaling via PPARgamma and its implications for metabolism, diabetes, and obesity

Dr. Birgit Watenberger from the Institute of Pharmacy/Pharmacognosy, University of Innsbruck presents a visual introduction (in a PowerPoint-style) to the scientific review “Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review”:

Abstract (as presented by the authors of the scientific work):

"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."

Concluding remarks (as presented by the authors of the scientific work):

"Natural products prove to be a rich source for the discovery of novel PPARγ ligands and many structurally diverse agonists of this receptor were recently identified from traditionally used medicinal plants or food sources. Interestingly, the majority of identified natural compounds are rather weak agonists of PPARγ, often activating the receptor as partial agonists, with activation pattern distinct from the full thiazolidinedione agonists and more similar to endogenous ligands with weaker activation potential such as fatty acids and prostanoids. Noteworthy, several PPARγ agonists were identified in plants used as culinary spices, beverages or food sources, opening the possibility to consider modulation of the activity of this nuclear receptor through dietary interventions. While most of the identified natural products only activate PPARγ as SPPARMs, some are dual agonists able to also activate PPARα (Table 2). An especially interesting activation pattern is observed for the neolignans magnolol and honokiol, which are ligands for both PPARγ and its dimer activation partner RXR. The neolignan honokiol and several other natural products have also demonstrated beneficial metabolic effects in diabetic animal models, with reduced side effects in comparison to full thiazolidinedione agonists. Many extracts from medicinal plants reported in the literature as PPARγ activators are so far not thoroughly investigated. The identification of their active constituents might provide further interesting ligands in the future.

In conclusion, a range of PPARγ activating natural products and plant extracts were recently described that bear a good potential to be further explored for therapeutic effectiveness as well as to be studied as potential dietary supplements to counteract the metabolic syndrome and type 2 diabetes"

Full-text access of the referenced scientific work:

Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C,
Blazevic T, Schwaiger S, Rollinger JM, Heiss EH, Schuster D, Kopp B, Bauer R,
Stuppner H, Dirsch VM, Atanasov AG. Natural product agonists of peroxisome
proliferator-activated receptor gamma (PPARγ): a review. Biochem Pharmacol. 2014
Nov 1;92(1):73-89. doi: 10.1016/j.bcp.2014.07.018. Epub 2014 Jul 30. Review.
PubMed PMID: 25083916; PubMed Central PMCID: PMC4212005.


Prof. Atanas G. Atanasov (Dr. habil., PhD)

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