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Title: Constituents from Terminalia species increase PPAR-Alpha and PPAR-Gamma levels and stimulate glucose uptake without enhancing adipocyte differentiation

Author
item YANG, MIN HYE - University Of Mississippi
item VASQUEZ, YELKAIRA - University Of Mississippi
item ALI, ZULFIQAR - University Of Mississippi
item KHAN, IKHLAS - University Of Mississippi
item KHAN, SHABANA - University Of Mississippi

Submitted to: Journal of Ethnopharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/4/2013
Publication Date: 7/10/2013
Citation: Yang, M., Vasquez, Y., Ali, Z., Khan, I.A., Khan, S.I. 2013. Constituents from Terminalia species increase PPAR-Alpha and PPAR-Gamma levels and stimulate glucose uptake without enhancing adipocyte differentiation. Journal of Ethnopharmacology. 149:490-498.

Interpretive Summary: In our previous screening test, the fruit extracts of T. bellerica and T. chebula showed PPAR alpha/gamma activation in HepG2 cells. This study is to find the constituents, which is responsible for the activity, isolated from those extracts. Out of 20 compounds, two ellagitannins, chebulagic acid corilagin, and three gallotannins, 2,3,6-tri-O-galloyl-ß-D-glucose, 1,2,3,6-tetra-O-galloyl-ß-D-glucose, and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose, significantly induced PPAR alpha and/or PPAR gamma expression. Compound 1,2,3,6-tetra-O-galloyl-ß-D-glucose was the most potent in increasing cellular glucose uptake without adipogenesis. This is first report to reveal PPAR alpha/gamma activation and glucose uptake stimulation by Terminalia compounds.

Technical Abstract: The fruits of Terminalia bellerica Roxb.(Combretaceae) and T. chebula Retz. (Combretaceae) are important components of triphala, a popular Ayurvedic formulation, for treating diabetes in Indian traditional medicine. The aim of this study was to evaluate the effects of the constituents of T. bellerica and T. chebula fruit extracts on PPAR alpha/gamma-activity, cellular glucose uptake and adipogenesis. The activation of PPAR alpha and PPAR gamma and the insulin-stimulated uptake of 2-NBDG were determined in HepG2 cells. The effects on adipogenesis were determined in 3T3-L1 cells by Oil red O staining and measurement of lipid content by AdipoRed reagent. Out of the twenty compounds, two ellagitannins, chebulagic acid (1) and corilagin (2), and three gallotannins, 2,3,6-tri-O-galloyl-ß-D-glucose (3), 1,2,3,6-tetra-O-galloyl-ß-D-glucose (4), and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (5), showed activation of PPAR alpha and/or PPAR gamma. Two of the gallotannins (4 and 5) also increased PPAR alpha and PPAR gamma protein expression, while all three (3-5) enhanced insulin-stimulated glucose uptake into HepG2 cells. Compound 1,2,3,6-tetra-O-galloyl-ß-D-glucose (4) was the most potent in increasing cellular glucose uptake (9.92-fold increase at 50 µM). In the test for adipogenesis, 3-5 did not enhance the differentiation of 3T3-L1 preadipocytes but antagonized the adipogenic effect of rosiglitazone. Three gallotannins (3-5) from Terminalia fruits acting as dual PPAR alpha/PPAR gamma agonists enhanced insulin-stimulated glucose uptake without enhancing the adipogenesis, with 1,2,3,6-tetra-O-galloyl-ß-D-glucose (4) being the most effective in enhancing glucose uptake and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (5) being most effective in increasing PPAR protein expression.