Constituents from Terminalia species increase PPARα and PPARγ levels and stimulate glucose uptake without enhancing adipocyte differentiation

Ethnopharmacological relevance: 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. Aim of the study: The aim of this study was to evaluate the effects of the constituents of T bellerica and T chebula fruit extracts on PPAR alpha and PPAR gamma signaling/expression, cellular glucose uptake and adipogenesis. Materials and methods: PPAR alpha and PPAR gamma signaling and expression (luciferase assay and western blot) 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. Results: Out of the 20 compounds, two ellagitannins, chebulagic acid (1) and corilagin (2), and three gallotannins, 2,3,6-tri-O-galloyl-beta-D-glucose (3), 1,2,3,6-tetra-O-galloyl-beta-D-glucose (4), and 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (5), showed the enhancement of PPAR alpha and/or PPAR gamma signaling. 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-beta-D-glucose (4) was the most potent in increasing cellular glucose uptake (9.92-fold increase at 50 mu M). In the test for adipogenesis, 3-5 did not enhance the differentiation of 3T3-L1 preadipocytes but inhibited the adipogenic effect of rosiglitazone. Conclusion: Three gallotannins (3-5) from Terminalia fruits acting as enhancers of both PPAR alpha and PPAR gamma signaling increased insulin-stimulated glucose uptake without inducing the adipogenesis, with 1,2,3,6-tetra-O-galloyl-beta-D-glucose (4) being the most effective in stimulating glucose uptake and 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (5) being most effective in increasing PPAR protein expression. (C) 2013 Elsevier Ireland Ltd. All rights reserved.