title: Constituents from Terminalia species increase PPARα and PPARγ levels and stimulate glucose uptake without enhancing adipocyte differentiation.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the effects of the constituents of T. bellerica and T. chebula fruit extracts on PPARα and PPARγ signaling/expression, cellular glucose uptake and adipogenesis.
  
  
  METHODS
  PPARα and PPARγ 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-β-D-glucose (3), 1,2,3,6-tetra-O-galloyl-β-D-glucose (4), and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (5), showed the enhancement of PPARα and/or PPARγ signaling. Two of the gallotannins (4 and 5) also increased PPARα and PPARγ protein expression, while all three (3-5) enhanced insulin-stimulated glucose uptake into HepG2 cells. Compound 1,2,3,6-tetra-O-galloyl-β-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 inhibited the adipogenic effect of rosiglitazone.
  
  
  CONCLUSIONS
  Three gallotannins (3-5) from Terminalia fruits acting as enhancers of both PPARα and PPARγ signaling increased insulin-stimulated glucose uptake without inducing the adipogenesis, with 1,2,3,6-tetra-O-galloyl-β-D-glucose (4) being the most effective in stimulating glucose uptake and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (5) being most effective in increasing PPAR protein expression.
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, MS 38677, USA.
authors.forename: Min Hye
authors.initials: MH
authors.lastname: Yang
authors.forename: Yelkaira
authors.initials: Y
authors.lastname: Vasquez
authors.forename: Zulfiqar
authors.initials: Z
authors.lastname: Ali
authors.forename: Ikhlas A
authors.initials: IA
authors.lastname: Khan
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D029766:Terminalia
chemical_list: D047348:Hydrolyzable Tannins; D047493:PPAR alpha; D047495:PPAR gamma; D010936:Plant Extracts; D005947:Glucose
keywords: Adipogenesis; Gallotannin; Glucose uptake stimulation; PPARα and PPARγ signaling; Terminalia bellerica; Terminalia chebula