Isomeric C₁₂-alkamides isolated from purple coneflower (Echinacea purpurea (L.) Moench) exhibit characteristics of a PPARγ partial agonist

Nuclear hormone receptor PPARγ is predominantly found in adipose tissue and plays a role in regulating adipogenesis and glucose homeostasis. PPARγ belongs to the superfamily of transcription factors that bind DNA and regulate transcription in a ligand-dependent manner.
A dichloromethane extract of Echinacea purpurea roots increasing glucose uptake (GU) and activating PPARγ was subjected to bioassay-guided chromatographic fractionation. Basal and insulin-dependent GU in 3T3-L1 adipocytes and PPARγ transactivation assay were used to assess the bioactivity of extract, fractions and isolated metabolites. Two novel isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic acid 2-methylbutylamides together with two known C12-alkamides and -linolenic acid were isolated from active fractions. The compounds were found to activate PPARγ but only the isomeric alkamides were able to increase basal and insulin-dependent GU in adipocytes in a dose dependent manner. Docking studies were performed to determine possible binding modes of the novel isomeric C12-alkamides and the potential contacts within the PPARγ ligand binding domain. The weak activation of PPARγ by the novel isomeric C12-alkamides as well as the results of docking mode of the novel isomeric C12-alkamides suggests that these compounds exhibit characteristics of a PPARγ partial agonist indicating that they may represent a chemical scaffold for the development of novel compounds with insulin sensitizing potential. Partial PPARγ agonists are believed not to promote the same magnitude of undesirable side effects as the insulin sensitizing drugs prescribed for the treatment of insulin resistance e.g. thiazolidinediones.