Polyacetylenes from Notopterygium incisum-New Selective Partial Agonists of Peroxisome Proliferator-Activated Receptor-Gamma

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPAR gamma agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPAR gamma activation using a PPAR gamma-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPAR gamma agonists in the luciferase reporter model. Since PPAR gamma activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 mu M) in the luciferase reporter model was blocked upon co-treatment with the PPAR gamma antagonist T0070907 (1 mu M). Falcarindiol bound to the purified human PPAR gamma receptor with a K-i of 3.07 mu M. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPAR gamma expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPAR gamma agonists, having potential to be further explored as pharmaceutical leads or dietary supplements.