A selective peroxisome proliferator-activated receptor-γ (PPARγ) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) agonists such as the thiazolidinediones are insulin sensitizers used in the treatment of type 2 diabetes. These compounds induce adipogenesis in cell culture models and increase weight gain in rodents and humans. We have identified a novel PPARγ ligand, LG100641, that does not activate PPARγ but selectively and competitively blocks thiazolidinedione-induced PPARγ activation and adipocyte conversion. It also antagonizes target gene activation as well as repression in agonist-treated 3T3-L1 adipocytes. This novel PPARγ antagonist does not block adipocyte differentiation induced by a ligand for the retinoid X receptor (RXR), the heterodimeric partner for PPARγ, or by a differentiation cocktail containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthine. Surprisingly, LG100641, like the PPARγ agonist rosiglitazone, increases glucose uptake in 3T3-L1 adipocytes. Such selective PPARγ antagonists may help determine whether insulin sensitization by thiazolidinediones is mediated solely through PPARγ activation, and whether there are PPARγ-ligand-independent pathways for adipocyte differentiation. If selective PPARγ modulators block adipogenesis in vivo, they may prevent obesity, lower insulin resistance, and delay the onset of type 2 diabetes.