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

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