Mukherjee R, Hoener P A, Jow L, Bilakovics J, Klausing K, Mais D E, Faulkner A, Croston G E, Paterniti J R
Department of Pharmacology, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA.
Mol Endocrinol. 2000 Sep;14(9):1425-33. doi: 10.1210/mend.14.9.0528.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma ligand, LG100641, that does not activate PPARgamma but selectively and competitively blocks thiazolidinedione-induced PPARgamma activation and adipocyte conversion. It also antagonizes target gene activation as well as repression in agonist-treated 3T3-L1 adipocytes. This novel PPARgamma antagonist does not block adipocyte differentiation induced by a ligand for the retinoid X receptor (RXR), the heterodimeric partner for PPARgamma, or by a differentiation cocktail containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthine. Surprisingly, LG100641, like the PPARgamma agonist rosiglitazone, increases glucose uptake in 3T3-L1 adipocytes. Such selective PPARgamma antagonists may help determine whether insulin sensitization by thiazolidinediones is mediated solely through PPARgamma activation, and whether there are PPARgamma-ligand-independent pathways for adipocyte differentiation. If selective PPARgamma modulators block adipogenesis in vivo, they may prevent obesity, lower insulin resistance, and delay the onset of type 2 diabetes.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，如噻唑烷二酮类药物，是用于治疗2型糖尿病的胰岛素增敏剂。这些化合物在细胞培养模型中诱导脂肪生成，并在啮齿动物和人类中增加体重。我们鉴定出一种新型PPARγ配体LG100641，它不激活PPARγ，但能选择性地竞争性阻断噻唑烷二酮诱导的PPARγ激活和脂肪细胞转化。它还能拮抗激动剂处理的3T3-L1脂肪细胞中的靶基因激活以及抑制作用。这种新型PPARγ拮抗剂不会阻断由视黄酸X受体（RXR，PPARγ的异二聚体伴侣）的配体或含有胰岛素、地塞米松和1-甲基-3-异丁基黄嘌呤的分化混合物诱导的脂肪细胞分化。令人惊讶的是，LG100641与PPARγ激动剂罗格列酮一样，能增加3T3-L1脂肪细胞对葡萄糖的摄取。这种选择性PPARγ拮抗剂可能有助于确定噻唑烷二酮类药物的胰岛素增敏作用是否仅通过PPARγ激活介导，以及是否存在不依赖PPARγ配体的脂肪细胞分化途径。如果选择性PPARγ调节剂能在体内阻断脂肪生成，它们可能预防肥胖、降低胰岛素抵抗并延缓2型糖尿病的发病。
