Waki Hironori, Park Kye Won, Mitro Nico, Pei Liming, Damoiseaux Robert, Wilpitz Damien C, Reue Karen, Saez Enrique, Tontonoz Peter
Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Metab. 2007 May;5(5):357-70. doi: 10.1016/j.cmet.2007.03.010.
PPARgamma is the master regulator of adipogenesis and the molecular target of the thiazolidinedione antidiabetic drugs. By screening for compounds that promote adipogenesis, we identified a small molecule that targets the PPARgamma pathway by a distinct mechanism. This molecule, harmine, is not a ligand for the receptor; rather, it acts as a cell-type-specific regulator of PPARgamma expression. Administration of harmine to diabetic mice mimics the effects of PPARgamma ligands on adipocyte gene expression and insulin sensitivity. Unlike thiazolidinediones, however, harmine does not cause significant weight gain or hepatic lipid accumulation. Molecular studies indicate that harmine controls PPARgamma expression through inhibition of the Wnt signaling pathway. This work validates phenotypic screening of adipocytes as a promising strategy for the identification of bioactive small molecules and suggests that regulators of PPARgamma expression may represent a complementary approach to PPARgamma ligands in the treatment of insulin resistance.
过氧化物酶体增殖物激活受体γ（PPARγ）是脂肪生成的主要调节因子，也是噻唑烷二酮类抗糖尿病药物的分子靶点。通过筛选促进脂肪生成的化合物，我们鉴定出一种通过独特机制靶向PPARγ途径的小分子。这种分子，即 harmine，不是该受体的配体；相反，它作为PPARγ表达的细胞类型特异性调节因子发挥作用。给糖尿病小鼠施用 harmine 可模拟PPARγ配体对脂肪细胞基因表达和胰岛素敏感性的影响。然而，与噻唑烷二酮类不同，harmine 不会导致显著的体重增加或肝脏脂质积累。分子研究表明，harmine 通过抑制Wnt信号通路来控制PPARγ的表达。这项工作验证了脂肪细胞的表型筛选作为鉴定生物活性小分子的一种有前景的策略，并表明PPARγ表达的调节因子可能代表了一种在治疗胰岛素抵抗方面补充PPARγ配体的方法。
