Nakae Jun, Kitamura Tadahiro, Kitamura Yukari, Biggs William H, Arden Karen C, Accili Domenico
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Dev Cell. 2003 Jan;4(1):119-29. doi: 10.1016/s1534-5807(02)00401-x.
An outstanding question in adipocyte biology is how hormonal cues are relayed to the nucleus to activate the transcriptional program that promotes adipogenesis. The forkhead transcription factor Foxo1 is regulated by insulin via Akt-dependent phosphorylation and nuclear exclusion. We show that Foxo1 is induced in the early stages of adipocyte differentiation but that its activation is delayed until the end of the clonal expansion phase. Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. Further, Foxo1 haploinsufficiency protects from diet-induced diabetes in mice. We propose that Foxo1 plays an important role in the integration of hormone-activated signaling pathways with the complex transcriptional cascade that promotes adipocyte differentiation.
脂肪细胞生物学中的一个突出问题是激素信号如何传递至细胞核，以激活促进脂肪生成的转录程序。叉头转录因子Foxo1受胰岛素通过Akt依赖的磷酸化作用和核排除调控。我们发现，Foxo1在脂肪细胞分化早期被诱导表达，但其激活延迟至克隆扩增阶段结束。组成型激活的Foxo1可阻止前脂肪细胞分化，而显性负性Foxo1可恢复胰岛素受体缺陷小鼠成纤维细胞的脂肪细胞分化。此外，Foxo1单倍体不足可保护小鼠免受饮食诱导的糖尿病影响。我们提出，Foxo1在激素激活的信号通路与促进脂肪细胞分化的复杂转录级联反应的整合中发挥重要作用。
