The role of FoxK1 in insulin signaling and adipose tissue metabolism

胰岛素是调节营养和能量平衡的中心激素。随着2型糖尿病和肥胖症在全球范围内的惊人增长，研究的一个主要焦点是了解这些代谢紊乱特征的胰岛素抵抗机制。叉头盒（FOX）转录因子家族成员FOXO和FOXA2已被证明在胰岛素代谢活动中发挥作用。宿主组获得的数据表明，另一种先前与胰岛素作用无关的FOX蛋白FOXK1也可能在这一过程中发挥作用。有趣的是，与FOXO蛋白相反，FOXK1在胰岛素刺激下易位进入细胞核。在本项目中，我们提出FOXK1作为一种介导脂肪细胞胰岛素反应的新因子的研究。通过全面的体外和体内研究，本项目将描述导致FOXK1激活的信号事件、其磷酸化位点、结合伙伴和靶基因。此外，将产生脂肪细胞特异性缺失FOXK1的小鼠，用于研究该因子在白色和棕色脂肪组织中的生理功能，以及其在肥胖和胰岛素抵抗等病理状况中的潜在参与。

Insulin is a central hormone in the regulation of nutrient and energy homeostasis. In the wake of the alarming worldwide increase in type-2 diabetes and obesity, a major focus of research is understanding the mechanisms underlying the insulin resistance characteristic of these metabolic disorders. Members of the forkhead box (FOX) transcription factor family FOXO and FOXA2, have been shown to play a role in insulin metabolic actions. Data obtained by the hosting group demonstrate that another FOX protein, FOXK1, not previously linked to insulin action, may also play a role in this process. Interestingly, opposite of FOXO proteins, FOXK1 undergoes translocation into the nucleus in response to insulin stimulation. In this project, we propose the study of FOXK1 as a novel factor mediating insulin responses in adipocytes. By using comprehensive in vitro and in vivo studies this project will characterize the signaling events leading to FOXK1 activation, its phosphorylation sites, binding partners and target genes. In addition, mice with an adipocyte-specific deletion of FOXK1 will be generated for the study of the physiological function of this factor in white and brown adipose tissues, as well as its potential involvement in pathological conditions such as obesity and insulin resistance.