Cell Cycle Regulators in Diabetes and Obesity

在这个提议中，我们将使用在Cdk4位点有突变的小鼠模型。Cdk4-/-小鼠为糖尿病小鼠，体重偏瘦，而Cdk4R24C小鼠为非糖尿病小鼠，体重偏重。这些观察结果与文献记载的RB/E2F通路在脂肪形成和肌肉分化中的作用一致，尽管没有很好地表征。由于Cdk4是E2F-RB通路的上游调节因子，我们假设Cdk4活性可能调节脂肪形成和肌肉发育及功能。此外，Cdk4对胰岛素产生、性激素和葡萄糖调节的影响可能会影响Cdk4R24C模型中的能量平衡。我们正在通过评估Cdk4小鼠不同代谢器官中依赖Cdk4的功能来研究糖耐量和能量稳态的机制。这些发现揭示了Cdk4在调节能量平衡过程中的重要作用。

In this proposal we will use mouse models that have mutations in the Cdk4 locus. Cdk4-/- mice are diabetic and lean, and in contrast, Cdk4R24C mice are non-diabetic and heavier. These observations are consistent with the documented, albeit not very well characterized, role of the RB/E2F pathway in adipogenesis amd muscle differentiation. Since Cdk4 is an upstream regulator of the E2F-RB pathway, we hypothesize that Cdk4 activity may regulate adipogenesis and muscle development and function. Further, the effect of Cdk4 on production of insulin, sex hormones and glucose regulation may impact the energy balance in the Cdk4R24C model. We are studying mechanisms of glucose tolerance and energy homeostasis by evaluating CDk4-dependent functions in different metabolic organs in the Cdk4 mice. The findings are revealing important role of Cdk4 in process that modulate energy balance.