ROLE OF INSULIN AND IGF-1 ON BROWN ADIPOCYTES

棕色脂肪组织(BAT)专门用于新生儿的非颤抖产热。调节BAT活性是维持能量平衡的关键。胰岛素和胰岛素样生长因子-1(IGF-1)都被认为在多种细胞环境中对细胞的增殖、存活和代谢起着重要的调节作用。然而，这些因素在BAT中的作用还没有完全阐明。我们的实验室已经成功地从新生小鼠建立了棕色前脂肪细胞系，并制定了体外分化这些细胞的方案。该模型为研究胰岛素和IGF-1在新陈代谢和细胞存活调节中的作用以及描述相关的信号通路提供了一个很好的系统。这里提出的研究将初步比较胰岛素和IGF-1信号通路在葡萄糖代谢和保护细胞凋亡方面的异同。一旦确定了特征，我将把实验系统的范围扩大到不同的细胞系，这些细胞系来自于不同的胰岛素受体底物(IRS)蛋白基因被破坏的小鼠。这些研究将提供对各种IRS蛋白在多大程度上发挥独特的与多余的作用的理解。此外，已有研究表明，肿瘤坏死因子-α参与了肥胖相关的胰岛素抵抗。在拟议的研究中，将检查肿瘤坏死因子-α和胰岛素/胰岛素样生长因子-1信号通路之间的串扰。这些研究的完成将进一步加深我们对激素对棕色脂肪细胞代谢和存活的控制的理解。

Brown adipose tissue (BAT) is specialized for non-shivering thermogenesis in neonates. Regulation of BAT activity is critical to maintain energy homeostasis. Both insulin and insulin-like growth factor-1 (IGF-1) have been postulated to play important roles in regulation of cellular proliferation, survival, and metabolism in a variety of cellular contexts. However, the actions of these factors in BAT have not been fully elucidated. Our laboratory has successfully established brown pre-adipocyte cell lines from newborn mice and developed protocols to differentiate these cells in vitro. This model provides an excellent system to study the role of insulin and IGF-1 on regulation of metabolism and cell survival and delineate the signaling pathways involved. The studies proposed here will initially compare the similarities and differences between insulin and IGF-1 signaling pathways for glucose metabolism and protection from apoptosis. Once characterized, I will expand the scope of experimental system to different cells lines derived from mice in which the genes for distinct insulin receptor substrate (IRS) proteins are disrupted. These studies will provide understandings on the extent to which the various IRS proteins play unique versus redundant role. Furthermore, TNF-alpha has been shown to mediate obesity-linked insulin resistance. In the proposed studies, cross-talk between TNF-alpha and insulin/IGF-1 signaling pathways will be examined. Accomplishment of the proposed studies will further our understanding on hormonal controls of metabolism and survival of brown adipocytes.