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性产热。BAT活性的调节对于维持能量稳态至关重要。胰岛素和胰岛素样生长因子-1（IGF-1）被认为在多种细胞环境中调节细胞增殖、存活和代谢中发挥重要作用。然而，这些因素在BAT中的作用尚未完全阐明。我们的实验室已经成功地建立了棕色前脂肪细胞系从新生小鼠和开发协议，以分化这些细胞在体外。该模型提供了一个优秀的系统来研究胰岛素和IGF-1对代谢和细胞生存调节的作用并描绘相关的信号通路。这里提出的研究将首先比较胰岛素和IGF-1信号通路之间的相似性和差异，葡萄糖代谢和保护细胞凋亡。一旦表征，我将扩大实验系统的范围，以不同的细胞系来自小鼠，其中不同的胰岛素受体底物（IRS）蛋白的基因被破坏。这些研究将提供对各种IRS蛋白发挥独特与冗余作用的程度的理解。此外，TNF-α已被证明介导肥胖相关的胰岛素抵抗。在拟议的研究中，将检查TNF-α和胰岛素/IGF-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棕色脂肪细胞代谢和存活的激素控制的理解。

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.