CONTROL OF ADIPOGENESIS AND METABOLISM BY INSULIN

胰岛素对脂肪生成和代谢的控制

• 批准号: 2770635
• 负责人: Robert E. Lewis
• 金额: $ 19.02万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770635
• 关键词: 3T3 cells; adipocytes; biological signal transduction; cell differentiation; colony stimulating factor; cytoplasm; enzyme induction /repression; glucose transport; guanine nucleotide binding protein; insulin; insulin receptor; insulinlike growth factor; mitogen activated protein kinase; phosphorylation; protein tyrosine kinase; receptor expression; tissue /cell culture; tissue mosaicism

DESCRIPTION (Adapted from applicant's abstract): The long term goal of this research is to define molecular mechanisms involved in the regulation of adipocyte differentiation and metabolism by insulin and insulin-like growth factors. The signal transduction pathways involved in these processes are not fully understood, though integral components of several insulin-stimulated pathways have been identified and characterized. The central hypothesis of this proposal is that multiple, distinct signals emanate from the insulin receptor cytoplasmic domain upon activation of the receptor tyrosine kinase, and that those signals act separately and/or in combination to elicit the pleiotropic effects on cell fate and metabolism that are characteristic of insulin action. A chimeric receptor cDNA consisting of the extracellular. ligand-binding domain of the colony stimulating factor-l (CSF-l ) receptor spliced to the transmembrane and cytoplasmic domains of the insulin receptor has been constructed to test this hypothesis. Expression of the CSF/IR allows CSF-l to mimic the ability of insulin and IGF I to initiate adipoblast differentiation and to activate glucose transport without activation of endogenous insulin receptors. Furthermore, mutations within the cytoplasmic domain of the CSF IR/IR inhibit discrete actions of insulin while leavened others intact. This model system will be used to examine the molecular mechanisms used by insulin and IGF I to regulate adipocyte differentiation and metabolism including the following: The role of subdomains and phosphorylation sites within the insulin receptor cytoplasmic domain in coupling receptor signals to the induction and activity of important mediators of adipogenesis. The contribution of the Ras proteins in mediating the IGF l/insulin-stimulated induction of adipogenesis The capacity of modulators of Ins Ras/Raf/MEK/MAP kinase pathway to influence the ability of the insulin receptor cytoplasmic domain to induce adipogenesis. The role of subdomains and phosphorylation sites within the insulin receptor cytoplasmic domain in regulation of adipocyte metabolism including activation of glucose transport and inhibition of lipolysis.

描述（改编自申请人的摘要）：本项目的长期目标 研究的目的是定义参与调节的分子机制 胰岛素和胰岛素样生长引起的脂肪细胞分化和代谢 因素。 参与这些过程的信号转导途径是 尚未完全理解，尽管几个组成部分 胰岛素刺激途径已被识别和表征。 这 该提案的中心假设是多个不同的信号 在胰岛素受体激活后从细胞质结构域发出 受体酪氨酸激酶，并且这些信号单独作用和/或在 组合以引发对细胞命运和代谢的多效性影响 这是胰岛素作用的特征。 嵌合受体cDNA 由细胞外组成。 集落的配体结合域 刺激因子-l (CSF-l) 受体剪接至跨膜和 胰岛素受体的细胞质结构域已被构建来测试 这个假设。 CSF/IR 的表达允许 CSF-1 模仿这种能力 胰岛素和 IGF I 启动脂肪细胞分化并激活 葡萄糖转运而不激活内源性胰岛素受体。 此外，CSF IR/IR 胞质结构域内的突变 抑制胰岛素的离散作用，同时使其他作用保持完整。 这 模型系统将用于检查所使用的分子机制 胰岛素和 IGF I 调节脂肪细胞分化和代谢 包括以下内容： 胰岛素受体内亚结构域和磷酸化位点的作用 细胞质结构域将受体信号耦合到诱导和 脂肪生成重要介质的活性。 的贡献 Ras 蛋白介导 IGF1/胰岛素刺激的诱导 脂肪生成 Ins Ras/Raf/MEK/MAP 激酶调节剂的能力 影响胰岛素受体胞质结构域能力的途径 诱导脂肪生成。 子结构域和磷酸化位点的作用 胰岛素受体胞质结构域内脂肪细胞的调节 代谢，包括激活葡萄糖转运和抑制 脂肪分解。