Adipocyte insulin signaling in metabolism and aging

代谢和衰老中的脂肪细胞胰岛素信号传导

• 批准号: 7115045
• 负责人: STEVEN J RUSSELL
• 金额: $ 5.2万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-30 至 2007-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115045
• 关键词: adipocytes; adiponectin; adipose tissue; dietary restriction; gene expression; genetically modified animals; glucose tolerance; hormone regulation /control mechanism; insulin; insulin receptor; insulin sensitivity /resistance; laboratory mouse; longevity; metabolism; nutrition related tag; obesity; postdoctoral investigator

DESCRIPTION (provided by applicant): Fat-specific insulin receptor deletion confers obesity resistance, increased insulin sensitivity, and prolonged lifespan in mice. The Cre-lox system used previously is limited by inconsistent gene deletion, potential ectopic Cre expression in macrophages driven by the Ap2 promoter used, and constitutive deletion starting in embyronic life. We are developing transgenic models using alternate fat specific promoters (adiponectin, perilipin) to drive expression of constitutive and inducible Cre recombinases to achieve more tissue specificity and temporal control over recombination. We will characterize these models and use them to: Confirm the metabolic phenotype without confounding by possible macrophage effects. Investigate the role of adipocyte insulin signaling in maintenance of established fat depots. Determine whether disruption of insulin signaling in adipocytes of adult animals can reproduce the metabolic phenotype of the constitutive knockout. Dissect the role of adipocyte insulin signaling versus adiposity in the metabolic phenotype of FIRKO mice. Compare gene expression changes after interruption of adipocyte insulin signaling in adult mice with our gene array data from constitutive fat-specific insulin receptor knockout mice at various ages.

描述（由申请人提供）：小鼠脂肪特异性胰岛素受体缺失赋予肥胖性抗性，胰岛素敏感性的提高和长时间的寿命。先前使用的CRE-LOX系统受到不一致的基因缺失，由所使用的AP2启动子驱动的巨噬细胞中的潜在异位CRE表达，以及在Embyronic Life中开始的构型缺失。我们正在使用替代脂肪特异性启动子（脂联素，Peripin）来开发转基因模型，以驱动组成型和可诱导的CRE重组酶的表达，以实现更多的组织特异性和对重组的时间控制。我们将表征这些模型并使用它们来：确认代谢表型，而不会因可能的巨噬细胞效应而混淆。研究脂肪细胞胰岛素信号传导在维持既定脂肪库中的作用。确定成年动物脂肪细胞中胰岛素信号传导的破坏是否可以重现本构敲除的代谢表型。剖析脂肪细胞胰岛素信号传导与肥胖在Firko小鼠的代谢表型中的作用。比较成年小鼠脂肪细胞胰岛素信号传导中断与我们的基因阵列数据中断后，基因表达的变化以及来自各个年龄段的本构脂肪特异性胰岛素受体敲除小鼠的基因阵列数据。