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

基本信息

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
项目类别：
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

项目摘要

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）：脂肪特异性胰岛素受体缺失赋予小鼠肥胖抵抗力、胰岛素敏感性增加和寿命延长。之前使用的 Cre-lox 系统受到不一致的基因删除、所使用的 Ap2 启动子驱动的巨噬细胞中潜在的异位 Cre 表达以及从胚胎生命开始的组成型删除的限制。我们正在开发转基因模型，使用替代脂肪特异性启动子（脂联素、perilipin）来驱动组成型和诱导型 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。我们将描述这些模型的特征，并将其用于：确认代谢表型，而不与可能的巨噬细胞效应混淆。研究脂肪细胞胰岛素信号传导在维持已建立的脂肪库中的作用。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组成型敲除的代谢表型。剖析脂肪细胞胰岛素信号传导与肥胖在 FIRKO 小鼠代谢表型中的作用。将成年小鼠脂肪细胞胰岛素信号传导中断后的基因表达变化与不同年龄的组成型脂肪特异性胰岛素受体敲除小鼠的基因阵列数据进行比较。