Lifespan Extension Despite Greatly Elevated Insulin and Body Fat

尽管胰岛素和体脂大幅升高，寿命仍延长

• 批准号: 8417685
• 负责人: DAVID E HARRISON
• 金额: $ 33.46万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417685
• 关键词: Adipocytes; Adipose tissue; Adult; Age; Age-Months; Aging; Body Composition; Body fat; Categories; Cell Size; Cessation of life; Childhood; Cholesterol; Clinical; Data; Disease; Dissection; Drug or chemical Tissue Distribution; Elderly; Electron Transport; Fasting; Fatty acid glycerol esters; Food; Free Radicals; Gastrocnemius Muscle; Genetic; Gluconeogenesis; Glucose; Glycogen Synthase Kinase 3; Glycosylated hemoglobin A; High Density Lipoproteins; Histone H2B; Human; Hyperinsulinism; Hypertension; Image; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Interleukin-6; Intervention; Leptin; Life; Light; Lipids; Liver; Liver Mitochondria; Longevity; MAPK8 gene; MAPK9 gene; Mediating; Mesentery; Metabolic; Metabolic Pathway; Metabolic syndrome; Mitochondria; Modeling; Mus; Muscle Mitochondria; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obesity; Pathology; Pathway interactions; Pattern; Phenotype; Phosphorylation; Population; Precipitation; Production; Proteins; Raptors; Sampling; Signal Transduction; Signal Transduction Pathway; Site; Specific qualifier value; Staging; TSC2 gene; Testing; Thinness; Tissues; Triglycerides; Tumor Necrosis Factor-alpha; Visceral; Western Blotting; Work; X-Ray Computed Tomography; adenylate kinase; adipokines; adiponectin; dietary restriction; fasting glucose; feeding; follow-up; glucose tolerance; glycogenolysis; human FRAP1 protein; human TNF protein; in vivo; inhibitor/antagonist; insulin sensitivity; mutant; oxidation; programs; public health relevance; research study; resistin; respiratory; subcutaneous

DESCRIPTION (provided by applicant): New data from diet restricted Lepob (ob/ob) mutant C57BL/6J mice-our DR-OB model-challenge the paradigm that benefits of diet restriction (DR) require insulin sensitivity, low insulin, and low adiposity. DR-OB mice have severe insulin resistance, high insulin levels, as well as high adiposity, but live as long as diet restricted controls (DR +/?) that are insulin sensitive with low insulin and low adiposity. This model will be used to test three categories of mechanisms proposed to produce the beneficial effects of DR: 1) the insulin, IGF-1, mTOR, and nutrient signaling transduction pathways, 2) fuel utilization pathways, 3) adipose tissue function. Five groups of mice will be compared at 6, 12, and 22 months of age: DR-OB, partially restricted ob/ob (partial DR-OB), ad lib fed ob/ob (AL-OB), diet restricted and ad lib fed genetic controls (DR +/?) and (AL +/?). Signal transduction, fuel utilization, and adipose tissue markers that differ between DR-OB and DR +/? will identify candidate mechanisms that correlate with low insulin and low adiposity but do not increase lifespan. Markers that are similar in DR-OB and DR +/?, and that correlate with lifespan in DR-OB, partial DR-OB and AL-OB, will specify candidate mechanisms by which DR may increase lifespan, which will be further tested later. The current project is unique in that it distinguishes features of DR-associated hypoinsulinemia and leanness that extend lifespan from features that do not. This work will specify the set of candidate mechanisms comprising those critical for DR-mediated, extended lifespan by testing the following hypotheses: Aim 1. That, in DR-OB mice, critical branches of the mTOR, AMP-kinase, and insulin/IGF-1 signal transduction pathways shift from patterns typical of insulin resistance, hyperinsulinemia and obesity to patterns typical of DR and extended longevity. Key intermediates of these pathways will be tested in liver and gastrocnemius muscle, using western blots to compare protein pool and site-specific phosphorylation levels. Aim 2. That, in DR-OB mice, fuel utilization pathways shift-at or before a critical point necessary to extend lifespan-from patterns typical of metabolic syndrome to patterns typical of DR that reduce mitochondrial free radical production. In vivo tests to identify this point will include short-term fasting glucose and insulin levels, glucose tolerance, insulin sensitivity, gluconeogenesis, glycogenolysis, beta-oxidation, glucose utilization, lipid utilization, and 24-hr respiratory exchange ratio. Collaborators will test free radical damage to proteins of the electron transport chains for liver and muscle mitochondria. Aim 3. That, in DR-OB mice, critical aspects of adipose tissue reflect the lean state of DR +/? mice rather than the obese state of AL-OB mice. The following will be determined: body composition and subcutaneous/visceral fat tissue distribution (using computerized tomography imaging); circulating adipokines (adiponectin, resistin, IL-6, and TNF-alpha); circulating and tissue levels of free fatty acids, triglyceride and cholesterol; and fat cell size distribution in mesenteric and subcutaneous fat tissue.

描述（由申请人提供）：来自饮食受限的LEPOB（OB/OB）的新数据C57BL/6J小鼠 - 我们的DR-OB模型 - 挑战 - 饮食限制（DR）的范式需要胰岛素敏感性，低胰岛素和低脂肪。 DR-OB小鼠具有严重的胰岛素耐药性，高胰岛素水平以及高肥胖性，但只要饮食受限的对照（DR +/？）才能生存，这些对照（DR +/？）具有低胰岛素和低肥胖性的胰岛素敏感性。该模型将用于测试提出的三类机制，以产生DR的有益作用：1）胰岛素，IGF-1，MTOR和营养信号转导途径，2）燃料利用途径，3）3）脂肪组织功能。将在6、12和22个月大的时候比较五组小鼠：DR-OB，部分受限的OB/OB（部分DR-OB），AD lib for ob/ob（Al-OB），饮食受限和adlib for遗传控制（DR +/？）和（al +/？）。 DR-OB和DR +/之间不同的信号转导，燃料利用和脂肪组织标记？将确定与低胰岛素和低肥胖相关但不会增加寿命的候选机制。 DR-OB和DR +/？的标记以及与DR-OB，部分DR-OB和AL-OB中的寿命相关的标记将指定DR可以增加寿命的候选机制，以后将进一步测试。当前的项目是独一无二的，因为它区分了与DR相关的低胰岛素血症和瘦弱的特征，这些功能从没有的功能中延长了寿命。这项工作将指定一组候选机制，包括那些对DR介导的，延长寿命至关重要的机制，通过测试以下假设：目标1。长寿。这些途径的关键中间体将在肝脏和胃肌肉肌肉中进行测试，使用蛋白质印迹比较蛋白质池和特定地点的磷酸化水平。 AIM 2。在DR-OB小鼠中，燃料利用途径在at-at-at-at-at-at-at-ther-the tros-forter-form-form-form-form-form-form-from模式的典型代谢综合征模式延长到典型的DR模式，从而减少了线粒体自由基生产。体内测试以识别这一点，将包括短期禁食葡萄糖和胰岛素水平，葡萄糖耐受性，胰岛素敏感性，糖异生，糖元溶解，β-氧化，葡萄糖利用，脂质利用率，脂质利用率和24小时呼吸道交换比率。合作者将对肝脏和肌肉线粒体的电子传输链的蛋白质进行自由基损害。目标3。在DR-OB小鼠中，脂肪组织的关键方面反映了Dr +/的瘦状态？小鼠而不是肥胖的Al-OB小鼠。将确定以下内容：身体成分和皮下/内脏脂肪组织分布（使用计算机断层扫描成像）；循环脂肪因子（脂联素，抵抗素，IL-6和TNF-Alpha）；游离脂肪酸，甘油三酸酯和胆固醇的循环和组织水平；肠系膜和皮下脂肪组织中的脂肪细胞大小分布。