IL-15, Body Compositition and Insulin Sensivity in Aging

IL-15、身体成分和衰老过程中的胰岛素敏感性

• 批准号: 7365086
• 负责人: LEBRIS S QUINN
• 金额: $ 21.36万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365086
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Age; Age-Months; Aging; Aging-Related Process; Area; Basic Science; Blood Glucose; Body Composition; Cardiovascular Diseases; Clinical; Condition; Data; Deposition; Development; Diagnostic; Diet; Exhibits; Fasting; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Hormonal; Hormones; Human; Incidence; Inflammation; Insulin; Insulin Resistance; Interleukin-15; Interleukin-2; Interleukin-6; Laboratories; Laboratory mice; Lead; Leptin; Maintenance; Measures; Messenger RNA; Metabolic; Molecular; Monitor; Motor Activity; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Predisposition; Prevention; Production; Protein Overexpression; Rate; Research; Research Personnel; Rodent; Serum; Serum Markers; Signal Pathway; Site; Skeletal Muscle; Skeletal system; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Week; Weight; Work; adiponectin; age related; aged; cohort; cytokine; feeding; food consumption; frailty; improved; insulin secretion; insulin sensitivity; interleukin-15 receptor; mRNA Expression; male; normal aging; oxidation; programs; promoter; protein expression; sarcopenia; wasting

PROJECT SUMMARY: Normal aging in humans and rodents is characterized by reductions-in skeletal muscle mass (termed sarcopenia), as well as by increases in white adipose tissue mass, resulting in an increased fat:lean body composition ratio. Consequences of these changes are age-related increases in the incidence of obesity, cardiovascular disease, insulin resistance, type-2 diabetes, and physical frailty. Recent progress in understanding the hormonal control of body composition has been made through identification of factors produced by adipose tissue which regulate other tissues, including muscle. A reciprocal signaling pathway, in which factors secreted by muscle affect adipose tissue, has not been demonstrated. Interleukin- 15 (IL-15) is an anabolic cytokine whose major site of expression is skeletal muscle. Data from my laboratory indicate IL-15inhibits muscle wasting, reduces adipose tissue mass, and stimulates secretion of the insulin- sensitizing hormone adiponectin. The proposed study will test the hypothesis that age-related declines in IL- 15 secretion by muscle occur, and that maintenance of IL-15 secretion by muscle tissue will inhibit age- associated changes in fat:lean body composition and susceptibility to insulin resistance. The proposed study will utilize two kinds of transgenic mice in which IL-15is overexpressed from a muscle-specific promoter, as well as normally aging mice. The specific aims of the project are to: 1. Characterize changes in muscle IL-15 mRNA and protein expression/secretion, serumIL-15 concentrations, and IL-15receptor mRNA expression in muscle and adipose tissue, during the aging process in normal laboratory mice. 2. Determine if muscle-specific overexpression and/or oversecretion of IL-15in mice inhibit age- associated changes in white adipose tissue and skeletal muscle mass. 3. Determine if muscle-specific overexpression and/or oversecretion of IL-15 in mice inhibit development of obesity and/or insulin resistance in adult and aged mice exposed to a high-fat/high calorie diet. 4. Determine if adult and aged mice which overexpress and/or oversecrete IL-15display difference in food consumption, locomotor activity, metabolic rate, or metabolic substrate utilization. RELEVANCE: This project comprises basic science studies to determine if declines in the IL-15 signaling pathway contribute to the loss of skeletal muscle and increases in fatlean body composition during normal aging. This research may lead to development of improved diagnostic, prevention, or treatment strategies for the common age-associated clinical conditions of frailty, sarcopenia, obesity, insulin resistance, and type-2 diabetes.

项目摘要：人类和啮齿动物的正常衰老以骨骼减少为特征 肌肉质量(称为骨质疏松症)，以及白色脂肪组织质量的增加，导致 脂肪增加：精瘦的身体构成比。这些变化的后果是与年龄相关的 肥胖、心血管疾病、胰岛素抵抗、2型糖尿病和身体虚弱的发生率。近期 在理解荷尔蒙对身体成分的控制方面取得了进展，通过识别 脂肪组织产生的调节包括肌肉在内的其他组织的因子。互惠的信号 肌肉分泌的因子影响脂肪组织的途径尚不清楚。白介素2- 15(IL-15)是一种合成代谢细胞因子，其主要表达部位为骨骼肌。来自我的实验室的数据 提示IL-15抑制肌肉萎缩，减少脂肪组织质量，并刺激胰岛素的分泌- 致敏激素脂联素。这项拟议的研究将检验这一假设，即与年龄相关的IL-2水平下降 肌肉分泌IL-15，肌肉组织维持IL-15分泌将抑制年龄- 脂肪的相关变化：瘦的身体成分和对胰岛素抵抗的易感性。建议进行的研究 将利用两种转基因小鼠，在其中IL-15从肌肉特异性启动子过表达，如 和正常衰老的小鼠一样。该项目的具体目标是： 1.肌肉IL-15基因和蛋白表达/分泌、血清IL-15变化特征 衰老过程中肌肉和脂肪组织中IL-15受体的表达 在正常的实验小鼠身上进行。 2.确定小鼠肌肉特异性IL-15的过度表达和/或过度分泌是否抑制年龄- 白色脂肪组织和骨骼肌群的相关变化。 3.确定小鼠肌肉特异性IL-15的过度表达和/或过度分泌是否抑制 高脂/高脂饮食对成年和老年小鼠肥胖和/或胰岛素抵抗的影响 卡路里饮食。 4.确定过度表达和/或过度分泌IL-15的成年和老年小鼠在 食物消耗、运动活动、代谢率或代谢底物利用率。 相关性：该项目包括基础科学研究，以确定IL-15信号是否下降 在正常情况下，导致骨骼肌丧失和脂肪身体成分增加的途径 衰老。这项研究可能导致改进的诊断、预防或治疗策略的发展 常见的与年龄相关的临床情况，如虚弱、骨骼减少、肥胖、胰岛素抵抗和2型 糖尿病。