IL-15, Body Composition and Insulin Sensitivity in Aging

IL-15、身体成分和衰老过程中的胰岛素敏感性

• 批准号: 7195776
• 负责人: LEBRIS S QUINN
• 金额: $ 21.8万
• 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/7195776
• 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

DESCRIPTION (provided by applicant): 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-15 inhibits 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-15 is 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, serum IL-15 concentrations, and IL-15 receptor 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-15 in 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-15 display 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 fat:lean 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.

描述（由申请人提供）：人类和啮齿动物的正常衰老的特征是减少骨骼肌质量（称为肌肉减少症），以及白色脂肪组织质量的增加，导致脂肪增加：瘦体内组成比。这些变化的后果是肥胖，心血管疾病，胰岛素抵抗，2型糖尿病和身体虚弱的发生率的增加。了解人体组成的激素控制的最新进展是通过鉴定由调节其他组织（包括肌肉）的脂肪组织产生的因素而做出的。尚未证明一种相互信号通路，其中肌肉分泌的因素会影响脂肪组织。白介素15（IL-15）是一种合成代谢细胞因子，其主要表达部位是骨骼肌。我实验室的数据表明IL-15抑制肌肉浪费，减少脂肪组织质量并刺激胰岛素敏化激素脂联素的分泌。拟议的研究将检验以下假设：与年龄相关的IL-15肌肉分泌下降，并且肌肉组织对IL-15分泌的维持将抑制脂肪的年龄变化：瘦体的组成和胰岛素抵抗的易感性。拟议的研究将利用两种转基因小鼠，其中IL-15与肌肉特异性启动子和正常老化的小鼠过表达。该项目的具体目的是：1。在正常实验室小鼠的衰老过程中，肌肉IL-15 mRNA和蛋白质表达/分泌，血清IL-15浓度和IL-15受体mRNA表达的变化。 2。确定在小鼠中IL-15的肌肉特异性过表达和/或过度分泌是否抑制白色脂肪组织和骨骼肌质量的年龄变化。 3。确定在小鼠中抑制肥胖和/或胰岛素抵抗的小鼠中IL-15的肌肉特异性过表达和/或过度分泌是否会暴露于高脂/高卡路里饮食中。 4.确定过表达和/或过度乳管IL-15的成年小鼠是否显示出食物消耗，运动活性，代谢率或代谢底物利用率的差异。相关性：该项目包括基础科学研究，以确定IL-15信号通路中的下降是否有助于骨骼肌的丧失和脂肪的增加：正常衰老期间的瘦体组成。这项研究可能会导致改善诊断，预防或治疗策略，以针对脆弱的年龄相关临床状况，肌肉减少症，肥胖症，胰岛素抵抗和2型糖尿病。