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特征是骨骼肌质量减少（称为肌肉减少症），以及白色脂肪组织质量增加，导致脂肪与瘦肉的身体成分比例增加。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病率增加。通过识别脂肪组织产生的调节其他组织（包括肌肉）的因子，在了解身体成分的激素控制方面取得了最新进展。肌肉分泌的因子影响脂肪组织的相互信号传导途径尚未得到证实。白细胞介素-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 可以抑制肌肉萎缩，减少脂肪组织质量，并刺激胰岛素增敏激素脂联素的分泌。拟议的研究将检验这样的假设：肌肉 IL-15 分泌会出现与年龄相关的下降，而肌肉组织维持 IL-15 分泌将抑制与年龄相关的脂肪：瘦身体成分和胰岛素抵抗易感性的变化。拟议的研究将利用两种转基因小鼠以及正常衰老的小鼠，其中IL-15通过肌肉特异性启动子过度表达。该项目的具体目标是： 1. 表征正常衰老过程中肌肉 IL-15 mRNA 和蛋白表达/分泌、血清 IL-15 浓度以及肌肉和脂肪组织中 IL-15 受体 mRNA 表达的变化。实验室小鼠。 2.确定小鼠中IL-15的肌肉特异性过度表达和/或过度分泌是否抑制白色脂肪组织和骨骼肌质量的年龄相关变化。 3.确定小鼠中IL-15的肌肉特异性过度表达和/或过度分泌是否抑制暴露于高脂肪/高热量饮食的成年和老年小鼠的肥胖和/或胰岛素抵抗的发展。 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、运动活性、代谢率或代谢底物利用方面是否表现出差异。相关性：该项目包括基础科学研究，以确定 IL-15 信号通路的下降是否会导致正常衰老过程中骨骼肌的损失和脂肪的增加：瘦身体成分。这项研究可能会导致针对与年龄相关的常见临床病症（如虚弱、肌肉减少症、肥胖、胰岛素抵抗和 2 型糖尿病）改进诊断、预防或治疗策略。