IL-15, Body Composition and Insulin Sensitivity in Aging

描述(申请人提供)：人类和啮齿动物的正常衰老的特征是骨骼肌量减少(称为骨质疏松症)，以及白色脂肪组织质量的增加，导致脂肪：精瘦身体组成比增加。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生率增加。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，最近在理解荷尔蒙对身体成分的控制方面取得了进展。肌肉分泌的因子影响脂肪组织的相互信号通路尚未被证实。白介素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表明，IL-15抑制肌肉萎缩，减少脂肪组织质量，并刺激胰岛素敏化激素脂联素的分泌。这项拟议的研究将检验这样一种假设，即肌肉分泌的IL-15会随着年龄的增长而下降，肌肉组织保持IL-15的分泌将抑制与年龄相关的脂肪变化：瘦的身体成分和对胰岛素抵抗的敏感性。这项拟议的研究将利用两种转基因小鼠，其中IL-15通过肌肉特异性启动子过表达，以及正常衰老的小鼠。1.研究正常小鼠衰老过程中肌肉IL-15的表达/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。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白色脂肪组织和骨骼肌群与年龄相关的变化。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了暴露在高脂肪/高卡路里饮食中的成年和老年小鼠肥胖和/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、运动活动、代谢率或代谢底物利用方面是否存在差异。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骨骼肌的损失和脂肪的增加：正常衰老过程中的瘦身体成分。这项研究可能导致改进的诊断、预防或治疗策略，以应对常见的与年龄相关的临床状况，如虚弱、骨质疏松症、肥胖、胰岛素抵抗和2型糖尿病。

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.