IL-15, Body Composition and Insulin Sensitivity in Aging

描述（由申请人提供）：人类和啮齿类动物的正常衰老特征为骨骼肌质量减少（称为肌肉减少症）以及白色脂肪组织质量增加，导致脂肪：瘦体重组成比增加。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病率增加。最近的进展，在了解激素控制的身体组成已通过确定的因素产生的脂肪组织，调节其他组织，包括肌肉。肌肉分泌的因子影响脂肪组织的相互信号通路尚未得到证实。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。拟议的研究将测试以下假设：肌肉分泌IL- 15发生年龄相关性下降，肌肉组织分泌IL-15的维持将抑制脂肪：瘦体组成和胰岛素抵抗易感性的年龄相关性变化。这项研究将利用两种转基因小鼠，其中IL-15从肌肉特异性启动子过度表达，以及正常衰老的小鼠。该项目的具体目标是：1.表征正常实验室小鼠衰老过程中肌肉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。2.确定小鼠中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中的年龄相关变化。3.确定小鼠中IL-15的肌肉特异性过表达和/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中肥胖和/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摄食量、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有助于骨骼肌的损失和脂肪的增加：在正常衰老过程中的瘦体成分。这项研究可能会导致开发改进的诊断，预防或治疗策略，用于与年龄相关的常见临床疾病，如虚弱，肌肉减少症，肥胖症，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.