IL-15, Body Compositition and Insulin Sensivity in Aging

项目总结：人类和啮齿动物正常衰老的特征是骨骼减少 肌肉质量（称为肌肉减少症），以及增加白色脂肪组织质量，导致 增加脂肪：瘦身体组成比。这些变化的后果是与年龄有关的增加， 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。最近 在了解身体组成的激素控制方面取得了进展， 脂肪组织产生的调节其他组织（包括肌肉）的因子。一个相互的信号 肌肉分泌的因子影响脂肪组织的途径尚未得到证实。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抑制肌肉萎缩，减少脂肪组织质量，并刺激胰岛素分泌， 致敏激素脂联素。这项拟议的研究将检验与年龄相关的IL-10下降的假设。 IL-15由肌肉分泌，并且维持肌肉组织分泌IL-15将抑制衰老。 脂肪相关变化：瘦体成分和胰岛素抵抗易感性。拟定研究 将利用两种转基因小鼠，其中IL-15从肌肉特异性启动子过表达， 以及正常衰老的小鼠。该项目的具体目标是： 1.表征肌肉IL-15 mRNA和蛋白表达/分泌、血清IL-15 在衰老过程中，肌肉和脂肪组织中IL-15浓度和IL-15受体mRNA的表达 在正常的实验室老鼠。 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年龄增长- 白色脂肪组织和骨骼肌质量的相关变化。 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 在暴露于高脂肪/高胰岛素的成年和老年小鼠中肥胖和/或胰岛素抵抗的发展 卡路里饮食。 4.确定过表达和/或过分泌IL-15的成年小鼠和老年小鼠在 食物消耗、自发活动、代谢率或代谢底物利用。 相关性：该项目包括基础科学研究，以确定IL-15信号转导的下降是否 在正常情况下，骨骼肌的损失和脂肪体成分的增加是通过一种途径实现的。 衰老这项研究可能会导致开发更好的诊断，预防或治疗策略， 常见的与年龄相关的临床状况，如虚弱、肌肉减少、肥胖、胰岛素抵抗和2型糖尿病， 糖尿病

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.