IL-15, Body Composition and Insulin Sensitivity in Aging

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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.