Obesity is a risk factor for development of insulin resistance, type 2 diabetes, cardiovascular disease, osteoarthritis, and some forms of cancer. Many of the adverse health consequences of excess fat deposition are caused by increased secretion of proinflammatory adipokines by adipose tissue. Reciprocal muscle-to-fat signaling factors, or myokines, are starting to be identified. Interleukin-15 (IL-15) is a cytokine that is highly expressed in muscle tissue and that, on the basis of cell culture experiments, has been proposed to act as a circulating myokine that inhibits adipose tissue deposition. To test this hypothesis in vivo, two lines of transgenic mice that overexpressed IL-15 mRNA and protein in skeletal muscle tissue were constructed. By substitution of the inefficient native IL-15 signal peptide with a more efficient signal peptide, one of the transgenic mouse lines also exhibited elevated secretion of IL-15 in the circulation. Overexpression of IL-15 in muscle tissue without secretion in the bloodstream resulted in no differences in body composition. Elevated circulating levels of IL-15 resulted in significant reductions in body fat and increased bone mineral content, without appreciably affecting lean body mass or levels of other cytokines. Elevated circulating levels of IL-15 also inhibited adiposity induced by consumption of a high-fat/high-energy diet in male, but not female, transgenic mice. Female mice with elevated serum IL-15 exhibited increased deposition of lean body mass on a low-fat/low-energy diet and a high-fat/high-energy diet. These findings indicate that muscle-derived circulating IL-15 can modulate adipose tissue deposition and support addition of IL-15 to the growing list of potential myokines that are increasingly being implicated in regulation of body composition.