Interleukin-15 (IL-15) is a proinflammatory cytokine with multifunctional effects outside the immune system. Previous studies have indicated that treatment of normal rats with IL-15 reduces white adipose tissue (WAT) mass, but it was unclear if these effects were direct or indirect. In the present study, the effects of IL-15 on WAT mass and lipid metabolism were studied in two genetic models of obesity: the leptin receptor-negative fa/fa Zucker rat and the leptin-deficient ob/ob mouse. Lean Zucker rats, lean (+/+), and obese mice (ob/ob) responded to IL-15 with reductions in WAT mass and lipoprotein lipase activity (LPL), with no decreases in food intake. In contrast, fa/fa Zucker rats did not respond to IL-15 administration by any of the above measures of fat mass or lipid metabolism. In addition, ribonuclease protection assays (RPAs) were used to demonstrate that all three subunits (gamma(c), beta and alpha) of the IL-15 receptor complex are expressed by rat and mouse WAT, suggesting that the effects of IL-15 on adipose tissue metabolism could be direct. Additionally, the fa/fa rats expressed 84% lower levels of the gamma(c) signaling receptor subunit than lean Zucker rats, suggesting this decrease may play a role in the lack of adipose tissue response to IL-15 in the fa/fa genotype and lending further support for a direct action of IL-15 on adipose tissue.