IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity

IL-15R alpha is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15R alpha take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15R alpha promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15R alpha on metabolism and obesity are currently unknown. We report that mice lacking IL-15R alpha (IL-15R alpha(-/-)) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15R alpha(-/-) mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15R alpha(-/-) are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15R alpha in metabolism and obesity.