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␣ take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15R␣ 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␣ on metabolism and obesity are currently unknown. We report that mice lacking IL-15R␣ (IL-15R␣ Ϫ/Ϫ ) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15R␣ Ϫ/Ϫ 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␣ Ϫ/Ϫ are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15R␣ in metabolism and obesity.interleukin-15 receptor alpha; diet-induced obesity; muscle; fatty acid oxidation; fatigue recovery; glucose homeostasis ACCUMULATION OF EXCESSIVE body fat is a physiological consequence of unnecessary caloric intake. With greater worldwide food production, often the caloric intake largely exceeds the physiological energy requirements, and as a result, the obesity pandemic is growing at alarming rates in both developed and developing countries (21,47). Apart from the role of environmental factors, particularly an energy-dense diet and sedentary lifestyle, obesity also has important genetic determinants that have been conserved across species. Identifying the molecular mechanisms regulating metabolic efficiency (the capacity to convert energy intake into storable energy forms) is of great interest because of the low success in using caloric restriction as a means to manage obesity. Indeed, a number of pathways have been recently identified that reduce the extent of dietinduced obesity (DIO) by decreasing metabolic efficiency rather than energy input (8,10,11,43,56,59,60). Targeting these pathways with pharmacological approaches may also have the advantage of reproducing some of the benefits normally associated with physical exercise. Together with caloric restriction, exercise is a mainstay of a healthy life style and contributes to the control of metabolic efficiency. In addition to converting energy into movement, exercise increases the rates of lipolysis and fat oxidation, promotes heat dissipation (49, 53), and causes long-term changes in the expression of numerous genes, including IL-15R␣/IL-15 (55).IL-15 and its primary binding partner IL-15R␣ have emerged as important regulators of cell functions in both lymphoid and nonlymphoid tissues. Their transcripts are detectable in a variety of tissues, including skeletal muscle, liver, or adipose (http://biogps.org/#gotoϭwelcome). Some of the proposed noncanonical roles of IL-15/IL-15R␣ signaling are mediating anabolic...