Insulin acts within the central nervous system to alter numerous physiological outcomes including energy balance and glucose homeostasis. Insulin is transported into the central nervous system by a saturable-receptor mediated process that is proposed to be dependent on the insulin receptor. Transport of insulin into the brain is altered by numerous factors including diet induced obesity (1). It has previously been observed that the weight sparing effect of detemir insulin, relative to other long-acting insulin formulations, is associated with increased transport into the central nervous system (2). We hypothesized that the effects of detemir insulin on energy balance would be mediated by an increase in central nervous system insulin signalling. Chronic treatment with detemir insulin resulted in reductions in both food intake and weight gain relative to insulin glargine or normal insulin treatment in C57BL/6J mice. Acute peripheral detemir insulin treatment resulted in reduced food intake, with increased phosphorylated Akt also observed in the arcuate nucleus of the hypothalamus of detemir insulin treated mice, relative to other insulin treatments. When mice were maintained on a high fat diet the acute effects of detemir insulin on both energy balance and phosphorylated Akt were inhibited. Furthermore, when specific neuronal populations of insulin receptors were knocked out, animals were insensitive to the acute effects of detemir insulin on energy balance. These data demonstrate that detemir insulin reduces weight gain by acting on the central nervous system to reduce food intake. The inhibition of this effect in high fat diet treated animals indicates that detemir insulin is subject to resistance of insulin transport into the brain.