Insulin signalling in the central nervous system is involved in the control of energy balance and glucose homeostasis. However, it has previously been observed that ablation of insulin receptors in the AgRP or POMC neurons that regulate energy homeostasis are dispensable in maintaining normal energy balance. We have recently demonstrated that NPY-specific insulin signaling regulates food intake and energy expenditure, and lack of insulin signaling in NPY neurons leads to increased energy stores and an obese phenotype(1). Here we examined the effects of infusion of different insulin formulations into the CNS and periphery of mice lacking NPY-specific insulin signaling. Chronic CNS NPH insulin infusion reduced in food intake, body weight and fat mass in wildtype animals, no changes in energy balance were observed in mice lacking NPY-specific insulin signaling. Peripheral chronic NPH insulin infusion led to weight gain in both wildtype mice and mice lacking insulin signaling in NPY cells, while insulin detemir inhibited weight gain in wildtype but not mice lacking NPY-specific insulin signaling. Peripheral NPH insulin or insulin detemir infusion led significantly more phosphorylation of Akt in both wildtype mice and mice than lacking insulin signaling in NPY cells. Together these data support the hypotheses that NPY neurons mediate the effects of CNS insulin on energy balance and that ability of insulin detemir to inhibit weight gain is mediated by activity at NPY neurons.