In obesity, due to the resistance of leptin receptors at the blood brain barrier (BBB), increased peripheral leptin levels cannot act appropriately at brain sites relevant for appetite regulation. In this study we focused on the intranasal application of leptin. This mode of administration provides a promising tool for a direct access of peptides to the brain by circumventing the BBB. Male Wistar rats were treated daily with 0.1 or 0.2 mg/kg leptin intranasally for four weeks. Compared with controls, leptin treated animals gained significantly less weight and exhibited significantly reduced food and water intake. Corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus (PVN) showed a tendency for up-regulation by leptin; neuropeptide Y (NPY) mRNA expression in the arcuate nucleus (ARC) was decreased. In the central nucleus of the amygdala (CeN), CRF mRNA was significantly elevated in leptin treated animals, suggesting a role in affective and/or emotional aspects of food intake. Serum leptin levels were unchanged, indicating a direct action of leptin in the central nervous system (CNS) without prior access to the periphery. The intranasal application thus represents a useful tool to administer leptin in a non-invasive way with rapid permeation into the CNS.