Feeding a high-fat diet (HFD) to rabbits results in increased blood pressure and renal sympathetic nerve activity (RSNA) and marked increases in plasma leptin and insulin. We determined the contribution of insulin and leptin signaling in the central nervous system to the increased blood pressure and RSNA during a HFD using specific antagonists. New Zealand White rabbits were implanted with an intracerebroventricular (ICV) catheter and RSNA electrode and placed on a normal or 13.5% HFD for 1 or 3 weeks. Blood pressure, heart rate, and RSNA were recorded before and for 90 minutes after ICV administration of a leptin antagonist (100 µg), insulin antagonist (0.5 U), or vehicle (50 µL) on separate days. Rabbits had higher blood pressure (+8%, +17%) and RSNA (+55%, +71%), at 1 and 3 weeks, respectively, of HFD compared with controls (n=7-11). ICV leptin antagonist reduced blood pressure by 9% and RSNA by 17% (P<0.001) after 3 weeks of HFD but had no effect at week 1. ICV administration of the insulin antagonist reduced blood pressure by ≈5% at both times (P<0.05) but there was no effect on RSNA. Leptin and insulin antagonist doses were confirmed to effectively block the pressor responses to ICV leptin and insulin, respectively. The elevation of blood pressure and RSNA induced by a HFD is predominantly mediated by central actions of leptin. Central actions of insulin contribute a smaller proportion of the hypertension but independently of RSNA.