We recently demonstrated that in a rodent model of obesity (agouti yellow mice), there is a selective leptin resistance with preservation of the sympathetic actions despite loss of appetite and weight-reducing actions of systemic leptin. Here, we examined whether selective leptin resistance exists in agouti mice during central neural administration of leptin. In agouti obese mice and lean controls, we tested the effects of single intracerebroventricular (ICV) injection of leptin or vehicle on food intake and body weight in the conscious state and on renal sympathetic nerve activity during anesthesia. Agouti obese mice had higher (P<0.0001) mean arterial pressure (100 +/- 2 mm Hg) than lean controls (90 +/- 2 mm Hg). In lean controls (n=9 to 10), ICV leptin caused a dose-dependent decrease in body weight (P<0.001) and food intake (P<0.001). For example, ICV leptin (3 microg) decreased food intake and body weight, respectively, by 3.3 +/- 0.3 g (P<0.001) and 2.6 +/- 0.3 g (P<0.001) in lean mice. However, in agouti obese mice (n=9 to 10), ICV leptin did not significantly decrease food intake or body weight. ICV leptin caused in RSNA a significant and dose-dependent increase in renal sympathetic nerve activity that was of the same magnitude in the lean and agouti obese mice. The rise in renal sympathetic nerve activity induced by ICV leptin (3 microg) was 274 +/- 67% (P<0.001) in lean controls and 275 +/- 46% (P<0.001) in the agouti obese mice. In summary, this study indicates that selective leptin resistance in agouti obese mice occurs with central neural administration of leptin, suggesting that selective leptin resistance in this model is not due to a defect in leptin transport across the blood brain barrier. It seems to result instead from alterations in the central neural pathways mediating effects of leptin.