This study examines the acute, subacute (overnight), and chronic (7-day) effects of intracerebroventricular (ICV) administration of r-metMuLeptin on insulin sensitivity and systemic glucose turnover in conscious unrestrained rats (body weight, 250 to 300 g). Under postabsorptive conditions, acute ICV leptin ([AL] 10 μg bolus) did not affect tracer (3-³H-glucose)-determined glucose production (GP) and utilization (GU) rates during the 2-hour hyperinsulinemic (2 mU · kg⁻¹ · min⁻¹) euglycemic clamp. Chronic ICV leptin ([CL] 10 μg/d for 7 days) administered by osmotic pumps markedly reduced the daily food consumption (P < .05), body weight (P < .05), and postabsorptive basal plasma glucose level (P < .01). During the glucose clamp, GP was markedly suppressed (55%) with CL (P < .001 v vehicle and pair-fed control groups). The insulin-induced increment in GU was significantly greater with CL (23.3 ± 1.8 mg⁻¹ · kg⁻¹ · min⁻¹) than with vehicle (16.9 ± 0.2) and pair-feeding (17.1 ± 0.6, both P < .001). Subacute ICV leptin ([SL] 10 μg bolus) moderately but insignificantly decreased overnight food consumption (−18%) and body weight (−2.5 ± 1.5 g). The glucose infusion rate during the final 60 minutes of the glucose clamp was 43% greater than glucose clamp. Thus, we conclude that ICV administered leptin has strong actions on the central nervous system during the glucose clamp. Thus, we conclude that ICV administered leptin has strong actions on the central nervous system that result in significant increases in insulin sensitivity and systemic GU, and these effects are achieved as early as overnight after leptin administration.