Interactions of hypothalamic signaling pathways that control body temperature (BT), blood pressure (BP), and energy balance are poorly understood. We investigated whether the chronic BP and metabolic actions of leptin are differentially modulated by changes in ambient temperature (TA ). Mean arterial pressure (MAP), heart rate (HR), BT, motor activity (MA), and oxygen consumption (Vo2) were measured 24 h/d at normal laboratory TA (23 degrees C), at thermoneutral zone (TNZ, 30 degrees C) for mice or during cold exposure (15 degrees C) in male wild-type mice. After control measurements, leptin (4 mug/kg/min) or saline vehicle was infused for 7 d. At TNZ, leptin reduced food intake (-11.0 +/- 0.5 g cumulative deficit) and body weight by 6% but caused no changes in MAP or HR. At 15 degrees C, leptin infusion did not alter food intake but increased MAP and HR (8 +/- 1 mmHg and 33 +/- 7 bpm), while Vo2 increased by approximately 10%. Leptin reduced plasma glucose and insulin levels at 15 degrees C but not at 30 degrees C. These results demonstrate that the chronic anorexic effects of leptin are enhanced at TNZ, while its effects on insulin and glucose levels are attenuated and its effects on BP and HR are abolished. Conversely, cold TA caused resistance to leptin's anorexic effects but amplified its effects to raise BP and reduce insulin and glucose levels. Thus, the brain circuits by which leptin regulates food intake and cardiovascular function are differentially influenced by changes in TA.