Melanocortin-4 Receptor Mediates Chronic Cardiovascular and Metabolic Actions of Leptin

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Abstract
This study tested whether the melanocortin 4-receptor (MC4R) is essential for the chronic cardiovascular and metabolic actions of leptin. Twenty- to 22-week–old male wild-type (WT) C57BL/6J and obese MC4R (−/−) mice (N=5 to 6 per group) were implanted with radiotelemetric transmitters and catheters for measuring mean arterial pressure (MAP) and heart rate 24 hours per day and intravenous infusions. After a 3-day stable control period, leptin was infused (2 μg/kg per minute IV) for 7 days in WT, obese ad libitum–fed MC4R (−/−), and nonobese pair–fed MC4R (−/−) mice. WT mice receiving vehicle for 7 days served as controls. MC4 (−/−) mice were 30% heavier and had 4- and 11-fold increases in plasma insulin and leptin levels, respectively, compared with WT mice. Despite obesity, MAP and heart rate tended to be lower in MC4R (−/−) mice compared with WT mice. Chronic leptin infusion in the different groups increased plasma leptin levels to 45 to 65 ng/mL. Seven-day leptin infusion in WT mice increased MAP by 12±3 mm Hg despite a 35% reduction in food intake and an 8% reduction in body weight. Leptin did not alter plasma glucose but reduced plasma insulin in WT mice (5.9±1.0 versus 3.0±0.5 μU/mL). These cardiovascular and metabolic actions of leptin were abolished in obese and nonobese MC4R (−/−) mice. These data suggest that MC4R deficiency, and not obesity-induced leptin resistance, abolished the cardiovascular and metabolic actions of leptin in obese MC4R (−/−) mice. Thus, a functional MC4R is essential for the chronic cardiovascular and metabolic actions of leptin.