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(Hypertension. 2006;48:58.)
© 2006 American Heart Association, Inc.

Original Articles

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

Lakshmi S. Tallam; Alexandre A. da Silva; John E. Hall

From the Department of Physiology, School of Medicine, University of Mississippi Medical Center, Jackson, Miss.

Correspondence to John E. Hall, Department of Physiology, School of Medicine, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216. E-mail jehall{at}physiology.umsmed.edu

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.

Key Words: hypertension • arterial pressure • heart rate • insulin • insulin resistance • obesity • hypothalamus • sympathetic nervous system

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