Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin.
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 microg/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 microU/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.
Tallam
Lakshmi S
LS
Department of Physiology, School of Medicine, University of Mississippi Medical Center, Jackson, Miss 39216, USA.
da Silva
Alexandre A
AA
Hall
John E
JE
D050154:Adiposity / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects*; D004435:Eating / Q000187:drug effects*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000502:physiology; D008820:Mice, Obese / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency / Q000502:physiology*; D054411:Receptors, Leptin
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D044105:Receptor, Melanocortin, Type 4; D054411:Receptors, Leptin; C515447:leptin receptor, mouse