期刊
HYPERTENSION
卷 48, 期 1, 页码 58-64出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.HYP.0000227966.36744.d9
关键词
hypertension; arterial pressure; heart rate; insulin; insulin resistance; obesity; hypothalamus; sympathetic nervous system
资金
- NHLBI NIH HHS [P01HL-51971] Funding Source: Medline
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 mu g/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 mu U/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.
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