Tallam Lakshmi S, da Silva Alexandre A, Hall John E
Department of Physiology, School of Medicine, University of Mississippi Medical Center, Jackson, Miss 39216, USA.
Hypertension. 2006 Jul;48(1):58-64. doi: 10.1161/01.HYP.0000227966.36744.d9. Epub 2006 Jun 5.
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.
本研究检测了黑皮质素4受体（MC4R）对于瘦素的慢性心血管和代谢作用是否至关重要。将20至22周龄的雄性野生型（WT）C57BL/6J小鼠和肥胖的MC4R基因敲除（-/-）小鼠（每组N = 5至6只）植入无线电遥测发射器和导管，以每天24小时测量平均动脉压（MAP）和心率，并进行静脉输注。在3天的稳定对照期后，对WT小鼠、自由进食的肥胖MC4R（-/-）小鼠和配对进食的非肥胖MC4R（-/-）小鼠静脉输注瘦素（2微克/千克·分钟），持续7天。接受7天载体注射的WT小鼠作为对照。与WT小鼠相比，MC4（-/-）小鼠体重重30%，血浆胰岛素和瘦素水平分别增加了4倍和11倍。尽管肥胖，但与WT小鼠相比，MC4R（-/-）小鼠的MAP和心率往往较低。不同组慢性输注瘦素使血浆瘦素水平升高至45至65纳克/毫升。WT小鼠输注7天瘦素后，尽管食物摄入量减少35%，体重减轻8%，但MAP仍升高了12±3毫米汞柱。瘦素未改变WT小鼠的血浆葡萄糖水平，但降低了血浆胰岛素水平（5.9±1.0对3.0±0.5微单位/毫升）。肥胖和非肥胖的MC4R（-/-）小鼠中，瘦素的这些心血管和代谢作用均被消除。这些数据表明，在肥胖的MC4R（-/-）小鼠中，是MC4R缺乏而非肥胖诱导的瘦素抵抗消除了瘦素的心血管和代谢作用。因此，功能性MC4R对于瘦素的慢性心血管和代谢作用至关重要。
