Melanocortin-4 Receptor Signaling Is Required for Weight Loss after Gastric Bypass Surgery
Melanocortin-4 Receptor Signaling Is Required for Weight Loss after Gastric Bypass Surgery
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DOI：
10.1210/jc.2011-3432
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发表时间：
2012-06-01
影响因子：
5.8
通讯作者：
Kaplan, Lee M.
中科院分区：
文献类型：
--
作者：
Hatoum, Ida J.;Stylopoulos, Nicholas;Kaplan, Lee M.
背景：Roux-en-Y胃旁路术（RYGB）是治疗严重肥胖症最有效的长期疗法之一。最近的证据表明RYGB通过多种生理机制影响体重减轻，包括能量消耗，食物摄入，食物偏好和奖励pathways.Objective：由于中枢黑皮质素信号在能量稳态调节中起着重要作用，我们研究了啮齿动物和人类黑皮质素-4受体（MC 4 R）的遗传破坏是否影响RYGB后的体重减轻。在这里，我们报告了MC 4 R（-/-）小鼠在手术后比野生型动物体重减轻得少，表明MC 4 R信号传导对于RYGB在该模型中的体重减轻作用是必要的。MC 4 R杂合子小鼠对胃旁路术保持完全响应。为了确定突变是否会影响人类手术诱导的体重减轻，我们对972名接受RYGB的患者的MC 4 R基因进行了测序。MC 4 R突变杂合子患者术后体重减轻的幅度和分布与无此类突变的患者相同，这表明尽管MC 4 R基因的两个正常拷贝对于正常体重调节是必要的，但MC 4 R基因的单个正常拷贝足以介导RYGB的体重减轻效果。MC 4 R是第一个被发现的基因，它是减肥手术持续效果所必需的。RYGB在小鼠中的减肥效果需要MC 4 R信号传导，这强调了该过程的生理作用机制，并表明RYGB影响并依赖于调节能量平衡的正常途径。（临床内分泌代谢杂志97：E1023-E1031，2012）
Context: Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways.Objective: Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB.Methods and Results: Here we report that MC4R(-/-) mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB.Conclusions: MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance. (J Clin Endocrinol Metab 97: E1023-E1031, 2012)