Divergence of melanocortin pathways in the control of food intake and energy expenditure
Divergence of melanocortin pathways in the control of food intake and energy expenditure
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DOI：
10.1016/j.cell.2005.08.035
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发表时间：
2005-11-04
期刊：
影响因子：
64.5
通讯作者：
Lowell, BB
中科院分区：
文献类型：
--
作者：
Balthasar, N;Dalgaard, LT;Lowell, BB
黑皮质素-4-受体（MC 4 R）的激活通过减少食物摄入和增加能量消耗来减少体内脂肪储存。MC 4 R在多个CNS位点表达，其中任何数量的位点都可以介导这些作用。为了鉴定MC 4 R表达的功能相关位点，我们产生了可以被Cre重组酶再激活的IoxP修饰的无效Mc 4 r等位基因（IoxTB Mc 4 r）。IoxTB Mc 4 r等位基因纯合的小鼠不表达MC 4 R，并且明显肥胖。使用Sim 1-Cre转基因小鼠，恢复室旁下丘脑（PVH）和杏仁核神经元亚群中MC 4 R的表达，可预防60%的肥胖。值得注意的是，增加的食物摄入，典型的Mc 4 r无效小鼠，被完全拯救，而减少的能量消耗不受影响。这些发现表明PVH和/或杏仁核中的MC 4 R控制食物摄入，但其他地方的MC 4 R控制能量消耗。食物摄入和能量消耗的分离揭示了控制能量平衡的黑皮质素途径的意外分歧。
Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we generated a IoxPmodified, null Mc4r allele (IoxTB Mc4r) that can be reactivated by Cre-recombinase. Mice homozygous for the IoxTB Mc4r allele do not express MC4Rs and are markedly obese. Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity. Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected. These findings demonstrate that MC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure. Disassociation of food intake and energy expenditure reveals unexpected divergence in melanocortin pathways controlling energy balance.