The melanocortin receptors: Lessons from knockout models
The melanocortin receptors: Lessons from knockout models
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DOI：
10.1054/npep.2002.0890
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发表时间：
2002-04-01
期刊：
影响因子：
2.9
通讯作者：
Cone, RD
中科院分区：
文献类型：
--
作者：
Butler, AA;Cone, RD
确定黑素皮质素系统在调节能量稳态中的作用依赖于遗传和药理学研究。主要发现包括：1)致死性黄（A(Y)/ A）小鼠的毛色表型是由于刺鼠基因产物对黑素皮质素-1受体（MC1R）的拮抗作用所致；2) MC3R和MC4R在参与能量稳态的中枢神经系统中心表达；3)药理学研究表明针刺是MC4R的拮抗剂，转基因研究表明MC4R的抑制或缺失重现了致死性黄色表型。亲阿片黑素皮质素（POMC）， MC3R和MC4R敲除是肥胖的，现在被用于进一步分析黑素皮质素受体功能。在MC3R和MC4R基因敲除（KO）中观察到的肥胖表型明显不同。MC4RKO小鼠贪食，不调节增加能量消耗（饮食诱导的产热）和身体活动的途径，并可发展为2型糖尿病。相比之下，MC3R缺陷小鼠不会贪食，对增加的能量消耗有正常的代谢反应，也不会发生糖尿病。MC3R基因敲除导致肥胖增加的机制尚不清楚，但可能与营养分配或身体活动的变化有关。(C) 2002年Elsevier Science Ltd.出版
Identifying the role of the melanocortin system in regulating energy homeostasis has relied on both genetic and pharmacological studies. The key findings included 1) that the coat color phenotype in the lethal yellow (A(Y)/a) mouse is due to antagonism of the melanocortin-1 receptor (MC1R) by the agouti gene product; 2) the MC3R and MC4R are expressed in CNS centers involved in energy homeostasis, and 3) the combined results of pharmacological studies showing that agouti is an antagonist of the MC4R and transgenic studies showing that inhibition or loss of the MC4R recapitulate the lethal yellow phenotype. Pro-opiomelanocortin (POMC), MC3R, and MC4R knockouts are obese and are now being used to further analyze melanocortin receptor function. The obesity phenotype observed in the MC3R and MC4R knockouts (KO) differ markedly. MC4RKO mice are hyperphagic, do not regulate pathways that increase energy expenditure (diet-induced thermogenesis) and physical activity in response to hyperphagia, and can develop type 2 diabetes. In contrast, MC3R deficient mice are not hyperphagic, have a normal metabolic response to increased energy consumption, and do not develop diabetes. The mechanism underlying the increased adiposity in the MC3R knockout remains unclear, but might be related to changes in nutrient partitioning or physical activity. (C) 2002 Published by Elsevier Science Ltd.