Genetic Dissection of the Functions of the Melanocortin-3 Receptor, a Seven-transmembrane G-protein-coupled Receptor, Suggests Roles for Central and Peripheral Receptors in Energy Homeostasis
Genetic Dissection of the Functions of the Melanocortin-3 Receptor, a Seven-transmembrane G-protein-coupled Receptor, Suggests Roles for Central and Peripheral Receptors in Energy Homeostasis
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DOI：
10.1074/jbc.m111.278374
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发表时间：
2011-11-25
影响因子：
4.8
通讯作者：
Butler, Andrew A.
中科院分区：
文献类型：
--
作者：
Begriche, Karima;Levasseur, Peter R.;Butler, Andrew A.
黑皮质素-3受体（MC 3R）基因是多效性的，影响身体组成，钠尿，免疫功能，和昼夜节律的营养摄入的夹带。MC 3R在脑的下丘脑和边缘区以及外周组织中表达。为了研究中心MC 3R的作用，我们在小鼠Mc 3r基因的翻译起始密码子的5'端插入“lox-stop-lox”（LoxTB），并使用神经元特异性Cre转基因小鼠重新激活转录。如基于Mc 3r敲除小鼠的早期观察所预测的，Mc 3r（TB/TB）小鼠显示出瘦体重减少、脂肪量增加和饮食诱导的肥胖加速。令人惊讶的是，使用Nestin-Cre转基因拯救神经系统中的Mc 3r表达仅部分拯救了饮食喂养条件下的肥胖，并且对加速饮食诱导的肥胖表型没有影响。下丘脑腹内侧区（VMH）是调节摄食相关行为和代谢稳态的神经网络中的关键节点，相对于其他脑区，其表现出密集的Mc 3r表达。为了靶向VMH MC 3R表达，我们使用类固醇生成因子-1 Cre转基因小鼠。虽然恢复VMH MC 3R信号传导对肥胖也有适度的影响，但观察到代谢稳态的显着改善。VMH MC 3R信号传导不足以拯救瘦体重表型或预测食物预期的行为调节。这些结果表明，影响能量稳态的MC 3R的作用涉及中枢和外周作用位点。中央MC 3R对行为和代谢的影响涉及不同的途径; VMH MC 3R信号改善代谢稳态，但对预测营养可用性的行为表达没有显着影响。
The melanocortin-3 receptor (MC3R) gene is pleiotropic, influencing body composition, natriuresis, immune function, and entrainment of circadian rhythms to nutrient intake. MC3Rs are expressed in hypothalamic and limbic regions of the brain and in peripheral tissues. To investigate the roles of central MC3Rs, we inserted a "lox-stop-lox" (LoxTB) 5' of the translation initiation codon of the mouse Mc3r gene and reactivated transcription using neuron-specific Cre transgenic mice. As predicted based on earlier observations of Mc3r knock-out mice, Mc3r(TB/TB) mice displayed reduced lean mass, increased fat mass, and accelerated diet-induced obesity. Surprisingly, rescuing Mc3r expression in the nervous system using the Nestin-Cre transgene only partially rescued obesity in chow-fed conditions and had no impact on the accelerated diet-induced obesity phenotype. The ventromedial hypothalamus (VMH), a critical node in the neural networks regulating feeding-related behaviors and metabolic homeostasis, exhibits dense Mc3r expression relative to other brain regions. To target VMH MC3R expression, we used the steroidogenic factor-1 Cre transgenic mouse. Although restoring VMH MC3R signaling also had a modest impact on obesity, marked improvements in metabolic homeostasis were observed. VMH MC3R signaling was not sufficient to rescue the lean mass phenotype or the regulation of behaviors anticipating food anticipation. These results suggest that actions of MC3Rs impacting on energy homeostasis involve both central and peripheral sites of action. The impact of central MC3Rs on behavior and metabolism involves divergent pathways; VMH MC3R signaling improves metabolic homeostasis but does not significantly impact on the expression of behaviors anticipating nutrient availability.