Overexpression of melanocortin 2 receptor accessory protein 2 (MRAP2) in adult paraventricular MC4R neurons regulates energy intake and expenditure.
Overexpression of melanocortin 2 receptor accessory protein 2 (MRAP2) in adult paraventricular MC4R neurons regulates energy intake and expenditure.
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DOI：
10.1016/j.molmet.2018.09.010
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发表时间：
2018-12
影响因子：
8.1
通讯作者：
Chan LF
中科院分区：
文献类型：
--
作者：
Bruschetta G;Kim JD;Diano S;Chan LF
黑皮质素2受体辅助蛋白2（MRAP 2）在能量稳态中具有关键作用。虽然MRAP 2已被证明可以调节许多参与代谢的GPCR，但在MRAP 2缺陷动物中负责严重肥胖表型的关键神经元尚不清楚。此外，迄今为止，所有鼠MRAP 2模型都涉及MRAP 2的产前缺失。为了靶向下丘脑室旁核（PVN）中的黑皮质素4受体（MC 4 R）表达神经元，我们使用AAV在成年Mc 4 r-cre小鼠中出生后选择性过表达MRAP 2进行立体定位手术。我们评估了能量稳态、葡萄糖代谢、核心体温和对MC 3R/MC 4 R激动剂MTII的反应。与对照Mc 4 r-crePVN-GFP小鼠相比，标准食物饮食的Mc 4 r-crePVN-MRAP 2雌性小鼠具有较少的年龄相关的体重增加和改善的葡萄糖/胰岛素谱。这些变化与食物摄入量减少和能量消耗增加有关。相比之下，Mc 4 r-crePVN-MRAP 2雄性小鼠在普通饮食上没有显示出改善，但在高脂肪饮食（HFD）喂养后观察到能量和葡萄糖代谢的改善。此外，在饲喂标准饲料的雌性和饲喂HFD的雄性中均发现核心体温升高。与对照组相比，Mc 4 r-crePVN-MRAP 2雌性和雄性小鼠显示PVN中的神经元活化增加，雌性小鼠在MTII处理后神经元活化进一步增加。我们的数据表明，MRAP 2在PVN MC 4 R表达神经元中在调节食物摄入和能量消耗的基线条件下增强MC 4 R神经元活化中的位点特异性作用。出生后MRAP 2过表达调节能量平衡、产热和葡萄糖代谢。MRAP 2在表达MC 4 R的神经元中的过表达增加PVN神经元活化。在代谢保护的程度上存在性别差异，女性的瘦型更明显。
Melanocortin 2 receptor accessory protein 2 (MRAP2) has a critical role in energy homeostasis. Although MRAP2 has been shown to regulates a number of GPCRs involved in metabolism, the key neurons responsible for the phenotype of gross obesity in MRAP2 deficient animals are unclear. Furthermore, to date, all the murine MRAP2 models involve the prenatal deletion of MRAP2. To target Melanocortin 4 receptor (MC4R)-expressing neurons in the hypothalamic paraventricular nucleus (PVN), we performed stereotaxic surgery using AAV to selectively overexpress MRAP2 postnatally in adult Mc4r-cre mice. We assessed energy homeostasis, glucose metabolism, core body temperature, and response to MC3R/MC4R agonist MTII. Mc4r-crePVN-MRAP2 female mice on a standard chow diet had less age-related weight gain and improved glucose/insulin profile compared to control Mc4r-crePVN-GFP mice. These changes were associated with a reduction in food intake and increased energy expenditure. In contrast, Mc4r-crePVN-MRAP2 male mice showed no improvement on a chow diet, but improvement of energy and glucose metabolism was observed following high fat diet (HFD) feeding. In addition, an increase in core body temperature was found in both females fed on standard chow diet and males fed on HFD. Mc4r-crePVN-MRAP2 female and male mice showed increased neuronal activation in the PVN compared to controls, with further increase in neuronal activation post MTII treatment in females. Our data indicate a site-specific role for MRAP2 in PVN MC4R-expressing neurons in potentiating MC4R neuronal activation at baseline conditions in the regulation of food intake and energy expenditure. Postnatal overexpression of MRAP2 regulates energy balance, thermogenesis and glucose metabolism. Overexpression of MRAP2 in MC4R expressing neurons increases PVN neuronal activation. There is a sex difference in extent of metabolic protection, with a more marked lean phenotype in females.
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影响因子：
4.8
作者：
Babischkin, Jeffery S.;Aberdeen, Graham W.;Albrecht, Eugene D.
通讯作者：
Albrecht, Eugene D.
DOI：
10.1073/pnas.1406000111
发表时间：
2014-08-12
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
Srisai D;Yin TC;Lee AA;Rouault AAJ;Pearson NA;Grobe JL;Sebag JA
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影响因子：
7.7
作者：
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Sebag, Julien A.
DOI：
10.1073/pnas.0809918106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Chan, Li F.;Webb, Tom R.;Clark, Adrian J. L.
通讯作者：
Clark, Adrian J. L.