MC4R Deficiency Causes Dysregulation of Postsynaptic Excitatory Synaptic Transmission as a Crucial Culprit for Obesity
MC4R Deficiency Causes Dysregulation of Postsynaptic Excitatory Synaptic Transmission as a Crucial Culprit for Obesity
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MC4R 缺乏导致突触后兴奋性突触传递失调，是肥胖的罪魁祸首
DOI：
10.2337/db22-0162
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Shuli Zhang
中科院分区：
文献类型：
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作者：
Xiaohui Wang;Xiaoli Cui;Yang Li;Fei Li;Yue Li;Jinye Dai;Han Hu;Xuefeng Wang;Jianyuan Sun;Yan Yang;Shuli Zhang
下丘脑室旁核（PVH）的黑素皮质素4受体（MC4R）在调节摄食和能量平衡方面具有双向性。在这里，我们证明MC4R敲低（MC4R KD）在PVH可以减弱AMPA受体（AMPAR）介导的突触后反应，通过改变AMPAR GluA1亚基磷酸化通过蛋白激酶A（PKA）依赖的信号级联反应，同时导致体重迅速增加。此外，PVH中的PKA敲低（PKA KD）产生与MC4R KD小鼠相似的电生理和行为表型。重要的是，我们观察到AMPAR GluA1表达的减少不仅导致突触反应减弱，而且导致体重增加，这表明突触反应的异常可能是肥胖的重要病因之一。我们的研究为PVH中MC4R如何调节体重提供了突触和分子解释。
Melanocortin-4 receptor (MC4R) in paraventricular nucleus in hypothalamus (PVH) shows bidirectional characterization in modulating food intake and energy homeostasis. Here, we demonstrated that MC4R knock down (MC4R KD) in PVH could attenuate AMPA receptor (AMPAR) mediated postsynaptic responses by altering AMPAR GluA1 subunit phosphorylation via protein kinase A (PKA) dependent signaling cascade and simultaneously lead to rapid body weight gain. Further, PKA knock down (PKA KD) in PVH engendered similar electrophysiological and behavioral phenotypes as MC4R KD mice. Importantly, we observed that the reduction of AMPAR GluA1 expression not only led to attenuated synaptic responses but also caused body weight gain, suggesting that the aberration of synaptic responses may be one of the crucial pathogeny for obesity. Our study provided the synaptic and molecular explanations of how body weight is regulated by MC4R in PVH.