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.

中文翻译：

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MC4R 缺陷导致突触后兴奋性突触传递失调，是肥胖的罪魁祸首

下丘脑 (PVH) 室旁核中的黑皮质素 4 受体 (MC4R) 在调节食物摄入和能量稳态方面显示出双向特征。在这里，我们证明了 PVH 中的 MC4R 敲低 (MC4R KD) 可以通过蛋白激酶 A (PKA) 依赖性信号级联改变 AMPAR GluA1 亚基磷酸化来减弱 AMPA 受体 (AMPAR) 介导的突触后反应，同时导致体重快速增加。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关键病因之一。