Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Diabetes. 2022 Nov 1;71(11):2331-2343. doi: 10.2337/db22-0162.
Melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVH) shows bidirectional characterization in modulating food intake and energy homeostasis. We demonstrate that MC4R knockdown (KD) in the PVH can attenuate AMPA receptor (AMPAR)-mediated postsynaptic responses by altering the phosphorylation of AMPAR GluA1 subunit through the protein kinase A (PKA)-dependent signaling cascade and simultaneously lead to rapid body weight gain. Furthermore, PKA KD in the PVH engendered similar electrophysiological and behavioral phenotypes as in 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 of obesity. Our study provides the synaptic and molecular explanations of how body weight is regulated by MC4R in the PVH.
下丘脑室旁核中的黑皮质素 4 受体 (MC4R) 在调节食物摄入和能量平衡方面表现出双向特征。我们证明，PVH 中的 MC4R 敲低 (KD) 可以通过改变 AMPAR GluA1 亚基的磷酸化来改变 AMPA 受体 (AMPAR) 介导的突触后反应，这种改变是通过蛋白激酶 A (PKA) 依赖性信号级联实现的，同时导致体重快速增加。此外，PVH 中的 PKA KD 产生了类似于 MC4R KD 小鼠的类似电生理和行为表型。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，还导致体重增加，这表明突触反应的异常可能是肥胖的关键病因之一。我们的研究提供了关于 MC4R 如何在 PVH 中调节体重的突触和分子解释。
