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MC4R deficiency causes dysregulation of postsynaptic excitatory synaptic transmission as a crucial culprit for obesity

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posted on 16.08.2022, 21:01 authored by Xiaohui Wang, Xiaoli Cui, Yang Li, Fei Li, Yue Li, Jinye Dai, Han Hu, Xuefeng Wang, Jianyuan Sun, Yan Yang, Shuli Zhang

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.

Funding

This work was supported by Ministry of Science and Technology of the People´s Republic of China (2021ZD0203800), CAS Key Laboratory of Brain Connectome and Manipulation (2019DP173024), Instrument Developing Project of the Chinese Academy of Sciences (YJKYYQ20180028), the National Natural Science Foundation of China (32070987 and 31871033), as well as Strategic Priority Research Program of Chinese Academy of Sciences (XDB37030303).

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