MC4R Deficiency Causes Dysregulation of Postsynaptic Excitatory Synaptic Transmission as a Crucial Culprit for Obesity

Author:

Wang Xiaohui1,Cui Xiaoli234,Li Yang24,Li Fei1,Li Yue5,Dai Jinye6,Hu Han24,Wang Xuefeng24,Sun Jianyuan247,Yang Yan24,Zhang Shuli24ORCID

Affiliation:

1. 1Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China

2. 2State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

3. 3Chinese Institute for Brain Research, Beijing, China

4. 4University of Chinese Academy of Sciences, Beijing, China

5. 5Guangwai Community Health Service Center of Xicheng District, Beijing, China

6. 6Howard Hughes Medical Institute and Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA

7. 7The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Beijing, China

Abstract

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.

Funder

CAS Key Laboratory of Brain Connectome and Manipulation

Strategic Priority Research Program of Chinese Academy of Sciences

National Natural Science Foundation of China

Instrument Developing Project of the Chinese Academy of Sciences

Ministry of Science and Technology of the People’s Republic of China

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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