TY - JOUR
T1 - Hypothalamic extended synaptotagmin-3 contributes to the development of dietary obesity and related metabolic disorders
AU - Zhang, Yi
AU - Guan, Yunliang
AU - Pan, Susu
AU - Yan, Lihong
AU - Wang, Ping
AU - Chen, Zhuo
AU - Shen, Qing
AU - Zhao, Faming
AU - Zhang, Xin
AU - Li, Juan
AU - Li, Juxue
AU - Cai, Dongsheng
AU - Zhang, Guo
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Drs. Minmin Luo and Cheng Zhan (National Institute of Biological Sciences) for sharing the POMC-Cre mice. This work was supported by the grants from the National Natural Science Foundation of China (81573146, 91539125), the Junior Thousand Talents Program of China and the Huazhong University of Science and Technology (to G.Z.). Juxue Li was supported by the grants from the National Natural Science Foundation of China (81570774) and the National Key Research and Development Program of China (2018YFC1003504).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - The C2 domain containing protein extended synaptotagmin (E-Syt) plays important roles in both lipid homeostasis and the intracellular signaling; however, its role in physiology remains largely unknown. Here, we show that hypothalamic E-Syt3 plays a critical role in diet-induced obesity (DIO). E-Syt3 is characteristically expressed in the hypothalamic nuclei. Whole-body or proopiomelanocortin (POMC) neuron-specific ablation of E-Syt3 ameliorated DIO and related comorbidities, including glucose intolerance and dyslipidemia. Conversely, overexpression of E-Syt3 in the arcuate nucleus moderately promoted food intake and impaired energy expenditure, leading to increased weight gain. Mechanistically, E-Syt3 ablation led to increased processing of POMC to α-melanocyte-stimulating hormone (α-MSH), increased activities of protein kinase C and activator protein-1, and enhanced expression of prohormone convertases. These findings reveal a previously unappreciated role for hypothalamic E-Syt3 in DIO and related metabolic disorders.
AB - The C2 domain containing protein extended synaptotagmin (E-Syt) plays important roles in both lipid homeostasis and the intracellular signaling; however, its role in physiology remains largely unknown. Here, we show that hypothalamic E-Syt3 plays a critical role in diet-induced obesity (DIO). E-Syt3 is characteristically expressed in the hypothalamic nuclei. Whole-body or proopiomelanocortin (POMC) neuron-specific ablation of E-Syt3 ameliorated DIO and related comorbidities, including glucose intolerance and dyslipidemia. Conversely, overexpression of E-Syt3 in the arcuate nucleus moderately promoted food intake and impaired energy expenditure, leading to increased weight gain. Mechanistically, E-Syt3 ablation led to increased processing of POMC to α-melanocyte-stimulating hormone (α-MSH), increased activities of protein kinase C and activator protein-1, and enhanced expression of prohormone convertases. These findings reveal a previously unappreciated role for hypothalamic E-Syt3 in DIO and related metabolic disorders.
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U2 - 10.1073/PNAS.2004392117
DO - 10.1073/PNAS.2004392117
M3 - Article
C2 - 32747560
AN - SCOPUS:85089787883
SN - 0027-8424
VL - 117
SP - 20149
EP - 20158
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 33
ER -
