Hypothalamic extended synaptotagmin-3 contributes to the development of dietary obesity and related metabolic disorders

Yi Zhang, Yunliang Guan, Susu Pan, Lihong Yan, Ping Wang, Zhuo Chen, Qing Shen, Faming Zhao, Xin Zhang, Juan Li, Juxue Li, Dongsheng Cai, Guo Zhang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20149-20158
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number33
DOIs
StatePublished - Aug 2020

ASJC Scopus subject areas

  • General

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