Hypothalamic extended synaptotagmin-3 contributes to the development of dietary obesity and related metabolic disorders.
Yi ZhangYunliang GuanSusu PanLihong YanPing WangZhuo ChenQing ShenFaming ZhaoXin ZhangJuan LiJuxue LiDongsheng CaiGuo ZhangPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
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.
Keyphrases
- weight gain
- weight loss
- body mass index
- metabolic syndrome
- insulin resistance
- birth weight
- protein kinase
- binding protein
- cell proliferation
- adipose tissue
- physical activity
- high fat diet induced
- genome wide
- amino acid
- blood pressure
- dna methylation
- skeletal muscle
- inflammatory response
- protein protein
- gene expression
- catheter ablation
- fatty acid
- single cell
- radiofrequency ablation