Neuronal O-GlcNAc transferase regulates appetite, body weight, and peripheral insulin resistance
Neuronal O-GlcNAc transferase regulates appetite, body weight, and peripheral insulin resistance
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神经元O-GlcNAc转移酶调节食欲、体重和外周胰岛素抵抗
DOI：
10.1016/j.neurobiolaging.2018.05.036
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发表时间：
2018-10-01
影响因子：
4.2
通讯作者：
Gong, Cheng-Xin
中科院分区：
文献类型：
--
作者：
Dai, Chun-ling;Gu, Jin-hua;Gong, Cheng-Xin
ogt基因编码O-连接的N-乙酰葡糖胺转移酶（O-GlcNAc转移酶[OGT]），其催化β-N-乙酰葡糖胺（GlcNAc）从尿苷二磷酸-GlcNAc转移至核质蛋白的丝氨酸或苏氨酸残基的羟基。该过程是一种常见的蛋白质翻译后修饰，称为蛋白质O-GlcNAc化，其是已知的葡萄糖代谢的细胞内传感器，在调节细胞信号传导、转录和代谢中起重要作用。然而，人们对OGT在大脑中的功能知之甚少。在这里，我们报告说，CaMKIIa启动子依赖的神经元敲除（KO）的OGT在成年小鼠导致短期暴饮暴食，体重增加，外周胰岛素抵抗。这些表型变化伴随着血清胰岛素和瘦素水平的显著升高以及下丘脑中的神经元细胞死亡，包括瘦素受体表达神经元的丧失。神经元OGT KO加重了高脂饮食诱导的肥胖和胰岛素抵抗。令人惊讶的是，由神经元OGT KO诱导的外周胰岛素抵抗在OGT KO后2-3个月被逆转，并且小鼠甚至在几个月后显示出增加的胰岛素敏感性。这些发现揭示了神经元OGT在调节摄食行为、体重和外周胰岛素敏感性中的重要作用。(C)2018爱思唯尔公司All rights reserved.
The ogt gene encodes O-linked N-acetylglucosamine transferase (O-GlcNAc transferase [OGT]) that catalyzes the transfer of b-N-acetylglucosamine (GlcNAc) from the uridine-diphosphate-GlcNAc to the hydroxyl group of serine or threonine residues of nucleocytoplasmic proteins. This process is a common protein posttranslational modification, called protein O-GlcNAcylation, which is a known intracellular sensor of glucose metabolism and plays an important role in regulating cellular signaling, transcription, and metabolism. However, little is known about the function of OGT in the brain. Here, we report that the CaMKIIa promoter-dependent neuronal knockout (KO) of OGT in adult mice led to short-term overeating, body weight gain, and peripheral insulin resistance. These phenotype changes were accompanied by marked elevation of serum insulin and leptin levels and neuronal cell death, including the loss of leptin receptor - expressing neurons, in the hypothalamus. The neuronal OGT KO exacerbated obesity and insulin resistance induced by high-fat diet. Surprisingly, the peripheral insulin resistance induced by neuronal OGT KO was reversed at its own 2-3 months after OGT KO, and the mice even showed increased insulin sensitivity several months later. These findings reveal an important role of neuronal OGT in the regulation of feeding behavior, body weight, and peripheral insulin sensitivity. (C) 2018 Elsevier Inc. All rights reserved.