Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.
Neurobiol Aging. 2018 Oct;70:40-50. doi: 10.1016/j.neurobiolaging.2018.05.036. Epub 2018 Jun 4.
The ogt gene encodes O-linked N-acetylglucosamine transferase (O-GlcNAc transferase [OGT]) that catalyzes the transfer of β-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 CaMKIIα 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.
ogt 基因编码 O-连接 N-乙酰氨基葡萄糖转移酶（O-GlcNAc 转移酶[OGT]），它催化 UDP-GlcNAc 上的 β-N-乙酰氨基葡萄糖转移到核细胞质蛋白丝氨酸或苏氨酸残基的羟基上。这一过程是一种常见的蛋白质翻译后修饰，称为蛋白质 O-GlcNAcylation，它是葡萄糖代谢的已知细胞内传感器，在调节细胞信号转导、转录和代谢中发挥重要作用。然而，OGT 在大脑中的功能知之甚少。在这里，我们报告在成年小鼠中，CaMKIIα 启动子依赖性神经元 OGT 敲除（KO）导致短期暴饮暴食、体重增加和外周胰岛素抵抗。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 加剧了高脂肪饮食引起的肥胖和胰岛素抵抗。令人惊讶的是，神经元 OGT KO 引起的外周胰岛素抵抗在 OGT KO 后 2-3 个月内得到逆转，几个月后小鼠甚至表现出更高的胰岛素敏感性。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方面的重要作用。
