Body weight control by hypothalamic OGT

项目概要/摘要 中枢神经系统在代谢中起着关键作用，其中腹内侧 下丘脑（VMH）对于适当调节体重和血糖水平至关重要。VMH的 感觉营养和循环激素，并整合其代谢信息，以协调效应器 维持机体内稳态的反应。O-连接β-D-N-乙酰葡糖胺（O-GlcNAc） 由O-GlcNAc转移酶（OGT）催化的修饰被认为是营养素的细胞传感器， 荷尔蒙我们最近的研究表明，VMH中的OGT是促进脂肪组织生长所必需的 通过调节VMH神经元活性和交感神经元活性， 对白色脂肪组织的神经支配。基于这些发现，我们假设VMH O-GlcNAc 信号通过体液和营养感测和过滤来确定体重设定点 脂肪分解信息到白色脂肪组织。为了验证这个假设，我们将联合收割机的增益和损失 功能模型与最先进的神经追踪和分子分析工具，光遗传学和 电生理记录和全面的生理评估，以描绘 VMH OGT调节脂肪组织功能和抑制体重增加的机制。目的 1将确定VMH神经元中的O-GlcNAc信号传导是否决定体重的设定点。 目的2描述OGT表达的VMH神经元传递脂解信息的神经回路 到白色脂肪组织。目标3将确定O-GlcNAc信号传导如何调节激素和营养 VMH神经元的感觉。详细了解下丘脑OGT对体重的控制， 支持开发肥胖症和合并症的新疗法。

Project Summary/Abstract The central nervous system plays a pivotal role in metabolism, within which the ventromedial hypothalamus (VMH) is crucial for proper regulation of body weight and blood glucose level. The VMH senses nutrients and circulating hormones and integrates its metabolic information to coordinate effector responses to maintain organismal homeostasis. O-linked beta-D-N-acetylglucosamine (O-GlcNAc) modification, catalyzed by O-GlcNAc transferase (OGT), is considered a cellular sensor of nutrients and hormones. Our recent studies reveal that OGT in the VMH is required for promoting adipose tissue lipolysis and maintaining energy balance by regulating the VMH neuronal activity and sympathetic innervations to white adipose tissues. Based on these findings, we hypothesize that VMH O-GlcNAc signaling determines a body weight setpoint by means of humoral and nutritional sensing and filtering lipolytic information to white adipose tissues. To test this hypothesis, we will combine gain- and loss-of- function models with state-of-the-art neural tracing and molecular profiling tools, optogenetic and electrophysiological recordings, and comprehensive physiological assessments to delineate the mechanisms by which VMH OGT regulates adipose tissue function and constrains body weight gain. Aim 1 will determine whether O-GlcNAc signaling in VMH neurons determines the setpoint of body weight. Aim 2 will delineate the neurocircuitry by which OGT-expressing VMH neurons relay lipolytic information to white adipose tissues. Aim 3 will identify how O-GlcNAc signaling regulates hormonal and nutritional sensing of VMH neurons. A detailed understanding of body weight control by hypothalamic OGT could support the development of novel therapies for obesity and co-morbidities.