Body weight control by hypothalamic OGT

项目摘要/摘要 中枢神经系统在新陈代谢中起着关键作用，在这个过程中，腹内侧部 下丘脑(VMH)对体重和血糖水平的适当调节至关重要。VMH 感知营养和循环中的荷尔蒙，并整合其代谢信息以协调效应器 维持机体动态平衡的反应。O-连接的β-D-N-乙酰氨基葡萄糖(O-GlcNAc) 在O-GlcNAc转移酶(OGT)的催化下，修饰被认为是一种细胞营养传感器和 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 调节VMH神经元活性和交感神经的脂解作用和维持能量平衡 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知和过滤来确定体重设定点 向白色脂肪组织提供脂解信息。为了检验这一假设，我们将把收益和损失结合起来 使用最先进的神经追踪和分子图谱工具的功能模型，光遗传和 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。目标 1将决定VMH神经元中的O-GlcNAc信号是否决定体重的设定点。 目标2将描述表达OGT的VMH神经元传递脂解信息的神经回路 白色脂肪组织。目标3将确定O-GlcNAc信号如何调节激素和营养 VMH神经元的感觉。对下丘脑OGT控制体重的详细了解可能 支持开发治疗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.