O-GlcNAc Modification in Metabolic Homeostasis

描述（由申请人提供）：代谢综合征是由于基因和环境之间复杂的相互作用导致代谢稳态紊乱的结果。对于代谢综合征是否存在统一的病理生理学还有待回答。调查人员已经研究了与这种疾病有关的特定遗传和环境因素。这种“还原论”的方法可能无法揭示该综合征的核心机制，因为代谢稳态是一个多方面的动态过程。为此，发现整合代谢系统和动态变化的分子基础是至关重要的。通过己糖胺生物合成途径的营养通量导致O-linked 2- n -乙酰氨基葡萄糖（O-GlcNAc）对细胞质和核蛋白的翻译后修饰。这一动态可逆的过程涉及O-GlcNAc转移酶（OGT）和O-GlcNAcase （OGA）两种酶，O-GlcNAc分别附着在蛋白质上和从蛋白质上去除。越来越多的证据表明O-GlcNAc在胰岛素信号传导和代谢调节中起着关键作用。我们最近的工作表明，肝脏中OGT或OGA的过度表达会产生胰岛素抵抗和血脂异常。这一令人惊讶的发现表明，平衡的O-GlcNAc水平对代谢稳态至关重要。我们的中心假设是O-GlcNAc作为系统内平衡的关键传感器和调节器，将营养过剩与代谢综合征联系起来。基于我们最近观察到的代谢综合征小鼠模型脂肪组织中O-GlcNAc明显紊乱，我们建议研究脂肪组织中O-GlcNAc在代谢综合征发病中的作用，并阐明O-GlcNAc在代谢中的功能调控机制。我们将通过执行以下具体目标来实现这些目标：在目标1中，我们将确定饮食和遗传诱导的代谢综合征小鼠模型中O-GlcNAc信号的变化。在Aim 2中，我们将测试脂肪组织中O-GlcNAc的遗传干预是否能改善代谢综合征小鼠模型中的代谢缺陷。目的3将探讨通过翻译后修饰对OGT和OGA的调控。了解这种调节开关对代谢生理的影响，为探索O-GlcNAc作为代谢综合征的治疗靶点奠定基础。

DESCRIPTION (provided by applicant): Metabolic syndrome is a result of the disturbance of metabolic homeostasis by complex interactions between genes and the environment. It has yet to be answered whether there is a unifying pathophysiology for metabolic syndrome. Investigators have looked into specific genetic and environmental factors involved in this medical condition. This "reductionist" approach may be ineffective to uncover the central mechanism(s) of the syndrome because metabolic homeostasis is a multifaceted and dynamic process. To this end, it would be critical to discover the molecular underpinnings that integrate systemic and dynamic variations in metabolism. Nutrient flux through the hexosamine biosynthetic pathway leads to the posttranslational modification of cytoplasmic and nuclear proteins by O-linked 2-N-acetylglucosamine (O-GlcNAc). This dynamic and reversible process involves two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), by which O-GlcNAc is attached to and removed from proteins, respectively. Growing evidence points to a pivotal role for O-GlcNAc in insulin signaling and metabolic regulation. Our recent work has shown that overexpression of either OGT or OGA in liver produces insulin resistance and dyslipidaemia. This surprising finding suggests that balanced O-GlcNAc levels are critical for metabolic homeostasis. Our central hypothesis is that O-GlcNAc serves as a key sensor and regulator of systemic homeostasis that links nutrient excess to metabolic syndrome. On the basis of our recent observation that O-GlcNAc is markedly disturbed in adipose tissue of mouse models of metabolic syndrome, we propose to investigate the contribution of O-GlcNAc in adipose tissue to the pathogenesis of metabolic syndrome and to delineate regulatory mechanisms for O-GlcNAc function in metabolism. We will accomplish these goals by executing the following Specific Aims: In Aim 1, we will determine changes in O-GlcNAc signaling in diet- and genetic-induced mouse models of metabolic syndrome. In Aim 2, we will test whether genetic intervention of O-GlcNAc in adipose tissue ameliorates metabolic defects in the mouse model of metabolic syndrome. Aim 3 will explore the regulation of OGT and OGA by posttranslational modifications. Understanding the impact of this regulatory switch on metabolic physiology shall lay a foundation for exploring O-GlcNAc as a therapeutic target for metabolic syndrome. PUBLIC HEALTH RELEVANCE: Metabolic syndrome affects at least 20% of the population in the United States, becoming one of the principal threats to human health in the twenty-first century. Completion of this proposal will establish the pathophysiological and mechanistic links between O-GlcNAc signaling and systemic metabolic homeostasis. Pharmacological intervention to reset O-GlcNAc levels may represent an innovative strategy for preventing and treating metabolic syndrome.