O-GlcNAc Modification in Metabolic Homeostasis

描述（由申请人提供）：代谢综合征是基因与环境之间复杂相互作用导致代谢稳态紊乱的结果。代谢综合征是否存在统一的病理生理机制还有待回答。研究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”的方法可能无法有效地揭示综合征的中心机制，因为代谢稳态是一个多方面的动态过程。为此，发现整合代谢中的系统和动态变化的分子基础至关重要。通过己糖胺生物合成途径的营养流导致O-连接的2-N-乙酰葡糖胺（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两种酶，O-GlcNAc转移酶（OGT）和O-GlcNAc酶（OGA），O-GlcNAc通过这两种酶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的过度表达会导致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作为一个关键的传感器和调节系统的稳态，营养过剩的代谢综合征。基于我们最近观察到O-GlcNAc在代谢综合征小鼠模型的脂肪组织中明显受到干扰，我们建议研究脂肪组织中O-GlcNAc在代谢综合征发病机制中的作用，并阐明O-GlcNAc在代谢中功能的调节机制。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信号传导的变化。在目的2中，我们将测试脂肪组织中O-GlcNAc的遗传干预是否改善代谢综合征小鼠模型中的代谢缺陷。目的3探讨翻译后修饰对OGT和OGA的调控作用。了解这种调节开关对代谢生理的影响，将为探索O-GlcNAc作为代谢综合征治疗靶点奠定基础。 公共卫生相关性：代谢综合征影响美国至少20%的人口，成为世纪人类健康的主要威胁之一。该提案的完成将建立O-GlcNAc信号传导和全身代谢稳态之间的病理生理学和机制联系。药物干预重置O-GlcNAc水平可能代表了预防和治疗代谢综合征的创新策略。

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.