O-GlcNAc Modification in Metabolic Homeostasis

描述(申请人提供)：代谢综合征是由基因和环境之间复杂的相互作用造成的代谢动态平衡紊乱的结果。代谢综合征是否有统一的病理生理学机制尚无定论。调查人员已经调查了与这种医疗状况有关的特定遗传和环境因素。这种“简化论”的方法可能不能有效地揭示该综合征的中心机制(S)，因为代谢动态平衡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将是至关重要的。通过氨基己糖生物合成途径的营养通量导致O-连接的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。这个动态和可逆的过程涉及O-GlcNAc转移酶(OGT)和O-GlcNAcase(OGA)两种酶，O-GlcNAc分别通过这两种酶附着在蛋白质上和从蛋白质中移除。越来越多的证据表明O-GlcNAc在胰岛素信号和代谢调节中起着关键作用。我们最近的工作表明，OGT或OGA在肝脏中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水平对代谢动态平衡至关重要。我们的中心假设是O-GlcNAc作为系统内稳态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O-GlcNAc在代谢综合征模型小鼠脂肪组织中的明显紊乱，我们建议探讨脂肪组织中O-GlcNAc在代谢综合征发病机制中的作用，并阐明O-GlcNAc在代谢中作用的调节机制。我们将通过执行以下特定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。在目标2中，我们将测试脂肪组织中O-GlcNAc的基因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。了解这种调节开关对代谢生理学的影响将为探索O-GlcNAc作为代谢综合征的治疗靶点奠定基础。 公共卫生相关性：代谢综合征影响着美国至少20%的人口，成为21世纪人类健康的主要威胁之一。这一提议的完成将建立O-GlcNAc信号与系统代谢稳态之间的病理生理和机制联系。重置O-GlcNAc水平的药物干预可能代表着一种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.