O-GlcNAc Modification in Metabolic Homeostasis

O-GlcNAc 修饰代谢稳态

• 批准号: 8535738
• 负责人: Xiaoyong Yang
• 金额: $ 32.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535738
• 关键词: Acetylglucosamine; Adipose tissue; Affect; Cardiovascular Diseases; Central obesity; Collection; Complex; Cytoplasmic Protein; Defect; Diabetic mouse; Diet; Dyslipidemias; Environment; Environmental Risk Factor; Enzymes; Equilibrium; Fatty acid glycerol esters; Foundations; Functional disorder; Futile Cycling; Genes; Genetic; Goals; Health; Hexosamines; Homeostasis; Hormonal; Human; Hypertension; Incidence; Individual; Insulin Resistance; Insulin Signaling Pathway; Intervention; Life Style; Link; Liver; Mass Spectrum Analysis; Medical; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modification; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Proteins; Nutrient; Nutritional; O-GlcNAc transferase; Output; Pathogenesis; Pathway interactions; Physiological; Physiology; Population; Post-Translational Protein Processing; Process; Proteins; Regulation; Research Personnel; Risk Factors; Role; Signal Transduction; Site; Site-Directed Mutagenesis; Societies; Syndrome; Testing; Transgenes; United States; Variant; Work; base; blood glucose regulation; db/db mouse; diabetic; feeding; gene therapy; improved; innovation; insight; insulin sensitivity; insulin signaling; mouse model; overexpression; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; prevent; public health relevance; response; sedentary; sensor; therapeutic target

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.

描述（由申请人提供）：代谢综合征是基因与环境之间复杂的相互作用扰乱代谢稳态的结果。代谢综合征是否存在统一的病理生理学尚未得到解答。研究人员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”方法可能无法有效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，发现整合代谢中系统性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物流动导致细胞质和核蛋白通过 O-连接 2-N-乙酰氨基葡萄糖 (O-GlcNAc) 进行翻译后修饰。这一动态且可逆的过程涉及两种酶：O-GlcNAc 转移酶 (OGT) 和 O-GlcNAcase (OGA)，分别通过这两种酶将 O-GlcNAc 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发挥着关键作用。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 水平对于代谢稳态至关重要。我们的中心假设是 O-GlcNAc 作为系统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代谢综合征小鼠模型的脂肪组织中 O-GlcNAc 受到明显干扰，我们建议研究脂肪组织中 O-GlcNAc 对代谢综合征发病机制的贡献，并描绘 O-GlcNAc 的调节机制。 -GlcNAc 在新陈代谢中发挥作用。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。在目标 2 中，我们将测试脂肪组织中 O-GlcNAc 的基因干预是否可以改善代谢综合征小鼠模型中的代谢缺陷。目标 3 将探索翻译后修饰对 OGT 和 OGA 的调节。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。该提案的完成将建立 O-GlcNAc 信号传导与全身代谢稳态之间的病理生理学和机制联系。重置 O-GlcNAc 水平的药物干预可能代表了预防和治疗代谢综合征的创新策略。