O-GlcNAc Modification in Metabolic Homeostasis

O-GlcNAc 修饰代谢稳态

• 批准号: 8719980
• 负责人: Xiaoyong Yang
• 金额: $ 34万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719980
• 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.

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的代谢稳态扰动的结果。是否有代谢综合征的统一病理生理学尚未回答。研究人员已经研究了这种疾病中涉及的特定遗传和环境因素。这种“还原主义”方法可能无效地揭示了综合征的中心机制，因为代谢稳态是一个多方面的动态过程。为此，发现整合新陈代谢的全身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通量导致通过O连接的2-N-乙酰葡萄糖胺（O-GLCNAC）对细胞质和核蛋白进行翻译后修饰。这个动态和可逆的过程涉及两种酶，O-GLCNAC转移酶（OGT）和O-GlCNACase（OGA），分别将O-GlCNAC连接到并从蛋白质中取出并去除。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的关键作用。我们最近的工作表明，肝脏中OGT或OGA的过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是全身稳态的关键传感器和调节剂，将营养过量与代谢综合征联系起来。根据我们最近的观察，在代谢综合征的小鼠模型的脂肪组织中，O-GLCNAC显着干扰，我们建议研究O-GlCNAC在脂肪组织中对代谢综合征的发病机理的贡献，并为O-GLCNAC在代谢功能中的调节机制而言。我们将通过执行以下特定目标来实现这些目标：在AIM 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O-GLCNAC在脂肪组织中的遗传干预是否可以改善代谢综合征小鼠模型中的代谢缺陷。 AIM 3将通过翻译后修改探索OGT和OGA的调节。了解这种调节性转换对代谢生理的影响应为探索O-GLCNAC作为代谢综合征的治疗靶点奠定基础。