Mechanism of Integrative Metabolic Regulation by Iron and Hypoxia

铁和缺氧综合代谢调节机制

• 批准号: 10514581
• 负责人: DONALD A. MCCLAIN
• 金额: --
• 依托单位: W G HEFNER VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10514581
• 关键词: Adipose tissue; Affect; Altitude; Beta Cell; Blood Donations; Blood Glucose; CREB1 gene; Cell Respiration; Cell physiology; Cells; Complex; Data; Dependence; Diabetes Mellitus; Diabetes prevention; Diet; Dietary Iron; EP300 gene; Elements; Enzymes; Exposure to; FOXO1A gene; FRAP1 gene; Fatty acid glycerol esters; Gene Activation; Genetic Transcription; Genus Hippocampus; Glucosamine; Glucose; Goals; Harvest; Health; Hepatic; Hexosamines; Homeostasis; Human; Hypoxia; Hypoxia Pathway; Impairment; Individual; Insulin; Insulin Resistance; Iron; Iron Overload; Leptin; Link; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mixed Function Oxygenases; Modification; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; Nutrient; Nutrient availability; Obesity; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathogenesis; Pathologic; Pathway interactions; Phosphorylation; Physiology; Post-Translational Protein Processing; Production; Proteins; Proteomics; Publishing; Regulation; Risk Factors; Sea; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirtuins; System; Technology; Testing; Tissues; Transcriptional Regulation; Work; adiponectin; blood glucose regulation; detection of nutrient; diabetes mellitus therapy; glucose metabolism; glucose production; glycosylation; human tissue; insulin secretion; insulin sensitivity; islet; modifiable risk; mouse model; normoxia; novel; oxidant stress; oxidation; personalized medicine; pharmacologic; pleiotropism; promoter; recruit; response; sensor; sugar; transcription factor; transcriptome sequencing

PROJECT SUMMARY Insulin resistance, excess hepatic glucose production, and impaired insulin secretion are the hallmarks of type 2 diabetes mellitus (T2DM), and tissue iron levels significantly affect all three. In mice and humans, we have shown that high iron impairs insulin secretion and down regulates leptin and adiponectin. Our preliminary data show further that these effects of iron are fuel-dependent, with much of this difference based on higher iron levels supporting higher levels of fat oxidation. Our mechanistic work on these effects of iron has revealed the involvement of numerous pathways, including transcriptional regulation (notably by CREB, FoxO1, and PGC1α) and nutrient/metabolite signaling (AMPK, sirtuins, and mTOR). Thus, the effects of iron are complex, pleiotropic, and cannot be explained by invoking a single linear signal transduction pathway. Recently our work on the mechanism by which iron regulates leptin secretion has revealed a unifying concept for these pleiotropic effects: High tissue iron down-regulates a central integrator of nutrient and redox status, the O-linked N-acetyl glucosamine (O-GlcNAc) pathway. This pathway results in the O-GlcNAc modification of most transcription factors and numerous enzymes that regulate metabolism. Activation of the pathway is often a direct readout of cellular nutrient fluxes, and we have shown it to be sufficient to induce changes in insulin sensitivity, insulin secretion, and hepatic glucose metabolism in ways that recapitulate T2DM. A second pathway that responds to both nutrient and oxidative stresses is the hypoxia-sensing pathway. Like the O-GlcNAc pathway, it functions at both ends of two metabolic spectra—low glucose and low oxygen as well as high glucose and oxidative stress. The pathways regulate one another and interact in determining hepatic glucose production, insulin sensitivity, and insulin secretion. Importantly, both the O- GlcNAc and hypoxia pathways are not only relevant to pathologic iron overload and hypoxia, but regulate metabolism in normal physiology, across the very broad range of “normal” iron and in individuals at sea level. In sum, the O-GlcNAc and hypoxia pathways cooperate to sense the availability or excess of two essential elements required for oxidative metabolism, iron and oxygen. Based on the above, our published work, and Preliminary Data, we therefore hypothesize that these two pathways integrate these signals to regulate several metabolic pathways involved in the pathogenesis of T2DM. Modulation of the O-GlcNAc pathway by iron affects numerous signal transduction pathways, leading to broad-based changes in metabolism that globally alter fuel utilization to confer adaptive responses to either a lack or excess of iron. In parallel, the hypoxia pathway performs a parallel function based on oxygen availability or excess oxidant stress. Crosstalk between the two pathways can amplify their effects, resulting in integration and a “fine-tuning” of metabolism based on nutrient availability, iron and oxygen levels, and oxidant stress. To test these hypotheses, we propose the following Specific Aims: 1. Determine the mechanism by which O-GlcNAc mediates the regulation of leptin secretion by iron. 2. Define the effects of dietary iron on β-cell function in mice, in normoxia and hypoxia. 3. Determine the mechanism for the effects of iron on O-GlcNAc protein modification. The significance and impact of these studies is that they aim to define ideal levels of tissue iron that may be narrower than the broad “normal” range in humans, and tissue iron is easily modifiable by diet or blood donation. Ideal iron levels may also differ based on oxygen status (i.e. in those with different habitation altitudes), ultimately allowing personalized therapy for diabetes in those individuals. Finally, the studies will also identify new pathways to treat diabetes: For example, the HIF hydroxylases can be pharmacologically manipulated, and advances are also being made in doing so for the O-GlcNAc pathway. !

项目摘要 胰岛素抵抗，过量的肝葡萄糖产生和胰岛素分泌受损是标志 2型糖尿病（T2DM）和组织铁的水平显着影响所有三种。在老鼠和人类中，我们 已经表明，高铁会损害胰岛素的分泌，并下降可调节瘦素和脂联素。我们的初步 数据进一步表明，铁的这些影响是燃料依赖性的，其中大部分差异基于较高 铁水平支持更高水平的脂肪氧化。我们对铁的这些作用的机械工作已经揭示了 众多途径的参与，包括转录调节（尤其是Creb，Foxo1和 PGC1α）和营养/代谢物信号传导（AMPK，Sirtuins和MTOR）。那就是铁的影响很复杂， 多效性，无法通过调用单个线性信号转导途径来解释。 最近，我们对铁调节瘦素分泌的机制的工作揭示了一个统一 这些多效效应的概念：高组织铁下调营养和氧化还原的中央整合体 状态，O连接的N-乙酰基葡萄糖胺（O-GLCNAC）途径。该途径导致O-GLCNAC 修饰大多数转录因子和调节新陈代谢的众多酶。激活 途径通常是细胞营养通量的直接读数，我们已经证明它足以诱导 胰岛素敏感性，胰岛素分泌和肝葡萄糖代谢的变化以概括性的方式 T2DM。对养分和氧化应力均反应的第二个途径是缺氧感应 路径。像O-GLCNAC途径一样，它在两个代谢光谱的两端起作用 - 低葡萄糖和低 氧气以及高葡萄糖和氧化应激。该路径相互调节并相互作用 确定肝葡萄糖产生，胰岛素敏感性和胰岛素分泌。重要的是，两个O- GlcNAC和缺氧途径不仅与病理铁超负荷和缺氧有关，而且调节 正常生理学中的代谢，遍布非常广泛的“正常”铁和海平面的个体。 总而言之，O-GlCNAC和缺氧途径坐标以感知可用性或超过两个 氧化物代谢，铁和氧所需的基本要素。基于上述，我们出版了 因此，工作和初步数据，我们假设这两种途径将这些信号整合到 调节与T2DM发病机理有关的几种代谢途径。 O-GLCNAC的调节 铁的途径会影响众多信号转导途径，从而导致广泛的变化 全球改变燃料利用以赋予对铁缺乏或过量的自适应反应的代谢。 平行于低氧途径，基于氧气可用性或超过氧化剂的平行功能 压力。两种途径之间的串扰可以扩大它们的影响，从而导致整合和“微调” 基于养分利用率，铁和氧气水平以及氧化物胁迫的代谢。测试这些 假设，我们提出以下具体目的： 1。确定O-GlCNAC介导铁调节瘦素分泌的机制。 2。定义饮食铁对小鼠，常氧和缺氧的影响。 3。确定铁对O-GLCNAC蛋白质修饰的影响的机制。 这些研究的重要性和影响是，它们旨在定义理想水平的组织铁水平 可能比人类广泛的“正常”范围窄，并且可以通过饮食或血液来改变组织铁 捐款。理想的铁水平也可能根据氧气状态而有所不同（即在具有不同居住的人中 高度），最终允许对这些人的糖尿病进行个性化治疗。最后，研究将 还确定治疗糖尿病的新途径：例如，HIF羟化酶可以是药物的 操纵，并且为O-GLCNAC途径而做出了进步。 呢