Role of ADH5 in the Regulation of Brown Adipose Tissue Metabolic Homeostasis

ADH5 在棕色脂肪组织代谢稳态调节中的作用

• 批准号: 10684223
• 负责人: Ling Yang
• 金额: $ 49.74万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-19 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684223
• 关键词: Adipose tissue; Adrenergic Agents; Aging; Alcohol dehydrogenase; Animal Model; Brown Fat; Cardiovascular Diseases; Cell physiology; Chronic; Cues; Cysteine; Data; Defect; Disease; Down-Regulation; Equilibrium; Exposure to; Functional disorder; Glucose Intolerance; Goals; Health; Homeostasis; Human; Immune; Impairment; Inflammation; Inflammatory; Knockout Mice; Knowledge; Laboratory Research; Link; Liver; Mammals; Mediating; Mediator; Metabolic; Metabolic dysfunction; Metabolic stress; Metabolism; Mission; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Names; Nitric Oxide; Nutrient; Obesity; Outcome; Overnutrition; Oxidation-Reduction; Oxidoreductase; Pathogenesis; Physiology; Play; Post-Translational Protein Processing; Production; Protein S; Proteins; Proteomics; Public Health; Reactive Nitrogen Species; Reactive Oxygen Species; Regulation; Research; Respiration; Role; S-Nitrosoglutathione; SKIL gene; Signal Transduction; Skeletal Muscle; Stimulus; Stress; Sulfhydryl Compounds; Testing; Therapeutic; Thermogenesis; Tissues; United States National Institutes of Health; biological adaptation to stress; diet-induced obesity; disability; feeding; heat-shock factor 1; human disease; human model; immune cell infiltrate; improved; insight; nitrosative stress; novel; oxidation; pharmacologic; proteostasis; response; restoration; stressor; therapeutic target; transcription factor; uncoupling protein 1

PROJECT SUMMARY Dysregulated metabolic function and chronic inflammation are prominent features of obesity in both humans and animal models. Brown adipose tissue (BAT) plays a critical role in metabolic adaptation in response to stresses including overnutrition, wherein the metabolic adaptation is disrupted and inflammatory stress is elevated. However, there remains a key knowledge gap in the interplay between inflammatory and metabolic cues in BAT during overnutrition. Obesity-associated chronic inflammation is characterized by excessive nitric oxide (NO) production and aberrant protein cysteine nitrosylation (S-nitrosylation). Our preliminary data showed that diet- induced obesity (DIO) elevates BAT protein S-nitrosylation, including uncoupling protein 1 (UCP1). This aberrant BAT NO bioactivity is in part due to downregulation of alcohol dehydrogenase 5 (ADH5), the major denitrosylase modulating cellular nitro-thio redox balance. Moreover, we showed that BAT Adh5 deletion suppressed UCP1- dependent mitochondrial respiration, worsened glucose intolerance and increased BAT inflammation in mice with DIO. All of these defects were improved by restoration of Adh5 expression in the BAT. These data provide the first evidence that ADH5 plays a protective role in the BAT against metabolic stress. Thus, we hypothesize obesity compromises ADH5-regulated cellular nitrosative homeostasis in the thermogenic adipose tissue, contributing to obesity-associated metabolic dysfunction. We will test this hypothesis by completing two specific aims. In Aim 1, we will define the mechanism by which obesity suppresses ADH5 expression and its pathophysiological significance in obesity. In Aim 2, we will determine the molecular mechanisms underlying ADH5-mediated BAT metabolic homeostasis. The regulation of BAT metabolic function by nitro-redox signaling and the contribution of this regulation to metabolic dysfunction in obesity are new and unexplored concepts. Accomplishment of this project will provide first insights into the mechanisms by which aberrant NO signaling links BAT inflammatory cues to metabolic dysfunction and new avenues for developing of therapeutic targets to ameliorate BAT dysfunction in the context of obesity.

项目概要 代谢功能失调和慢性炎症是人类肥胖的突出特征 动物模型。棕色脂肪组织（BAT）在应对压力的代谢适应中发挥着关键作用 包括营养过剩，其中代谢适应被破坏并且炎症应激升高。 然而，BAT 中炎症和代谢线索之间的相互作用仍然存在关键的知识差距 营养过剩期间。肥胖相关的慢性炎症的特点是过量的一氧化氮 (NO) 产生和异常蛋白质半胱氨酸亚硝基化（S-亚硝基化）。我们的初步数据表明饮食- 诱导性肥胖 (DIO) 会升高 BAT 蛋白 S-亚硝基化，包括解偶联蛋白 1 (UCP1)。这个反常的 BAT NO 生物活性部分归因于主要脱亚硝基酶乙醇脱氢酶 5 (ADH5) 的下调 调节细胞硝基硫氧化还原平衡。此外，我们发现 BAT Adh5 缺失抑制了 UCP1- 小鼠依赖线粒体呼吸、葡萄糖耐受不良恶化和 BAT 炎症增加 与迪奥。所有这些缺陷都通过恢复 BAT 中的 Adh5 表达得到改善。这些数据提供 第一个证据表明 ADH5 在 BAT 中对抗代谢应激发挥保护作用。因此，我们假设 肥胖会损害产热脂肪组织中 ADH5 调节的细胞亚硝化稳态， 导致肥胖相关的代谢功能障碍。我们将通过完成两个具体的测试来检验这个假设 目标。在目标 1 中，我们将定义肥胖抑制 ADH5 表达的机制及其影响 肥胖的病理生理学意义。在目标 2 中，我们将确定潜在的分子机制 ADH5 介导的 BAT 代谢稳态。硝基氧化还原信号对 BAT 代谢功能的调节 这种调节对肥胖代谢功能障碍的影响是新的、未经探索的概念。 该项目的完成将首次深入了解异常 NO 信号传导的机制 将 BAT 炎症线索与代谢功能障碍联系起来，并开发治疗靶点的新途径 改善肥胖背景下的 BAT 功能障碍。