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.

项目摘要 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）在应激中在代谢适应中起关键作用 包括营养不良，其中代谢适应受到破坏，炎症应激升高。 但是，蝙蝠中的炎症和代谢线索之间的相互作用仍然存在关键知识差距 在营养期间。肥胖相关的慢性炎症的特征是过量一氧化氮（NO） 产生和异常的蛋白质半胱氨酸亚硝基化（S-硝基化）。我们的初步数据表明饮食 - 诱导的肥胖症（DIO）提高了BAT蛋白S-亚硝基化，包括解偶联蛋白1（UCP1）。这个异常 BAT没有生物活性的部分是由于醇脱氢酶5（ADH5）的下调，这是主要的脱硝基酶 调节细胞氮-THIO氧化还原平衡。此外，我们表明BAT ADH5删除抑制了UCP1- 依赖性线粒体呼吸，葡萄糖不耐症恶化并增加小鼠的蝙蝠炎症 与dio。所有这些缺陷都通过恢复BAT中的ADH5表达来改善。这些数据提供 第一个证据表明ADH5在反对代谢压力的蝙蝠中起保护作用。因此，我们假设 肥胖会损害热脂肪组织中ADH5调节的细胞硝化稳态， 导致肥胖相关的代谢功能障碍。我们将通过完成两个特定的特定来检验这一假设 目标。在AIM 1中，我们将定义肥胖抑制ADH5表达及其的机制 肥胖症中的病理生理意义。在AIM 2中，我们将确定基础机制 ADH5介导的蝙蝠代谢稳态。通过硝基 - 雷斯信号传导对BAT代谢功能的调节 这种调节对肥胖症代谢功能障碍的贡献是新的且未开发的概念。 该项目的完成将提供对无信号传递的机制的首先见解 将BAT炎症提示连接到代谢功能障碍和用于开发治疗靶标的新途径 在肥胖的背景下，可以改善蝙蝠功能障碍。