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

项目总结 代谢功能失调和慢性炎症是人类和 动物模型。棕色脂肪组织(BAT)在应激反应的代谢适应中起着关键作用 包括营养过剩，代谢适应被扰乱，炎性应激加剧。 然而，在BAT的炎症和代谢信号之间的相互作用方面，仍然存在一个关键的知识差距。 在营养过剩的时候。肥胖相关的慢性炎症以过量的一氧化氮(NO)为特征 生产和异常蛋白半胱氨酸亚硝化(S亚硝化)。我们的初步数据显示，节食- 诱导肥胖使包括解偶联蛋白1(UCP1)在内的BAT蛋白S-亚硝化水平升高。这种反常现象 BAT没有生物活性的部分原因是主要的脱氮酶乙醇脱氢酶5(ADH5)的下调 调节细胞硝基-硫代氧化还原平衡。此外，我们还发现BAT Adh5的缺失抑制了UCP1- 小鼠依赖线粒体呼吸、加重糖耐量和增加BAT炎症 使用DIO。通过恢复Adh5在BAT中的表达，所有这些缺陷都得到了改善。这些数据提供了 首次有证据表明ADH5对蝙蝠的代谢应激具有保护作用。因此，我们假设 肥胖损害了ADH5调节的生热脂肪组织中的细胞亚硝酸盐稳态， 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项目来验证这一假设 目标。在目标1中，我们将定义肥胖抑制ADH5表达的机制及其 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代谢动态平衡硝基氧化还原信号对BAT代谢功能的调节 而这种调节对肥胖症代谢功能障碍的贡献是新的和未被探索的概念。 该项目的完成将提供对异常NO信号转导机制的初步见解 将BAT炎症信号与代谢功能障碍联系起来，并为开发治疗靶点提供新途径 改善肥胖背景下的蝙蝠功能障碍。

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.