Burn induces hypermetabolism via browning of the white adipose tissue

烧伤通过白色脂肪组织褐变引起代谢亢进

• 批准号: 10660449
• 负责人: Marc Gerhard Jeschke
• 金额: $ 24.45万
• 依托单位: HAMILTON HEALTH SCIENCES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10660449
• 关键词: Burn; induces; hypermetabolism; via; browning

Project Summary/Abstract Despite the widely-recognized importance and complexity of the post-burn hypermetabolic response, the underlying mechanisms by which a thermal injury induces and sustains hypermetabolism for years after the injury are essentially unknown. Recently, adipose tissue has been recognized as an essential player in the induction and persistence of hypermetabolism after burn injury. Like cold stress, burn injury induces the browning of white adipose tissue (WAT), in which subcutaneous WAT converts to a more brown-like adipose termed beige/brite adipose tissue (BAT). These otherwise quiescent beige cells adopt brown-like features, including multilocular lipid droplets and high UCP1 expression. Moreover, browning drives a conversion in mitochondrial function, uncoupling the respiratory chain from ATP synthesis and predominantly producing heat, thereby sending these already hypermetabolic patients into metabolic overdrive. While browning can have beneficial effects in patients with obesity and diabetes, we believe that browning in burn patients fuels high metabolic rates and alters plasma lipid profiles, leading to accelerated development and progression of cachexia, hyperglycemia, and organ steatosis thereby worsening outcomes of severely burned patients. The overarching hypothesis of this proposal is that browning of the adipose tissue is a central process in the pathologic hypermetabolic response, and one of the main mediators of persistent hypermetabolism after burn. This hypothesis will be systematically tested using a series of murine knock outs in our established burn model. The aim of this proposal is to study the mediators, function, consequences and potential treatments of the browning response after burn. The four specific aims (SA’s) are, firstly, to determine the consequences of browning on outcomes after burn (SA 1). Next, we will determine the metabolic and physiologic consequences of browning after burn (SA 2). We will proceed to determine central mediators by which a burn induces browning and hypermetabolism (SA 3) before proceeding to uncover whether therapeutic targeting of browning can improve outcomes after burn (SA 4). In summary, to date, the cellular and molecular mechanisms underlying the post-burn hypermetabolic response have not been identified, and despite improved clinical care, the detrimental sequelae of this response lead to a substantial post-burn morbidity and mortality. In this proposal we will explore the mechanism of induction of beige adipose post-burn, the signals leading from adipose to hypermetabolism, catabolism and dysfunction of various organs, and explore targeted disruptions in these cascades in order to develop specific therapeutics to improve outcomes. Our work will be carried out with a systematic series of murine knock-outs using a validated burn model. This project has value from a basic science standpoint and is highly relevant for patient outcomes.

项目总结/摘要 尽管烧伤后高代谢反应的重要性和复杂性已被广泛认识， 热损伤诱导和维持高代谢的潜在机制， 受伤情况基本上是未知的。最近，脂肪组织已被认为是在肥胖中的重要参与者。 烧伤后高代谢诱导和持续。和冷应激一样，烧伤也会引起 白色脂肪组织（WAT）的布朗宁，其中皮下WAT转化为更类似棕色的脂肪 称为米色/棕色脂肪组织（BAT）。这些原本静止的米色细胞呈现出类似棕色的特征， 包括多室脂滴和高UCP 1表达。此外，布朗宁促使转化为 线粒体功能，从ATP合成中解偶联呼吸链，并主要产生热量， 从而使这些已经高代谢的患者进入代谢紊乱。虽然布朗宁可以 对于肥胖和糖尿病患者的有益效果，我们认为烧伤患者的布朗宁 代谢率和改变血脂谱，导致加速发展和进展， 恶病质、高血糖症和器官脂肪变性，从而使严重烧伤患者的预后恶化。的 该建议的首要假设是脂肪组织的布朗宁是在 病理性高代谢反应，是烧伤后持续高代谢的主要介质之一。 这一假设将系统地测试使用一系列的小鼠敲除在我们建立的烧伤 模型本提案的目的是研究的调解人，功能，后果和潜在的治疗， 烧伤后布朗宁反应。四个具体目标（SA）是，首先，确定 布朗宁对烧伤后结局的影响（SA 1）。接下来，我们将确定代谢和生理后果 烧伤后布朗宁的发生率（SA 2）。我们将继续确定烧伤诱导的中枢介质， 布朗宁和高代谢（SA 3），然后继续揭示是否治疗靶向布朗宁 能改善烧伤后的预后（SA 4）。总之，迄今为止，细胞和分子机制 潜在的烧伤后高代谢反应尚未确定，尽管临床护理有所改善， 这种反应的有害后遗症导致严重的烧伤后发病率和死亡率。在这 建议我们将探讨烧伤后米色脂肪的诱导机制， 脂肪代谢亢进，catastrophic和功能障碍的各种器官，并探讨有针对性的中断， 这些级联，以开发特定的治疗方法，以改善结果。我们的工作将得到开展 使用经验证的烧伤模型进行一系列系统的鼠基因敲除。这个项目的价值来自于 基本科学观点，与患者结局高度相关。