Innate Immune Mechanisms of Thermogenesis

项目摘要/摘要 肥胖是一种由能量摄入和能量消耗长期失衡引起的疾病 一些慢性病的独立危险因素，包括2型糖尿病、冠状动脉疾病、 脂肪肝、神经退行性疾病和一些癌症。简单地说，有两个主要的 对抗肥胖的方法：减少能量摄入或增加能量消耗。最新的发现 冷诱导的棕色/米色脂肪在人类中的作用引起了人们对其治疗作用的极大兴奋 以人类为靶点。然而，我们目前对允许产热的信号通路的了解 棕色/米色脂肪组织非常有限。 这个应用程序建立在我们的新发现基础上，免疫信号许可棕色的生热程序 小鼠脂肪组织。我们将利用小鼠遗传学、免疫学、基因组学和 新陈代谢以剖析免疫信号调节棕色产热的潜在机制 脂肪组织。我们将解决的三个具体问题是：1)通过 哪些免疫信号允许棕色脂肪细胞产热？2)细胞信号是什么？ 免疫调节棕色脂肪细胞非偶联呼吸的途径？以及3)免疫是如何 信号调节线粒体蛋白表达和呼吸？这些目标的成功实现将 为调节棕色脂肪热生成的细胞和分子途径提供了新的见解，从而 促进我们对如何通过治疗靶向这种组织来治疗人类肥胖和 2型糖尿病。

Project Summary/Abstract Obesity, which results from prolonged imbalance between energy intake and energy expenditure, is an independent risk factor for a number of chronic diseases, including type 2 diabetes, coronary artery disease, fatty liver disease, neurodegenerative disorders, and a number of cancers. Simplistically, there are two major ways of combating obesity: to decrease energy intake or to increase energy expenditure. The recent discovery of cold-induced brown/beige fat in humans has generated a great deal of excitement for its therapeutic targeting in humans. However, our current knowledge of the signaling pathways that license thermogenesis in brown/beige adipose tissue is very limited. This application builds on our new discoveries that immune signals license the thermogenic programs in brown adipose tissue of mice. We will utilize techniques from mouse genetics, immunology, genomics, and metabolism to dissect the underlying mechanisms by which immune signals regulate thermogenesis in brown adipose tissue. The three specific questions we will address are: 1) What are the physiologic mechanisms by which immune signals license thermogenesis in brown adipocytes?, 2) What are the cellular signaling pathways by which immunity regulates uncoupled respiration in brown adipocytes?, and 3) How do immune signals regulate mitochondrial protein expression and respiration? The successful completion of these aims will provide novel insights into cellular and molecular pathways that regulate brown fat thermogenesis, thus advancing our understanding of how to therapeutically target this tissue for the treatment of human obesity and type 2 diabetes.