Mechanistic characterization of the anti-inflammatory function of thermogenic fat for the treatment of metabolic disorders

项目概述：肥胖和相关的“炎症”是2型糖尿病的主要危险因素， 心血管疾病、非酒精性脂肪肝（NAFLD）和癌症。内脏“白色”肥胖驱动 这些致命的肥胖后遗症。相比之下，产热的“棕色”和“米色”脂肪可以独特地分解代谢 储存的脂肪，并有效地抗肥胖。产热脂肪细胞的抗肥胖活性需要 通过外周信号激活，这些信号的识别是利用治疗药物的关键。 这些细胞的潜力。这种产热脂肪也被认为是抗炎的，但其机制是， 其依据尚不清楚。了解促进这种抗炎功能的机制， 产热脂肪将具有重要的治疗潜力。产热脂肪富含线粒体， 大量的代谢物，其中许多具有信号传导能力。有趣的是， 中间体琥珀酸是一种重要的信号分子，其控制产热脂肪功能， 炎症我发现，产热脂肪有一种独特的能力，从细胞外螯合琥珀酸 环境（通过未定义的机制）促进产热;而免疫细胞表达G蛋白 偶联受体（称为琥珀酸受体1），其连接是有效的促炎性。我假设 产热脂肪组织的激活将通过改变 已知可以调节免疫细胞功能的重要信号代谢物，例如琥珀酸。此外，委员会认为， 我预测这些信号的操纵将有助于代谢疾病的治疗。 目的： 1)产热脂肪中琥珀酸盐的转运机制是什么？ 2)产热脂肪能限制循环琥珀酸和肥胖导致的炎症吗？ 3)我们能操纵产热脂肪来改变NAFLD的病理吗？ 这项工作将使用体外原代棕色脂肪细胞培养和内脏脂肪扩张的体内模型 和产热作用。这将与液相色谱/质谱法（LCMS）、遗传学 操作和药理学方法来阐明产热脂肪和炎症之间的因果关系 发信号。我的研究经验给了我一套世界上独一无二的技能， 来研究脂肪和免疫系统之间的代谢交互作用。与Chouchani博士一起工作， Spiegelman，产热和代谢领域的专家，我将成为精通的研究和 脂肪细胞生物学和LCMS分析的操作，这些技能将与我强大的背景相结合 在免疫学上。DFCI多样化和丰富的科学环境增加了我建立 我是一个独立的调查员，我决心确保我能成功。

PROJECT SUMMARY: Obesity and associated “meta-inflammation” are major risk factors for type-2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and cancers. Visceral “white” adiposity drives these deadly sequelae of obesity. In contrast, thermogenic “brown” and “beige” adipose can uniquely catabolize stored fat, and are potently anti-obesogenic. The anti-obesity activity of thermogenic adipocytes requires activation by peripheral signals, and the identification of these signals is key to leveraging the therapeutic potential of these cells. Such thermogenic adipose is also thought to be anti-inflammatory but the mechanistic basis of this is unclear. Understanding the mechanisms that promote this anti-inflammatory function of thermogenic fat would have major therapeutic potential. Thermogenic fat is rich in mitochondria which produce a vast array of metabolites, many of which possess signaling capacity. Interestingly the tricarboxylic acid intermediate succinate is an important signaling molecule that controls both thermogenic adipose function and inflammation. I identified that thermogenic fat has a unique capacity to sequester succinate from the extracellular milieu (through an undefined mechanism) to promote thermogenesis; while immune cells express a G-protein coupled receptor (termed succinate receptor 1), the ligation of which is potently pro-inflammatory. I hypothesize that activation of thermogenic adipose tissue will promote an anti-inflammatory phenotype by altering the levels of important signaling metabolites, such as succinate, that are known to regulate immune cell function. Moreover, I predict manipulation of these signals will aid in the treatment of metabolic disease. Objectives: 1) What is the succinate transport mechanism in thermogenic fat? 2) Can thermogenic fat limit circulating succinate and inflammation in obesity-driven pathologies? 3) Can we manipulate thermogenic fat to modify the pathology of NAFLD? This work will use both in vitro primary brown fat cell culture and in vivo models of visceral adipose expansion and thermogenesis. This will be coupled with liquid-chromatography/mass spectrometry (LCMS), genetic manipulation, and pharmacological methods to clarify the causality between thermogenic fat and inflammatory signaling. My research experience has afforded me with a skill set that is unique in the world, that will allow me to study the metabolic cross-talk between the adipose and immune systems. Working with Drs. Chouchani and Spiegelman, experts in the fields of thermogenesis and metabolism, I will become proficient in the study and manipulation of adipocyte biology and LCMS analysis and these skills will be coupled with my strong background in immunology. The diverse and rich scientific environment at DFCI adds fuel to my enthusiasm to establish myself as an independent investigator and drives my determination to ensure that I make a success of it.