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

项目摘要：肥胖和相关的“化生炎症”是2型糖尿病的主要危险因素， 心血管疾病、非酒精性脂肪性肝病(NAFLD)和癌症。发自内心的“白人”肥胖症 这些致命的肥胖症后遗症。相比之下，产热的“棕色”和“米色”脂肪可以独特地分解代谢。 储存脂肪，并有效地抗肥胖。生热脂肪细胞的抗肥胖活性需要 外周信号的激活，以及这些信号的识别是利用治疗的关键 这些细胞的潜能。这种生热脂肪也被认为是抗炎的，但机制是 这一点的基础尚不清楚。了解促进这种抗炎作用的机制 生热脂肪将有很大的治疗潜力。生热脂肪富含线粒体，线粒体可产生 大量的代谢物，其中许多具有信号传递能力。有趣的是，三元酸 中间体琥珀酸酯是一种重要的信号分子，它控制着生热脂肪的功能和 发炎。我发现，生热脂肪有一种独特的能力，可以将琥珀酸从细胞外隔离出来。 环境(通过未明确的机制)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作用。我假设 热源性脂肪组织的激活将通过改变水平来促进抗炎表型。 重要的信号代谢物，如琥珀酸，已知可调节免疫细胞功能。此外， 我预测，操纵这些信号将有助于新陈代谢疾病的治疗。 目标： 1)致热脂肪中琥珀酸的转运机制是什么？ 2)在肥胖驱动的病理中，热源性脂肪能否限制循环中的琥珀酸和炎症？ 3)我们能否通过操控生热脂肪来改变NAFLD的病理？ 这项工作将使用体外原代棕色脂肪细胞培养和体内内脏脂肪膨胀模型。 和生热作用。这将与液-色/质谱(LC-MS)、基因 操作和药理学方法来阐明热源性脂肪和炎症之间的因果关系 发信号。我的研究经验为我提供了世界上独一无二的技能，这将使我 研究脂肪和免疫系统之间的代谢串扰。与Chouchani博士和 斯皮格曼，生热和新陈代谢领域的专家们，我将精通这项研究和 掌握脂肪细胞生物学和LC MS分析以及这些技能将与我强大的背景相结合 在免疫学方面。DFCI多样化和丰富的科学环境为我建立 我作为一名独立的调查员，并促使我下定决心确保我的调查取得成功。

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.