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

生热脂肪抗炎功能治疗代谢紊乱的机制表征

• 批准号: 10554169
• 负责人: Evanna Louisa Mills
• 金额: $ 24.9万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2025-03-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554169
• 关键词: Adipocytes; Adipose tissue; Anti-Inflammatory Agents; Brown Fat; Cardiovascular Diseases; Cell Culture Techniques; Cell membrane; Cell physiology; Cells; Circulation; Coupled; Data; Disease; Environment; Etiology; Fatty acid glycerol esters; G-Protein-Coupled Receptors; Genetic; Glucose Intolerance; Immune; Immune system; Immunology; In Vitro; Inflammation; Inflammatory; Intervention; Knockout Mice; Ligation; Link; Lipids; Malignant neoplasm of liver; Mass Spectrum Analysis; Mediating; Membrane Transport Proteins; Metabolic; Metabolic Diseases; Metabolism; Methods; Mitochondria; Modeling; Molecular; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathogenesis; Pathology; Peripheral; Phenotype; Physiological; Process; Proteins; Research; Research Personnel; Respiration; Risk Factors; Role; Signal Transduction; Signaling Molecule; Stimulus; Succinates; Testing; Therapeutic; Thermogenesis; Tricarboxylic Acids; Visceral; Work; adipocyte biology; diet-induced obesity; experience; experimental study; extracellular; genetic manipulation; in vivo; in vivo Model; liquid chromatography mass spectrometry; liver inflammation; loss of function; metabolic abnormality assessment; metabolic phenotype; molecular phenotype; mouse model; non-alcoholic fatty liver disease; novel therapeutic intervention; obesity treatment; obesogenic; pharmacologic; receptor; skills; success; uptake

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.

项目摘要：肥胖和相关的“元炎”是2型糖尿病的主要危险因素， 心血管疾病，非酒精性脂肪肝病（NAFLD）和癌症。内脏的“白色”肥胖驱动器 这些致命的肥胖后遗症。相反，热的“棕色”和“米色”脂肪可以唯一地分解代谢 储存的脂肪，潜在的抗肥料。热脂肪细胞的抗肥胖活性需要 通过外围信号激活，识别这些信号是利用治疗的关键 这些细胞的潜力。这种热脂肪也被认为是抗炎的，但机械 这不清楚的基础。了解促进这种抗炎功能的机制 热脂肪将具有主要的治疗潜力。热脂肪富含线粒体，产生 许多代谢物，其中许多具有信号能力。有趣的是三核酸 中间琥珀酸酯是一个重要的信号分子，可以控制热脂肪功能和 炎。我发现热脂肪具有独特的能力，可以隔离细胞外 环境（通过不确定的机制）促进生热；免疫细胞表达G蛋白 耦合受体（称为琥珀酸酯受体1），其结扎的结扎可能是促炎的。我假设 热脂肪组织的激活将通过改变水平来促进抗炎表型 已知可以调节免疫细胞功能的重要信号代谢物（例如琥珀酸酯）。而且， 我预测这些信号的操纵将有助于治疗代谢疾病。 目标： 1）热脂肪脂肪中的琥珀酸酯运输机制是什么？ 2）热脂肪极限能否在肥胖驱动的病理中循环琥珀酸酯和炎症？ 3）我们可以操纵热脂肪以修饰NAFLD的病理吗？ 这项工作将使用体外原发性棕色脂肪细胞培养和内脏脂肪膨胀的体内模型 和热生成。这将与液相色谱/质谱法（LCMS），通用性结合 操纵和药物方法来阐明热脂肪与炎症之间的因果关系 信号。我的研究经验为我提供了世界上独特的技能，这将使我 研究脂肪和免疫系统之间的代谢串扰。与Drs一起工作。 chouchani和 Spiegelman是热生成和代谢领域的专家，我将精通研究和 操纵脂肪细胞生物学和LCMS分析以及这些技能将与我的强大背景结合起来 在免疫学上。 DFCI的潜水员和丰富的科学环境为我的热情增添了燃料 我自己是一名独立的调查员，并推动了我的决心，以确保我取得成功。