IMPC - Understanding the role of 18kDa Translocator protein (TSPO) in the regulation of energy homeostasis in mice

IMPC - 了解 18kDa 易位蛋白 (TSPO) 在小鼠能量稳态调节中的作用

• 批准号: MR/R014345/1
• 负责人: Kate Ellacott
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR014345%2F1
• 关键词: IMPC; Understanding; role; 18kDa; Translocator

Obesity is a global health problem that impacts greater than 25% of the adult population in the UK costing the NHS an estimated £4.2billion per year. Current treatments for obesity are limited and the development of effective drug therapies is hampered by our limited understanding of drivers of obesity on a molecular level.Obesity is essentially caused by an imbalance in energy in the body: typically when more energy is available from food than is needed. The extra energy is stored as fat in white adipose tissue (WAT). WAT is composed of multiple cell types including adipocytes (the fat storing cells) and immune cells such as macrophages. Various macrophage subtypes exist, depending on the molecules that they contain, which enable them to perform different functions. Macrophages are flexible and can switch subtype depending on the local microenvironment; in WAT, they are normally "M2-like", a subtype which helps to regulate the normal WAT function.Most people have some energy reserves in the form of WAT; however, the large energy excess in obesity expands adipocyte fat storage until they cannot cope - which leads to the cells becoming stressed and eventually dying. This cell death causes secretion of chemical signalling molecules, called cytokines, which attract more macrophages into WAT and change the predominant subtype of WAT macrophages to "M1-like". This process of cytokine secretion and macrophage recruitment to WAT in obesity is similar to what is seen in response to injury or infection in other organs of the body and is part of what is known as an inflammatory response. Short-term inflammation is usually helpful to promote healing and restore normal tissue function. Inflammation normally stops when a tissue heals and/or the infection is cleared by immune cells. However, if inflammation becomes chronic, it can cause significant damage. Long-term WAT inflammation in obesity impairs how organs respond to insulin, the hormone which controls blood sugar levels, leading to type-2 diabetes (T2D). All cells in the body require energy to function, coordinated by structures called mitochondria- the power house of the cell. Cells can make energy from different nutrients including sugars (by a process called glycolysis) and fats (by a process called fatty acid oxidation [FAO]); the overall process is called metabolism. Over the last few years scientists have discovered that changing metabolism in macrophages can alter their subtype. "M1-like" macrophages tend to break down sugar by glycolysis. In contrast, "M2-like" macrophages prefer to get their energy by FAO. The goal of this research project is to find out whether altering metabolism in these cells can help combat obesity and T2D by reducing inflammation. We have discovered that a molecule called Translocator protein (TSPO), present in mitochondria is found at higher levels in macrophages in WAT of obese mice compared with lean mice. The function of TSPO is not fully understood but it can regulate metabolism in some cell types. Drugs which inhibit TSPO are also known to be anti-inflammatory. We think that TSPO may be a functional link between inflammation and metabolism in obesity. This project will address the following questions: 1) Are mice which cannot make TSPO protected from obesity and WAT inflammation when given a high-fat diet which normally causes obesity?; 2) Do macrophages obtained from mice lacking TSPO show changes in their metabolism?; and 3) Do macrophages from mice lacking TSPO have the ability to change into the different macrophage subtypes?By answering these questions we will begin to understand whether TSPO could be a potential drug target to reduce obesity-associated WAT inflammation. If this pilot project is successful, we will work with a chemist who makes novel drugs which target TSPO to validate the results from these initial studies and investigate further the effectiveness of targeting TSPO function as a therapy for obesity.

肥胖是一个全球健康问题，影响英国成年人口的25％以上，估计每年42亿英镑。当前对肥胖症的治疗受到限制，有效的药物疗法的发展受到我们对肥胖驱动因素在分子水平上的有限理解的阻碍。肥胖基本上是由于体内能量失衡而引起的：通常，当食物中获得的能量比所需的能量更多时。额外的能量作为脂肪存储在白色脂肪组织（WAT）中。 WAT由多种细胞类型组成，包括脂肪细胞（脂肪存储细胞）和免疫细胞，例如巨噬细胞。存在各种巨噬细胞亚型，具体取决于它们所包含的分子，从而使它们能够执行不同的功能。巨噬细胞是灵活的，可以根据当地微环境切换亚型。在WAT中，它们通常是“ M2样”，这是一种亚型，有助于调节正常的WAT功能。大多数人以WAT形式有一些能源储备。然而，肥胖症中超过的大能量会扩大脂肪细胞脂肪的储存，直到无法应对为止 - 这会导致细胞变得压力并最终死亡。这种细胞死亡会导致化学信号分子的分泌，称为细胞因子，该分子吸引了更多的巨噬细胞进入WAT，并将主要的WAT巨噬细胞亚型改变为“ M1样”。对拥有的WAT的细胞因子分泌和巨噬细胞募集的过程类似于响应体内其他器官的损伤或感染，这是所谓的炎症反应的一部分。短期感染通常有助于促进愈合和恢复正常的组织功能。当组织愈合和/或感染被免疫细胞清除时，通常会停止炎症。但是，如果感染变得慢性，则可能造成重大损害。肥胖症中的长期WAT炎症会损害器官对控制血糖水平的胰岛素的反应，导致2型糖尿病（T2D）。体内的所有细胞都需要能量发挥作用，并由称为线粒体的结构协调 - 细胞的动力室。细胞可以从包括糖（称为糖酵解的过程）和脂肪（通过称为脂肪酸氧化的过程[FAO]的过程中）从不同营养物质中产生能量；总体过程称为代谢。在过去的几年中，科学家发现，巨噬细胞中的代谢改变会改变其亚型。 “ M1样”巨噬细胞倾向于通过糖酵解分解糖。相比之下，“类似M2的”巨噬细胞更喜欢通过粮农组织获得能量。该研究项目的目的是找出这些细胞中的新陈代谢改变是否可以通过减少注入来帮助肥胖和T2D。我们已经发现，与瘦小小鼠相比，在肥胖小鼠的巨噬细胞中发现了一种称为易位蛋白（TSPO）的分子，该分子在线粒体中存在。 TSPO的功能尚未完全了解，但可以调节某些细胞类型的代谢。抑制TSPO的药物也被称为抗炎。我们认为TSPO可能是肥胖症中炎症与代谢之间的功能联系。该项目将解决以下问题：1）当给予通常会引起肥胖症的高脂饮食时，小鼠无法保护TSPO免受肥胖和WAT炎症的影响； 2）从缺乏TSPO的小鼠获得的巨噬细胞显示其代谢变化？ 3）缺乏TSPO的小鼠的巨噬细胞能够变成不同的巨噬细胞亚型？通过回答这些问题，我们将开始理解TSPO是否可以成为减少肥胖相关的WAT注射的潜在药物靶标。如果该试点项目成功，我们将与化学家合作，该化学家生产新型药物，以TSPO验证这些初步研究的结果，并进一步研究靶向TSPO功能作为肥胖症治疗的有效性。