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

肥胖是一个全球性的健康问题，影响英国超过25%的成年人口，每年花费NHS估计42亿英镑。目前治疗肥胖症的方法有限，有效药物治疗的发展受到我们在分子水平上对肥胖症驱动因素的有限理解的阻碍。肥胖症本质上是由体内能量失衡引起的：通常是当食物中的能量超过所需时。多余的能量以脂肪的形式储存在白色脂肪组织（WAT）中。WAT由多种细胞类型组成，包括脂肪细胞（脂肪储存细胞）和免疫细胞，如巨噬细胞。存在各种巨噬细胞亚型，这取决于它们所包含的分子，这使它们能够执行不同的功能。巨噬细胞是灵活的，可以根据局部微环境切换亚型;在WAT中，它们通常是“M2样”，一种有助于调节正常WAT功能的亚型。大多数人都有一些WAT形式的能量储备;然而，肥胖症中大量的能量过剩会扩大脂肪细胞的脂肪储存，直到它们无法科普-这导致细胞变得紧张，最终死亡。这种细胞死亡导致化学信号分子的分泌，称为细胞因子，其吸引更多的巨噬细胞进入WAT并将WAT巨噬细胞的主要亚型改变为“M1样”。肥胖症中细胞因子分泌和巨噬细胞募集到WAT的过程类似于身体其他器官中对损伤或感染的反应，并且是所谓的炎症反应的一部分。短期炎症通常有助于促进愈合和恢复正常组织功能。当组织愈合和/或感染被免疫细胞清除时，炎症通常会停止。然而，如果炎症变成慢性，它可能会造成重大损害。肥胖症的长期WAT炎症损害器官对胰岛素的反应，胰岛素是控制血糖水平的激素，导致2型糖尿病（T2 D）。身体中的所有细胞都需要能量来运作，由称为线粒体的结构协调-细胞的动力室。细胞可以从不同的营养物质中产生能量，包括糖（通过一种称为糖酵解的过程）和脂肪（通过一种称为脂肪酸氧化的过程）;整个过程称为新陈代谢。在过去的几年里，科学家们发现，改变巨噬细胞的新陈代谢可以改变它们的亚型。“M1样”巨噬细胞倾向于通过糖酵解分解糖。相比之下，“M2样”巨噬细胞更喜欢通过FAO获得能量。该研究项目的目标是找出改变这些细胞的代谢是否可以通过减少炎症来帮助对抗肥胖和T2 D。我们发现，与瘦小鼠相比，肥胖小鼠WAT中的巨噬细胞中线粒体中存在一种称为转运蛋白（TSPO）的分子。TSPO的功能尚未完全了解，但它可以调节某些细胞类型的代谢。抑制TSPO的药物也已知是抗炎的。我们认为TSPO可能是肥胖症炎症和代谢之间的一个功能性联系。该项目将解决以下问题：1）当给予通常导致肥胖的高脂肪饮食时，不能产生TSPO的小鼠是否免受肥胖和WAT炎症的影响？2)从缺乏TSPO的小鼠获得的巨噬细胞是否显示其代谢的变化？缺乏TSPO的小鼠巨噬细胞是否具有转化为不同巨噬细胞亚型的能力？通过回答这些问题，我们将开始了解TSPO是否可能成为减少肥胖相关WAT炎症的潜在药物靶点。如果这个试点项目成功，我们将与一位制造靶向TSPO的新药的化学家合作，以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方法的有效性。

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.