Understanding the role of lipid remodelling in the modulation of human brown adipogenesis using a stem cell-based system

棕色脂肪组织是调节体温和能量耗散的重要器官。它的功能在小鼠中得到了很好的表征，最近在人类中引起了极大的兴趣，在人类中它显示出一些独特的分子和功能差异，但没有得到很好的表征。拥有大量棕色脂肪的人患糖尿病的风险较低，甘油三酯水平较低，脂肪分布更健康。相反，肥胖的胰岛素抵抗型糖尿病患者的棕色脂肪量少，活性低。尽管棕色脂肪组织与人类健康的潜在相关性，有关人类棕色脂肪的激活，开发和成熟所需的知识是微不足道的。最初的证据已经揭示了特定类型的脂质在维持干细胞未分化状态中的重要性，以及特定脂质种类对特化细胞类型分化的贡献。肥胖患者在脂肪细胞中表现出改变的脂质重塑特征，我们认为这些改变可能会影响棕色脂肪组织的成功成熟。研究人类棕色脂肪的生物合成有两个主要困难：a）对人类特有的棕色脂肪的分子成分了解不足，以及B）由于人类棕色脂肪稀少，并且通常在解剖学上散布在正常的白色脂肪中，因此限制了对人类棕色脂肪的获取。从人类干细胞分化来克服这两个瓶颈。干细胞解决了可扩展性的问题，提供了足够的人类棕色脂肪进行研究。此外，由于我们开发的方案在开发的每个阶段都在发展，这种新方法首次成功实现了我们阐明脂质在人类棕色脂肪细胞分化和活化中的动态作用的目标，并提供了一种独特的工具集，通过靶向其脂质代谢来优化其开发。

Brown adipose tissue is an essential organ for regulating body temperature and energy dissipation. Its function has been well characterised in mice and has recently attracted enormous interest in humans, where it shows some unique molecular and functional differences not well characterised. Individuals with substantial amounts of brown fat have a lower risk of diabetes, lower triglyceride levels and a healthier fat distribution. Conversely, obese insulin-resistant diabetic patients have few amounts and less active brown fat.Despite the potential relevance of brown adipose tissue to human health, the knowledge about human brown fat activation, development and maturation required for its exploitation is negligible. Initial evidence has revealed the importance of a specific type of lipids in maintaining an undifferentiated state in stem cells and the contribution of particular lipid species to the differentiation of specialised cell types. Obese patients exhibit altered lipid remodelling profiles in adipocytes, and we posit that these alterations may compromise successful brown adipose tissue maturation.There are two main difficulties to studying brown fat biogenesis in humans: a) insufficient knowledge about human-specific brown fat's molecular components and b) limited access to human brown fat because it is scarce and typically anatomically interspersed within the normal white fat.We have developed a unique protocol of brown fat adipocyte differentiation from human stem cells to overcome these two bottlenecks. Stem cells solve the problem of scalability, providing enough human brown fat to investigate. Also, because the protocol we have developed evolves through every stage of development, this novel approach enables for the first time the success in our objective of elucidating the dynamic role of lipids in human brown adipocytes differentiation and activation and provides a unique toolset to optimise its development by targeting its lipid metabolism.