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

使用基于干细胞的系统了解脂质重塑在调节人类棕色脂肪生成中的作用

• 批准号: BB/X001237/1
• 负责人: Antonio Vidal-Puig
• 金额: $ 102.32万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX001237%2F1
• 关键词: Understanding; role; lipid; remodelling; modulation

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.

棕色脂肪组织是调节体温和能量耗散的重要器官。它的功能已在小鼠身上得到了很好的表征，并且最近引起了对人类的极大兴趣，它显示出一些尚未得到很好表征的独特分子和功能差异。含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，肥胖的胰岛素抵抗糖尿病患者的棕色脂肪数量很少且活性较低。尽管棕色脂肪组织与人类健康具有潜在相关性，但对其利用所需的人类棕色脂肪活化、发育和成熟的了解却可以忽略不计。初步证据揭示了特定类型的脂质在维持干细胞未分化状态方面的重要性以及特定脂质种类对特殊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损害棕色脂肪组织的成功成熟。研究人类棕色脂肪的生物发生有两个主要困难：a）对人类特异性棕色脂肪的分子成分了解不足和b) 人类棕色脂肪的获取有限，因为它很稀缺，并且通常在解剖学上散布在正常的白色脂肪中。我们开发了一种独特的从人类干细胞分化棕色脂肪脂肪细胞的方案，以克服这两个瓶颈。干细胞解决了可扩展性问题，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每个发展阶段都在不断发展，因此这种新颖的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激活中的动态作用的目标，并提供了独特的工具集来优化其通过靶向其脂质代谢来发展。

项目成果

Fuelling the fire: de novo lipogenesis primes thermogenesis

火上浇油：从头脂肪生成引发产热

• DOI: 10.1038/s42255-023-00865-0
• 发表时间: 2023
• 期刊: Nature Metabolism
• 影响因子: 20.8
• 作者: Rodríguez-Fdez S