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

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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.