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

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.

Having active brown adipose tissue (BAT) correlates with a low risk of diabetes, lower blood pressure, lower triglyceridaemia and a healthier fat distribution. Thus, activating BAT is a promising and safe option to treat obesity and associated cardiometabolic comorbidities. However, several hurdles need to be overcome first: (1) the translational limitations of current knowledge of BAT physiology predominantly learned from mice and (2) inaccessibility to reliable human BAT for experiments given the limited amounts in obese and diabetic patients.
This project's big aim is to elucidate the unique role played by lipids in regulating BAT differentiation in humans. This innovative focus is enabled by the unique convergence of expertise in lipid metabolism and BAT stem cell differentiation and activity. We will define how lipid composition changes and specifically adapts throughout differentiation and how relevant this dynamic regulation is to promote the progression through the specific maturation stages. This information is critical to promoting BAT differentiation (and activation) and understanding how lipid composition alterations during obesity may prevent differentiation. Our data might reveal distinctive lipid signatures that are valid as a biomarker of the brown adipocyte's differentiation stage or thermogenic potential that is useful for precision medicine approaches to build thermogenic capacity.
We have developed a unique tool, a protocol to generate BAT from human stem cells that follows the physiological progression through every stage of development. We will use a multi-omics approach including proteomics, lipidomics and metabolomics at each stage of the differentiation coupled with selective perturbational analyses at crucial development stages to elucidate the dynamic role of lipid remodelling in BAT differentiation. The most promising targets for drug intervention will be further validated using human physiological data from a well-characterised cohort.