Obesity, Diabetes and Comorbidities

WAT is a critical metabolic organ that contributes to energy storage, endocrine homeostasis, and metabolic flexibility by efficiently storing the surplus of fuel and quickly mobilising lipids/energy to supply peripheral organs. In the context of the current obesity epidemic, the demands imposed on the expandability and functionality of WAT are paramount, overwhelming WAT capacity to store and mobilise fat promoting the development of metabolic comorbidities.

Whereas most research aims to understand why obese people develop comorbidities, we will study the opposite paradigm, why some obese people are resilient and do not develop comorbidities. Knowing all the molecular layers explaining how to uncouple having excess adiposity from developing metabolic complications is essential to keep obese people healthy. There is plenty of information about the unhealthy inflamed human adipose tissue. Paradoxically, there is a paucity of knowledge about the critical molecular components driving human WAT development and healthy expansion against comorbidities.

Our question is not why obese patients develop comorbidities but how to make them resilient, and we hypothesise that this depends on the mechanisms that keep their adipose tissue healthy irrespectively of its size.

To answer this question we will

• Identify genetic variants associated with increased risk of obesity but have protective cardiometabolic effects, and vice versa.
• Prioritise and genetically mutate the candidate genes using a human stem cell approach and CRIPRs/Cas9 technology
• Validate tin vitro and in vivo the functionality of the candidate genes.

Using the same approaches, we are also interested to prioritise and study candidate genes involved in human brown/beige adipocytes differentiation and activation as a strategy to counteract obesity and metabolic complications.