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Molecular Oncology Programme

Metabolism and Cell Signaling Group

Group Leader:  Alejo Efeyan
Research highlights

Mammals, including humans, have evolved in an environment where the ability to efficiently use limiting nutrient sources has been a key survival adaptation that has shaped all our responses to nutrients. Unprecedented nutrient overabundance is in conflict with our cellular and organismal responses, which are best tuned to operate under scarcity. These aberrant responses not only lie at the core of the pathogenesis of the metabolic alterations observed in diabetes, but are also key in cancer and the process of ageing. We use genetically engineered strains of mice as a physiological framework to understand the molecular bridges from elevated nutrient levels to human disease. In particular, we have genetically modified the RagA and RagC GTPases, key players in the sensing of nutrients that activate a master regulator of metabolism, a kinase called mTOR. Mice with gain-of-function mutations in RagA − therefore unable to sense a drop in nutrient levels − have an increased glycaemia in spite of a normal food intake and decreased adiposity. Furthermore, these mice show intolerance to glucose, which means that when glucose is administered it remains in the circulation, and peripheral organs (such as liver and skeletal muscle) are unable to uptake it. These perturbations are tightly associated with the development of type 2 diabetes. Indeed, when we examined the ability of peripheral tissues to respond to insulin we observed an impaired response to insulin, also known as insulin resistance, which leads to increased levels of glucose in circulation. We are currently characterising other metabolic imbalances observed in these mice and are performing a genetic dissection of these alterations by deregulating nutrient sensing in an organ-specific manner.