Descripción del proyecto
Dinámica multinivel de la hipertrofia adipocitaria
La hipertrofia adipocitaria es una enfermedad asociada con cuerpos lipídicos (orgánulos de los adipocitos que almacenan energía en forma de triglicéridos) más grandes de lo normal. La hipertrofia adipocitaria es independiente de la grasa corporal y provoca una amplia gama de procesos patológicos, que incluyen las enfermedades cardiometabólicas. El objetivo del proyecto SPHERES, financiado con fondos europeos, es investigar la hipótesis de que las alteraciones en la interacción entre las proteínas de los cuerpos lipídicos y la composición de los lípidos de los cuerpos lipídicos conducen a la hipertrofia adipocitaria. Dirigido por una red multidisciplinar de expertos, el proyecto desarrollará modelos y métodos punteros para estudiar la formación y el mantenimiento de los cuerpos lipídicos de adipocitos grandes. El trabajo allanará el camino para comprender mejor los mecanismos subyacentes de la hipertrofia adipocitaria, así como para identificar las estrategias terapéuticas dirigidas a los adipocitos.
Objetivo
The goal of SPHERES is to understand the dynamics and consequences of adipocyte hypertrophy (enlargement) through investigation of its large lipid droplet (LD). The adipocyte LD is a unique organelle specialized in storing energy in triglycerides (TGs). Its surface is composed of a phospholipid monolayer and specific LD-associated proteins (such as perilipins, CIDEs and lipases), which jointly regulate LD stability and TG turnover. Adipocyte hypertrophy due to an increase in LD size may, irrespective of body fat mass, cause a wide range of pathological conditions, notably cardiometabolic diseases. SPHERES PIs (Langin, Rydén, Antonny) postulate that disturbances in the interactions between LD proteins and LD lipid composition lead to adipocyte hypertrophy and its deleterious consequences. We have identified three fundamental unanswered questions: what determines the unique structure and dynamics of large LD; why does increased LD size alter the functional phenotype of the adipocyte; which factors cause inter-individual variations in LD size. To address these questions, SPHERES gathers expertise in clinical and cellular studies on human adipocytes, in/ex vivo investigations in mouse models, and biophysical analyses of LDs. At the core of this application is the development of beyond-state-of-the-art models and methods (spheroid cultures, native large LD preparation and reconstitution, proximity labelling of LD proteins, gene editing in cell and mouse models, and advanced LD imaging), only achievable through joint integrated effort of the PIs and co-workers. Spanning from molecular, cellular to the whole-body level, SPHERES will link new knowledge on the formation and maintenance of large adipocyte LDs to the deleterious impact of adipocyte hypertrophy. Altogether, SPHERES has a strong potential to discover novel pathogenic mechanisms, leading to a better understanding of highly prevalent diseases and identification of therapeutic strategies targeting adipocytes.
Ámbito científico
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Régimen de financiación
ERC-SyG - Synergy grantInstitución de acogida
31062 Toulouse Cedex 9
Francia