SPHERES is a 6-year project funded by the ERC Synergy Grant. He gathers three principal investigators and their networks: Dominique Langin, Mikael Rydén, Bruno Antonny…..

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). 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 principle investigators postulate that disturbances in the interactions between LD proteins and LD lipid composition lead to adipocyte hypertrophy and its deleterious consequences.

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The objectives of SPHERES are:
To decipher the mechanisms governing adipocyte unilocular LD growth and shrinkage;
To identify the major protein and lipid determinants of adipocyte LD dynamics;
To determine the factors explaining interindividual variations in adipocyte LD size.
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Three fundamental questions remain unanswered:
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 interindividual 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 project 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). 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.
Main project hypothesis & objectives
In humans, fat cell hypertrophy has emerged as the central adipose parameter associated with metabolic and cardiovascular complications. The volume of the unilocular LD is the main determinant of adipocyte size. Furthermore, the LD is a complex organelle that determines adipocyte lipid turnover, the latter being casually linked to a number of relevant metabolic disturbances. We therefore hypothesize that the molecular determinants of adipocyte LD size explain the pernicious impact of adipocyte hypertrophy.
Through the development of beyond-state-of-the-art models and methods as well as use of the most advanced technologies in our respective fields, the objectives of SPHERES are:
- to decipher the mechanisms governing adipocyte unilocular LD growth and shrinkage;
- to identify the major protein and lipid determinants of adipocyte LD dynamics;
- to determine the factors explaining inter-individual variations in adipocyte LD size.
By addressing these points, we will obtain novel insights and a significantly better understanding of how LD hypertrophy impacts adipocyte dysfunction and the consequences thereof at the wholebody level (B1 Fig. 1).
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