General overview of the project

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.

What is SPHERES? (A) We aim to fill in the gap between understanding the mechanisms that govern LD size/dynamics and the function of white adipocytes, whose hypertrophy causes cardiometabolic diseases. (B) We will merge our expertise, including: generating big data sets from patients, manipulating LD genes in mice, mastering a unique spheroid system to mimic the unilocular white adipocyte, and recapitulating the lipid-protein interactions. (C) A striking example of LD size control by an LD specific protein, PLIN4 (taken from 3). (D) Lipidomics allows precise analyses of lipids in LDs under experimental conditions, here a specific fatty acid diet. (E-F) Human white adipocyte spheroids generated by V. Lauschke (Large images: H&E staining; small images: bright field) and their transcriptomic characterization.