Establishing the link between fat cell dysfunction and cardiometabolic diseases.
Funded by a prestigious Synergy grant from the European Research Council (ERC) in 2019, SPHERES officially started last September for 6 years. Its objective is to understand the dynamics and consequences of the increase in the size of adipose cells by studying a part of their structure called lipid droplets.
Discover Dominique Langin’s interview, Professor at Toulouse III - Paul Sabatier University and future Director of the Institute of Metabolic and Cardiovascular Diseases (I2MC), one of the three project investigators.
Q : The SPHERES project, laureate of the ERC Synergy Grant call, brings together 3 principal investigators, yourself and Bruno Antonny, CNRS Researcher at the Institute of Molecular and Cellular Pharmacology in Nice and Professor Mikael Rydén from the Karolinska Institute in Sweden. Can you tell us how your collaboration was born and why you decided to carry out this project together?
A : Two years before applying for the ERC Synergy grant, I initiated discussion with Prof. Peter Arner and Prof. Mikael Rydén from the Karolinska Institute in Stockholm. We envisaged several outstanding questions in the field of adipose tissue biology that would require a combined approach of laboratories with complementary skills. From the various scenarii we discussed, one issue appeared of high clinical relevance and unresolved, the larger the fat cells in adipose tissue the higher the risk of developing cardiometabolic diseases. The size of the fat cell is determined by the growth of the lipid droplet, a cellular bag filled with energy-rich triglycerides. The laboratories in Stockholm and Toulouse brought expertise in human and animal work as well as unique cell models. But we were lacking competencies in biochemistry and biophysics. I had met Dr. Bruno Antonny at a conference in Paris where he showed the pioneering work of his laboratory at Sophia-Antipolis on lipid-protein interactions in cell membranes. The unique large lipid droplet of the fat cell was a puzzle to him and a fascinating challenge.
A : In Toulouse, Stockholm and Sophia-Antipolis, we sought the best experts that will help us to go beyond-state-of-the-art in clinical translational adipose research, murine metabolic studies and lipid membrane biochemistry and biophysics. Our approach was to built networks that went beyond our own laboratories both in our home cities but also in other places such as Paris in Montpellier. To address the objectives of this synergy grant, the collaborators have a very large range of expertise both technical and conceptual. Altogether, around 30 scientists are working on SPHERES. The number will increase with recruitments of doctoral and post-doctoral fellows as well as engineers and technicians. We also hired a project manager who coordinate the administrative and financial aspects of the project, in collaboration with the PIs and the administrative staff in UT3, KI and CNRS.
Q : The aim of this study is to understand the dynamics and consequences of the increase in the size of adipose cells by studying a part of their structure called the lipid droplet. Can you explain to us what a lipid droplet is, what it is used for and why you have made it your subject of study?
A : Within many cells in our body, lipids are stored in specialized structures called lipid droplets. The fat cell also called adipocyte is unique as it is the cell specialized in storing energy as triglycerides, energy-rich lipids. Compared to other cells, the fat cell has a unique very large lipid droplet. Whereas lipid droplets have been studied in various cell types, little is known on the dynamics of the large lipid droplet of the fat cell. We identified three fundamental unanswered questions. The structure of the surface composed of phosplipids and proteins is very imperfectly described. The determinants of the enlargement are to be characterized. Finally, the factors causing inter-individual variations in human lipid droplet size have to be identified.
Q : The ERC Synergy Grants fund research projects to address the major scientific challenges of our society: what is the major societal challenge of the SPHERES project?
A : Cardiometabolic diseases encompass a wide range of disorders, eg diabetes, dyslipidemia, fatty liver, cardiovascular disorders,... which prevalence increases worldwide along with the increasing number of obese and overweight individuals. We postulate that dysfunction in fat tissues is a common denominator of this array of troubles. An established predictor of cardiometabolic diseases is the size of the fat cells. As the size is determined by the growth and shrinkage of the unique lipid droplet, we proposed the SPHERES project to the ERC. We were baffled and delighted to pass all the stringent steps of evaluation. SPHERES is a fantastic challenge that will mobilize our energies for the next 6 years.
