Periodic Reporting for period 3 - SPHERES (Lipid droplet hypertrophy : the link between adipocyte dysfunction and cardiometabolic diseases)
Reporting period: 2023-09-01 to 2025-02-28
The SPHERES consortium studies how fat cells (adipocytes) and their storage structures, called lipid droplets, work and how they influence diseases like obesity, diabetes, and heart conditions—the leading causes of death worldwide. Enlarged fat cells, a hallmark of these diseases, are poorly understood, and SPHERES aims to uncover the reasons behind this to develop better treatments.
Using advanced scientific tools, SPHERES has made key discoveries. Researchers have identified how specific proteins (PLIN isoforms) associate to different lipid droplets according the speed at which they form. They’ve also shown that a key enzyme, hormone-sensitive lipase (HSL), has vital roles in fat development beyond breaking down fat. Other breakthroughs include understanding short-chain triglycerides (a type of fat) and their quick breakdown in cells, as well as the importance of fat breakdown in brown fat for heat production.
Additionally, SPHERES discovered unique enzymes, and developed long-lasting fat cell precursors that improve fat cell studies. By unraveling these mechanisms, SPHERES is paving the way for innovative treatments to improve metabolic health, reduce disease rates, and lessen the global burden of these chronic conditions.
Using advanced scientific tools, SPHERES has made key discoveries. Researchers have identified how specific proteins (PLIN isoforms) associate to different lipid droplets according the speed at which they form. They’ve also shown that a key enzyme, hormone-sensitive lipase (HSL), has vital roles in fat development beyond breaking down fat. Other breakthroughs include understanding short-chain triglycerides (a type of fat) and their quick breakdown in cells, as well as the importance of fat breakdown in brown fat for heat production.
Additionally, SPHERES discovered unique enzymes, and developed long-lasting fat cell precursors that improve fat cell studies. By unraveling these mechanisms, SPHERES is paving the way for innovative treatments to improve metabolic health, reduce disease rates, and lessen the global burden of these chronic conditions.
The SPHERES ERC Synergy consortium has significantly advanced our understanding of fat tissue (adipose) biology and its role in metabolic health. The project began with the development of cutting-edge models, including 3D adipocyte spheroids, which better mimic fat cells’ natural behavior compared to traditional 2D cultures. These innovations have deepened insights into lipid droplet (LD) dynamics and the diversity of adipocyte subtypes.
Key achievements include creating the Lipid Droplet Knowledge and Adipose Tissue Knowledge Portals, two central resources for LD and adipose tissue data, and applying CRISPR/Cas9 gene editing to produce precise models for studying adipose biology. The team identified distinct subtypes of white adipocytes with unique insulin responses, highlighting the complexity of adipose tissue and its impact on metabolic health. Proteomic and imaging advances have mapped molecular networks within fat cells, while studies clarified how perilipin proteins (PLINs) regulate LD stability and function.
Research also revealed that hormone-sensitive lipase (HSL) plays essential roles beyond fat breakdown, particularly in fat tissue development, using innovative knockout models. Explorations of short-chain triglycerides (TGs) uncovered their rapid breakdown at LD surfaces, which influences cellular metabolism. In brown fat, studies showed that intracellular fat breakdown is vital for heat production, identifying therapeutic targets for metabolic diseases.
Additionally, SPHERES discovered PLCXD1, a novel enzyme involved in adipocyte metabolism, and developed immortalized CD55+ precursor cells for advanced studies of adipocyte diversity. Together, these breakthroughs pave the way for new treatments targeting obesity, diabetes, and related conditions, demonstrating SPHERES’ potential to bridge science and clinical care.
Key achievements include creating the Lipid Droplet Knowledge and Adipose Tissue Knowledge Portals, two central resources for LD and adipose tissue data, and applying CRISPR/Cas9 gene editing to produce precise models for studying adipose biology. The team identified distinct subtypes of white adipocytes with unique insulin responses, highlighting the complexity of adipose tissue and its impact on metabolic health. Proteomic and imaging advances have mapped molecular networks within fat cells, while studies clarified how perilipin proteins (PLINs) regulate LD stability and function.
Research also revealed that hormone-sensitive lipase (HSL) plays essential roles beyond fat breakdown, particularly in fat tissue development, using innovative knockout models. Explorations of short-chain triglycerides (TGs) uncovered their rapid breakdown at LD surfaces, which influences cellular metabolism. In brown fat, studies showed that intracellular fat breakdown is vital for heat production, identifying therapeutic targets for metabolic diseases.
Additionally, SPHERES discovered PLCXD1, a novel enzyme involved in adipocyte metabolism, and developed immortalized CD55+ precursor cells for advanced studies of adipocyte diversity. Together, these breakthroughs pave the way for new treatments targeting obesity, diabetes, and related conditions, demonstrating SPHERES’ potential to bridge science and clinical care.
Building on innovative technologies and models developed during the first phase, SPHERES aims to deepen its exploration of adipocyte biology and lipid dynamics. Future work will leverage advanced cellular and murine models alongside unique clinical cohorts to unravel the intricate roles of lipid droplet-associated proteins and their interactomes in regulating lipid droplet (LD) and adipocyte function. A primary focus will be the comprehensive characterization of specific LD proteins, including their contributions to lipid dynamics, LD structure, and metabolic processes within adipocytes. These studies aim to elucidate how protein interactions at the LD surface influence lipid storage and turnover, providing insights into the mechanisms underlying adipocyte hypertrophy and metabolic health. Progress will also extend to investigating lipid dynamics and their interactions within LDs. By integrating cutting-edge lipidomics, proteomics, and bioenergetic analyses, SPHERES will address critical gaps in understanding the metabolic fate of lipids in both white and brown adipose tissues under physiological and pathological conditions. Ultimately, SPHERES seeks to translate these findings into clinically relevant outcomes, identifying potential therapeutic targets for cardiometabolic diseases. By bridging basic research and translational applications, the consortium aims to redefine strategies for combating obesity-associated metabolic disorders.