ECM2026, 14-17 June 2026, Copenhagen, DenmarkIntro
In this session, we focus on how matrix-derived signals drive disease processes, with endotrophin as a key example of how ECM components can act as potent bioactive mediators. Beyond its structural origin, endotrophin functions as a signaling molecule that promotes fibrosis, inflammation, and metabolic dysfunction through specific receptor-mediated pathways.
When Fat Gets Stuck: Lipid Droplets, Fibrosis, and the Metabolic Fallout of Obesity
Philipp Scherer, Professor in the Department of Internal Medicine at UT Southwestern Medical Center, and Director of the Touchstone Diabetes Center.
Abstract: Adipose tissue remains one of the most complex and dynamic organs in the body. The ubiquitous presence of adipocytes, their distribution across distinct anatomical depots, and the diversity of fat cell types—each derived from unique precursor populations—underscore the remarkable plasticity of this organ. Adipocytes can undergo hypertrophy, hyperplasia, transdifferentiation into other lipid-storing or thermogenic cell types, or even partial dedifferentiation, reflecting a staggering degree of adaptability. This complexity positions adipose tissue at the center of systemic energy homeostasis, making it a critical determinant of metabolic health.
Incretin-based therapies, particularly GLP-1 receptor agonists and dual or triple incretin agonists (e.g., GLP-1/GIP, GLP-1/GIP/glucagon), have revolutionized the treatment of obesity and metabolic disease. While many of their systemic benefits are closely tied to weight loss, an important mechanistic aspect lies in their ability to restore and rejuvenate adipose tissue physiology. Weight loss induced by incretins leads to a redistribution of lipid stores, reduction in adipocyte hypertrophy, and reactivation of healthy adipogenesis. These changes alleviate mechanical and metabolic stress within adipose tissue, reduce hypoxia, and diminish the secretion of pro-inflammatory cytokines. Furthermore, incretins enhance vascularization and oxygen delivery, thereby improving nutrient flux and mitochondrial function in adipocytes, which in turn increases insulin sensitivity and metabolic flexibility.
A critical determinant of adipose tissue plasticity is the extracellular matrix (ECM). The ECM provides structural scaffolding, mechanical stability, and key biochemical signals regulating cell function. In obesity, this finely tuned balance between ECM synthesis and degradation becomes disrupted, leading to excessive matrix accumulation that constrains adipocyte expansion and limits remodeling capacity. Incretin-induced weight loss helps reverse this pathological ECM remodeling—reducing fibrosis, normalizing matrix composition, and enabling renewed adipose tissue flexibility.
Through these combined effects—reducing inflammation, restoring ECM dynamics, and reestablishing healthy cellular turnover—adipose tissue regains its endocrine and metabolic resilience. Understanding how incretin pathways interface with adipose tissue remodeling is therefore central to explaining their therapeutic impact on systemic diseases linked to metabolic dysfunction, including diabetes, chronic kidney disease, metabolic-associated steatohepatitis (MASH), metabolic-associated fatty liver disease (MAFLD), and heart failure.
