LOX-mediated adipose tissue stiffening promotes weight rebound

Weight rebound remains the core challenge in the long-term management of obesity. Although current mechanistic understanding mainly focuses on physiological adaptations, the role of biomechanical factors remains largely unexplored. This study aims to investigate the contribution of lysyl oxidase (LOX)-mediated adipose tissue (AT) stiffening to the process of weight rebound. Our clinical analysis first established a correlation among obesity, elevated AT stiffness, and higher LOX levels. We then demonstrated that the weight rebound model mice displayed accelerated lipid accumulation and worsened metabolic functions. Importantly, AT stiffness dynamically increased during obesity, failed to normalize after weight loss due to persistent fibrosis, and reached its highest level during the regain stage. LOX expression followed an identical temporal pattern, showing a strong positive correlation with tissue stiffness. Mechanistically, mimicking a high-stiffness microenvironment in vitro promoted adipocyte differentiation and lipid accumulation in a LOX-dependent manner. Crucially, pharmacological inhibition of LOX in vivo significantly attenuated the rate of weight rebound. Our findings provide supportive evidence that LOX-mediated AT stiffening creates a pro-adipogenic mechanical microenvironment that contributes to accelerated weight rebound and metabolic deterioration, highlighting the LOX-stiffness axis as a potential therapeutic target for preventing weight rebound.