Abstract
Obesity induces pathological remodeling of white adipose tissue (WAT), including chronic inflammation and fibrosis, which drive metabolic dysfunction. Although weight loss (WL) is the cornerstone of obesity treatment and improves systemic metabolic health, its effect on WAT remodeling remains incompletely understood. Using a mouse model of diet-induced obesity followed by nutritional WL, we show that visceral WAT (vWAT) failed to fully recover despite normalization of body weight and marked metabolic improvement. Notably, vWAT fibrosis persisted and continued to progress after WL. This occurred while extracellular matrix (ECM) production by adipose progenitor cells was markedly reduced following WL, explaining why pharmacological inhibition of ECM synthesis fails to prevent fibrosis during WL. Instead, we observed impaired collagen degradation by both progenitor cells and macrophages, along with lysosomal dysfunction, during WL. This suggests that defective ECM degradation, rather than continued ECM production, underlies fibrosis persistence and aggravation during WL. Together, these findings identify impaired collagenolysis as a critical barrier to adipose tissue recovery after WL and suggest that enhancing ECM clearance, rather than inhibiting ECM synthesis, may represent a more effective therapeutic strategy to restore adipose tissue function.
Authors
Clémentine Rebière, Amanda Oliveira, Sébastien Dussaud, Iman Haddad, Agatha Assis-Ferreira, Adma M. Babetto, Christine Rouault, Fatiha Merabtene, Cheïma Benbida, Jimon Abatan, Simone Vargas da Silva, Laís Bhering Martins, Licia Torres, Ana Letícia M. Silveira, Cindy Rose, Laurent Genser, Fabrizio Andreelli, Isabelle Dugail, Marina Chaves de Oliveira, Joelle Vinh, Simon Lecoutre, Adaliene V.M. Ferreira, Karine Clément, Emmanuel L. Gautier, Genevieve Marcelin
