A weight loss fibrotic response in visceral fat is driven by defective lysosome-dependent collagenolysis
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
- Agatha de Assis-Ferreira (ORCID: https://orcid.org/0000-0002-5292-3689)
- Emmanuel L. Gautier (ORCID: https://orcid.org/0000-0003-2976-7566)
- Joëlle Vinh (ORCID: https://orcid.org/0000-0001-7184-2668)
- Sébastien Dussaud (ORCID: https://orcid.org/0000-0002-5365-8338)
- Laurent Genser (ORCID: https://orcid.org/0000-0001-7635-7813)
- Karine Clément (ORCID: https://orcid.org/0000-0002-2489-3355)
- Simone Vargas da Silva (ORCID: https://orcid.org/0000-0002-3368-2517)
- Geneviève Marcelin (ORCID: https://orcid.org/0000-0002-9779-5529)
- Cindy Rose (ORCID: https://orcid.org/0009-0003-6350-6308)
- Simon Lecoutre (ORCID: https://orcid.org/0000-0002-2536-6119)
- Lícia Torres (ORCID: https://orcid.org/0000-0002-2048-0318)
- Fatiha Merabtene
- Iman Haddad (ORCID: https://orcid.org/0000-0003-2919-178X)
- Fabrizio Andréelli (ORCID: https://orcid.org/0000-0002-1207-3624)
- Laís Bhering Martins (ORCID: https://orcid.org/0000-0002-9814-8649)
- Ana Letícia Malheiros Silveira (ORCID: https://orcid.org/0000-0003-1052-0854)
- Clémentine Rebière (ORCID: https://orcid.org/0009-0009-2816-6997)
- Cheïma Benbida
- Isabelle Dugail (ORCID: https://orcid.org/0000-0003-3631-2252)
- Jimon Boniface Abatan
- Christine Rouault
- Adma Maciel Babêtto
- Marina Chaves de Oliveira
- Amanda Oliveira
- Adaliene Versiani Matos Ferreira
Institutions
- Universidade Federal de Minas Gerais (BR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Sorbonne Université (FR)
- Universidade do Estado do Rio de Janeiro (BR)
- Nutrition et obésité : approches systémiques (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Pitié-Salpêtrière Hospital (FR)
- Spectrométrie de Masse Biologique et Protéomique (FR)
- ESPCI Paris (FR)
Publication Details
- Journal
- JCI Insight
- Published
- 2026-11-08
- DOI
- https://doi.org/10.1172/jci.insight.198123
- Primary Topic
- Adipokines, Inflammation, and Metabolic Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Sorbonne Université