A Weight Loss Fibrotic Response in Visceral Fat Is Driven by Defective Lysosome-Dependent Collagenolysis
- 1Inserm
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 impact on WAT remodeling remains incompletely understood. Using a mouse model of diet-induced obesity followed by nutritional weight loss, we show that visceral WAT (vWAT) fails to fully recover despite normalization of body weight and marked metabolic improvment. Notably, vWAT fibrosis persists and continues to progress after WL. This occurs while extracellular matrix (ECM) production by adipose progenitor cells is 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.
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BibTeX
@misc{rebiere2026weight,
title = {{A Weight Loss Fibrotic Response in Visceral Fat Is Driven by Defective Lysosome-Dependent Collagenolysis}},
author = {C. Rebiere and A. Oliveira and S. Dussaud and I. Haddad and A. de Assis Ferreira and A. Babetto and C. Rouault and F. Merabtene and C. Benbida and J. Boniface Abatan and S. Vargas da Silva and L. Bhering Martins and L. Torres and A. L. Malheiros Silveira and C. Rose and L. Genser and F. Andreelli and I. Dugail and M. Chaves de Oliveira and J. Vinh and S. Lecoutre and A. Versiani Matos Ferreira and K. Clement and E. L. Gautier and G. Marcelin},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755405},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755405v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A Weight Loss Fibrotic Response in Visceral Fat Is Driven by Defective Lysosome-Dependent Collagenolysis
AU - C. Rebiere
AU - A. Oliveira
AU - S. Dussaud
AU - I. Haddad
AU - A. de Assis Ferreira
AU - A. Babetto
AU - C. Rouault
AU - F. Merabtene
AU - C. Benbida
AU - J. Boniface Abatan
AU - S. Vargas da Silva
AU - L. Bhering Martins
AU - L. Torres
AU - A. L. Malheiros Silveira
AU - C. Rose
AU - L. Genser
AU - F. Andreelli
AU - I. Dugail
AU - M. Chaves de Oliveira
AU - J. Vinh
AU - S. Lecoutre
AU - A. Versiani Matos Ferreira
AU - K. Clement
AU - E. L. Gautier
AU - G. Marcelin
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755405
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755405v1
AB - 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 impact on WAT remodeling remains incompletely understood. Using a mouse model of diet-induced obesity followed by nutritional weight loss, we show that visceral WAT (vWAT) fails to fully recover despite normalization of body weight and marked metabolic improvment. Notably, vWAT fibrosis persists and continues to progress after WL. This occurs while extracellular matrix (ECM) production by adipose progenitor cells is 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.
ER -