Role of hypertrophic adipocytes, collagen VI, and CD38 in adipose tissue fibrosis in obesity

Adipose tissue fibrosis is associated with metabolic alterations in patients with obesity and involves three major collagen types: fibrillar collagens I and III and non-fibrillar collagen VI. In this study, fibrosis was found to be significantly increased only in visceral adipose tissue in patients with obesity (4.7% vs. 2.5% in controls, p < 0.001), whereas no significant difference was observed in subcutaneous adipose tissue. Transmission electron microscopy and high-resolution scanning electron microscopy suggested that hypertrophic adipocytes may contribute to the production of fibrillar collagens I and III. In vitro data were consistent with this interpretation. Expression of the COL6 gene, which encodes the non-fibrillar collagen VI, was reduced in adipose tissue from obese patients. Notably, patients carrying mutations in COL6 genes displayed increased fibrosis even in subcutaneous fat, approximately 6.5-fold higher than controls in the patient with the severe form (Ullrich) and 2.8-fold higher in two patients with the milder form (Bethlem). Approximately 15% of adipocytes in obese tissue appeared stressed or dead (perilipin-1 negative), and the associated infiltrating macrophages exhibited increased expression of CD38, an ectoenzyme implicated in systemic fibrosis. Correlations with gene expression also indicated the importance of myofibroblasts and the extracellular-matrix peptidase D. Taken together, our data suggest that obese adipocytes may contribute to fibrillar collagen production and identify collagen VI and CD38 as potential molecular contributors, consistent with the concept that adipose tissue fibrosis in humans has a multifactorial origin.

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Journal
Scientific Reports
Published
2026-04-28
DOI
https://doi.org/10.1038/s41598-026-49848-7
Primary Topic
Adipokines, Inflammation, and Metabolic Diseases
Type
article
Field-Weighted Citation Impact
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article

Role of hypertrophic adipocytes, collagen VI, and CD38 in adipose tissue fibrosis in obesity

Fabio Malavasi, Saverio Cinti, Giovanni Lezoche, Salvatore Pezzino et al.
Scientific Reports
Adipokines, Inflammation, and Metabolic Diseases
article

Role of hypertrophic adipocytes, collagen VI, and CD38 in adipose tissue fibrosis in obesity

Fabio Malavasi, Saverio Cinti, Giovanni Lezoche, Salvatore Pezzino, Vincenzo De Geronimo, Tatiana Spadoni, Luciano Merlini, Chiara Scuderi, Vincenza Barresi, Jessica Perugini, Nayra Figueiredo, Alessio Pieroni, Angelica Di Vincenzo, Maria Vittoria Napoli, Mario Tomasello, Patrizia Sabatelli, Laura Graciotti, Armando Gabrielli, Erika Casarotta, Sergio Castorina, Abele Donati, Christian Dani, D. F. Condorelli, Massimiliano Petrelli, Adriano Di Cristoforo, Antonio Giordano, Andrea Sbarbati, Monica Mattioli-Belmonte, Tonia Luca, Flavia Campos Corgosinho
article en

Abstract

Adipose tissue fibrosis is associated with metabolic alterations in patients with obesity and involves three major collagen types: fibrillar collagens I and III and non-fibrillar collagen VI. In this study, fibrosis was found to be significantly increased only in visceral adipose tissue in patients with obesity (4.7% vs. 2.5% in controls, p < 0.001), whereas no significant difference was observed in subcutaneous adipose tissue. Transmission electron microscopy and high-resolution scanning electron microscopy suggested that hypertrophic adipocytes may contribute to the production of fibrillar collagens I and III. In vitro data were consistent with this interpretation. Expression of the COL6 gene, which encodes the non-fibrillar collagen VI, was reduced in adipose tissue from obese patients. Notably, patients carrying mutations in COL6 genes displayed increased fibrosis even in subcutaneous fat, approximately 6.5-fold higher than controls in the patient with the severe form (Ullrich) and 2.8-fold higher in two patients with the milder form (Bethlem). Approximately 15% of adipocytes in obese tissue appeared stressed or dead (perilipin-1 negative), and the associated infiltrating macrophages exhibited increased expression of CD38, an ectoenzyme implicated in systemic fibrosis. Correlations with gene expression also indicated the importance of myofibroblasts and the extracellular-matrix peptidase D. Taken together, our data suggest that obese adipocytes may contribute to fibrillar collagen production and identify collagen VI and CD38 as potential molecular contributors, consistent with the concept that adipose tissue fibrosis in humans has a multifactorial origin.

Scientific Reports
University of Verona (IT), Marche Polytechnic University (IT), Centre National de la Recherche Scientifique (FR), Inserm (FR), Università degli Studi di Enna Kore (IT), University of Catania (IT), Düsseldorf University Hospital (DE), Fondazione Ricerca Molinette (IT), Ospedali Riuniti di Ancona (IT), Institut de Biologie Valrose (FR), Policlinico Universitario di Catania (IT), Istituto di Genetica Molecolare (IT), Istituto di Studi sul Mediterraneo (CNR - ISMed) (IT), Heinrich Heine University Düsseldorf (DE), Universidade Federal de Goiás (BR), University of Bologna (IT)
Conselho Nacional de Desenvolvimento Científico e Tecnológico, Università di Catania, Universidade Federal de Goiás
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Openalex Percentile: Top 12%
Adipokines, Inflammation, and Metabolic Diseases
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