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

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.