Lack of fibro-inflammatory response in human mammary adipose tissue in obesity

Abstract

Background: Understanding how obesity impacts human mammary adipose tissue (MAT) biology is crucial for deciphering its role in mammary epithelium during both physiological and pathophysiological processes, including breast cancer. Hypertrophic mammary adipocytes and Crown-Like Structures are present in MAT of patients with obesity but whether these changes initiate a fibro-inflammatory response at the tissue level remains insufficiently explored.

Objective: We investigated the markers of adipose tissue dysfunction (immune cell infiltration, secretion pattern and fibrosis) in tumor-free MAT of patients with obesity versus patients who are lean.

Methods: Tumor-free MAT were obtained from 96 women with (n = 43) or without (n = 53) obesity who underwent mastectomy for breast cancer risk reduction or treatment. Immune and non-immune cell infiltration were determined using flow cytometry. Bulk transcriptomic was used to characterize the phenotype of CD206+ macrophages whose infiltration is increased in patients with obesity. Conditioned-medium were prepared from MAT to characterize their secretome and dose adipokines and cytokines by ELISA assay. The extra-cellular matrix (ECM) deposition was evaluated by Masson trichrome staining on cross-stained sections, 3D imaging of red picrosirius-stained tissues and measure of hydroxyproline content.

Results: We observed an increase of CD206+/HLA-DR+ macrophages in the stromal vascular fraction of MAT from patients with obesity compared to patients who are lean. Other immune cell infiltration and endothelial or adipose progenitor cell numbers were similar between groups. Bulk transcriptomics on CD206+ macrophages revealed a significant decrease in ECM component expression and processing in obesity. In addition, no heightened secretion of pro-inflammatory cytokines, TGF-β1 or MCP-1 was observed in the samples from patients with obesity. ECM characterization revealed an absence of fibrosis, with MAT of patients with obesity showing even a slightly reduced collagen secretion and deposition compared with their lean counterparts.

Conclusions: Obesity is not associated with inflammation nor fibrosis in MAT, highlighting its unique behavior.