Adipose tissue macrophages in insulin-resistant subjects are associated withcollagen VI and fibrosis and demonstrate alternative activation.

摘要

Adipose tissue macrophages are associated with insulin resistance and are linked to changes in the extracellular matrix. To better characterize adiposemacrophages, the extracellular matrix, and adipocyte-macrophage interactions,gene expression from adipose tissue and the stromal vascular fraction wasassessed for markers of inflammation and fibrosis, and macrophages from obese andlean subjects were counted and characterized immunohistochemically. Cocultureexperiments examined the effects of adipocyte-macrophage interaction. Collagen VIgene expression was associated with insulin sensitivity and CD68 (r = -0.56 and0.60, P < 0.0001) and with other markers of inflammation and fibrosis. Comparedwith adipose tissue from lean subjects, adipose tissue from obese subjectscontained increased areas of fibrosis, which correlated inversely with insulinsensitivity (r = -0.58, P < 0.02) and positively with macrophage number (r =0.70, P < 0.01). Although macrophages in crownlike structures (CLS) were moreabundant in obese adipose tissue, the majority of macrophages were associatedwith fibrosis and were not organized in CLS. Macrophages in CLS werepredominantly M1, but most other macrophages, particularly those in fibroticareas, were M2 and also expressed CD150, a marker of M2c macrophages. Cocultureof THP-1 macrophages with adipocytes promoted the M2 phenotype, with a lowerlevel of IL-1 expression and a higher ratio of IL-10 to IL-12. Transforminggrowth factor-beta (TGF-beta) was more abundant in M2 macrophages and was furtherincreased by coculture with adipocytes. Downstream effectors of TGF-beta, such asplasminogen activator inhibitor-1, collagen VI, and phosphorylated Smad, wereincreased in macrophages and adipocytes. Thus adipose tissue of insulin-resistanthumans demonstrated increased fibrosis, M2 macrophage abundance, and TGF-betaactivity.