Figure 8.

Incomplete suppression of TGFβ signaling by glucocorticoids (GCs) in Om ASCs inhibits adipogenesis and may promote fibrosis. This model summarizes our findings and emphasizes the role of ASCs as a source of TGFβ ligands and their regulation by glucocorticoids. Om ASCs secrete higher levels of TGFβ ligands, activin A, and TGFβ, which act in an autocrine/paracrine loop to inhibit adipogenesis. Although glucocorticoids, as modeled by Dex, inhibited the high production of TGFβ ligands in Om and Abdsc ASCs, Om levels remained higher than levels for Abdsc. Abdsc ASCs were more sensitive to glucocorticoid-mediated inhibition of TGFβ signaling through SMAD2P (not shown) and stimulation of adipogenesis. Depot-dependent TGFβ signaling activity and its suppression by glucocorticoids were at least partially mediated by TGFBR3, which was more abundantly expressed and potently induced by glucocorticoids in Abdsc ASCs. The higher level of TGFβ activity may induce a myofibroblast-like phenotype (gray-shaded cells) in some Om ASCs as indicated by the higher SMA expression of Om cultures. These cells may proliferate and accumulate in the depot, contributing to pericellular fibrosis in Om. The in vivo clinical relevance of our cell culture model was supported by the strong associations of interindividual variations in pericellular fibrosis with basal tissue TGFβ signaling activity and rates of adipogenesis of ASCs isolated from the same tissues. Bold and larger fonts and thicker lines or arrows indicate the quantities of factors or magnitude of effects, respectively.