Impaired Glucocorticoid Suppression of TGFβ Signaling in Human Omental Adipose Tissues Limits Adipogenesis and May Promote Fibrosis

Abstract

Visceral obesity is associated with insulin resistance and higher risk of type 2 diabetes and metabolic diseases. A limited ability of adipose tissues to remodel through the recruitment and differentiation of adipose stem cells (ASCs) is associated with adipose tissue inflammation and fibrosis and the metabolic syndrome. We show that the lower adipogenesis of omental (Om) compared with abdominal subcutaneous (Abdsc) ASCs was associated with greater secretion of TGFβ ligands that acted in an autocrine/paracrine loop to activate SMAD2 and suppress adipogenesis. Inhibition of TGFβ signaling rescued Om ASC differentiation. In Abdsc ASCs, low concentrations of dexamethasone suppressed TGFβ signaling and enhanced adipogenesis, at least in part by increasing TGFBR3 protein that can sequester TGFβ ligands. Om ASCs were resistant to these dexamethasone effects; recombinant TGFBR3 increased their differentiation. Pericellular fibrosis, a hallmark of dysfunctional adipose tissue, was greater in Om and correlated with higher level of tissue TGFβ signaling activity and lower ASC differentiation. We conclude that glucocorticoids restrain cell-autonomous TGFβ signaling in ASCs to facilitate adipogenesis and healthy remodeling in Abdsc and these processes are impaired in Om. Therapies directed at overcoming glucocorticoid resistance in visceral adipose tissue may improve remodeling and help prevent metabolic complications of visceral obesity.

TGF-Β Family Inhibitors Blunt Adipogenesis Via Non-Canonical Regulation Of SMAD Pathways

“…Among co-receptors, only betaglycan (a.k.a. TGFβR3) was highly expressed, highlighting its recently described role in adipogenesis (Lee et al, 2019). The SMAD2/3 pathway activating ligands TGF-β1, TGF-β2, and Activin A were also significantly expressed.…”

“…Transforming Growth Factor-β (TGF-β) family ligands, which include TGF-β, Activin, GDF, and BMP family growth factors, have known roles in both adipogenesis and adipocyte hypertrophy (Lee, 2018, Tang & Lane, 2012, Zamani & Brown, 2011. Thus, TGF-β1, GDF-8, and Activins A and B inhibit adipogenesis (Choy, Skillington et al, 2000, Hirai, Yamanaka et al, 2005, Hoggard, Cruickshank et al, 2009, Ignotz & Massague, 1985, Kim, Liang et al, 2001, Lee, Pickering et al, 2019, Luo, Guo et al, 2019, Sparks, Allen et al, 1992, whereas several BMPs have been shown to promote adipogenesis and/or adipocyte hypertrophy (Gustafson, Hammarstedt et al, 2015, Huang, Song et al, 2009, Modica & Wolfrum, 2017, Schreiber, Dorpholz et al, 2017, Tang, Otto et al, 2004, Tseng, Kokkotou et al, 2008. Yet in spite of a large body of work in this area, fundamental questions remain unresolved, including what steps of adipogenesis are regulated by specific TGF-β family pathways, how are intracellular signaling pathways activated to direct adipocyte development, and can extracellular TGF-β family inhibitors help control adipogenesis.…”

AITC inhibits fibroblast-myofibroblast transition via TRPA1-independent MAPK and NRF2/HO-1 pathways and reverses corticosteroids insensitivity in human lung fibroblasts

“…Generally, TGF-β1 impairs corticosteroid action. Corticosteroids were not effective in modulating fibrotic processes that leads to remodeling [23,[30][31][32]. To confirm this phenomenon, we treated MRC-5 cells with either TGF-β1 or IL-4/IL-13 and incubated with dexamethasone.…”

Specialized immune responses in the peritoneal cavity and omentum

“…GATA6‐expressing LPMs are an important source of TGF‐β 19 . Importantly, TGF‐β suppresses adipogenesis by activating the transcription factor, mothers against decapentaplegic homolog 2 (SMAD2), 43 suggesting a negative feedback loop in which RA made by adipose resident stromal cells inhibits adipocyte proliferation by maintaining TGF‐β‐producing Mϕs 44 . Consistent with this idea, the CD206 + Mϕs in epididymal fat inhibit the growth and differentiation of adipocyte progenitors, thereby preserving adipose tissue homeostasis 45 .…”