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.

• Authors: Mi-Jeong Lee, R Taylor Pickering, Varuna Shibad, Yuanyuan Wu, Kalypso Karastergiou, Mike Jager, Matthew D Layne, Susan K Fried
• Journal: Diabetes (Diabetes) Vol. 68 Issue 3 Pg. 587-597 (03 2019) ISSN: 1939-327X [Electronic] United States
• PMID: 30530781 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by the American Diabetes Association.

Chemical References

• Glucocorticoids
• Interleukin-6
• Proteoglycans
• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta
• activin A
• Activins
• betaglycan
• Dexamethasone

Topics

• Activins (genetics, metabolism)
• Adipogenesis (drug effects, genetics)
• Adipose Tissue (cytology, metabolism)
• Adult
• Dexamethasone (pharmacology)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Female
• Fibrosis (genetics, metabolism)
• Glucocorticoids (pharmacology)
• Humans
• Interleukin-6 (genetics, metabolism)
• Male
• Middle Aged
• Omentum (drug effects, metabolism)
• Proteoglycans (genetics, metabolism)
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Stem Cells (cytology, drug effects, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Young Adult