Poster Topical Area: Energy and Macronutrient Metabolism

Location: Hall D

Poster Board Number: 469

P10-069 - Glucocorticoid – Transforming Growth Factor-beta (TGFβ) Crosstalk Modulates Depot Differences in Adipogenesis: Potential Role in Adipose Expansion and Remodeling

Monday, Jun 11
8:00 AM – 3:00 PM

Objectives: To understand mechanisms underlying lower adipogenesis and fibrosis in visceral obesity, we investigated the role of glucocorticoids (GCs) modulation of the antiadipogenic TGFβ signaling pathways contributed to the depot differences in adipogenesis and fibrosis.


Methods:
GC regulation of TGFβ signaling and adipogenesis was assessed in primary human omental (Om) and abdominal subcutaneous (Abdsc) ASCs. TGFβ activity and tissue fibrosis were determined in adipose tissue samples.


Results:
Om ASCs were less sensitive to the proadipogenic effects of GCs and their ability to suppress TGFβ signaling activity. Basal SMAD2 phosphorylation (SMAD2P) was elevated in Om than Abdsc ASCs and inversely correlated with differentiation degree of ASCs. Conditioned media (CM) from Om vs. Abdsc ASCs more potently inhibited adipogenesis and stimulated SMAD2P; culture of Om with dexamethasone downregulated the antiadipogenic effects of CM and decreased TGFβ ligands in CM. Inhibition of TGFβ signaling with SB431542 or silencing of both SMAD2 and 3 markedly improved adipogenesis. At the tissue level, SMAD2P levels were higher in Om than Abdsc and were associated with lower ASC adipogenesis and higher pericellular fibrosis.


Conclusion:
Overproduction of TGFβ ligands and resistance to GCs conspire to limit the hyperplastic growth of visceral depots, and therefore, their ability to expand in a healthy fashion. Targeting GC signaling to suppress TGFβ activity may provide therapeutic opportunities to limit fibrosis and prevent metabolic dysfunction in obesity.




Funding Source:

NIH R01 DK080448, ADA 7-14-BS-059 to SKF, and funds from Icahn School of Medicine at Mt. Sinai.

CoAuthors: Richard Pickering, PhD – Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai; Susan Fried, PhD – Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai

Mi-Jeong Lee

Assistant Prof.
Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai
New York, New York