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- Title
SMRT-GPS2 corepressor pathwa y dysregulation coincides with obesity-linked adipocyte inflammation.
- Authors
Toubal, Amine; Clément, Karine; Fan, Rongrong; Ancel, Patricia; Pelloux, Veronique; Rouault, Christine; Veyrie, Nicolas; Hartemann, Agnes; Treuter, Eckardt; Venteclef, Nicolas
- Abstract
Low-grade chronic inflammation is a major characteristic of obesity and results from deregulated white adi-pose tissue function. Consequently, there is interest in identifying the underlying regulatory mechanisms and components that drive adipocyte inflammation. Here, we report that expression of the transcriptional corepressor complex subunits GPS2 and SMRT was significantly reduced in obese adipose tissue, inversely correlated to inflammatory status, and was restored upon gastric bypass surgery-induced weight loss in mor-bid obesity. These alterations correlated with reduced occupancy of the corepressor complex at inflamma-tory promoters, providing a mechanistic explanation for elevated inflammatory transcription. In support of these correlations, RNAi-mediated depletion of GPS2 and SMRT from cultured human adipocytes pro-moted derepression of inflammatory transcription and elevation of obesity-associated inflammatory markers, such as IL-6 and MCP-1. Furthermore, we identified a regulatory cascade containing PPARy and TWTST1 that controlled the expression of GPS2 and SMRT in human adipocytes. These findings were clinically relevant, because treatment of diabetic obese patients with pioglitazone, an antidiabetic and antiinflammatory PPARy agonist, restored expression of TWIST1, GPS2, and SMRT in adipose tissue. Collectively, our findings iden-tify alterations in a regulatory transcriptional network in adipocytes involving the dysregulation of a specific corepressor complex as among the initiating events promoting adipose tissue inflammation in human obesity.
- Subjects
OBESITY; INFLAMMATION; FAT cells; GENE expression; GASTRIC bypass; GENETIC transcription
- Publication
Journal of Clinical Investigation, 2013, Vol 123, Issue 1, p362
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI64052