SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation
Amine Toubal, Karine Clément, Rongrong Fan, Patricia Ancel, Veronique Pelloux, Christine Rouault, Nicolas Veyrie, Agnes Hartemann, Eckardt Treuter, Nicolas Venteclef
Amine Toubal, Karine Clément, Rongrong Fan, Patricia Ancel, Veronique Pelloux, Christine Rouault, Nicolas Veyrie, Agnes Hartemann, Eckardt Treuter, Nicolas Venteclef
View: Text | PDF
Research Article Inflammation

SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation

Abstract

Low-grade chronic inflammation is a major characteristic of obesity and results from deregulated white adipose 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 morbid obesity. These alterations correlated with reduced occupancy of the corepressor complex at inflammatory 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 promoted 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 PPARγ and TWIST1 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 PPARγ agonist, restored expression of TWIST1, GPS2, and SMRT in adipose tissue. Collectively, our findings identify 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.

Authors

Amine Toubal, Karine Clément, Rongrong Fan, Patricia Ancel, Veronique Pelloux, Christine Rouault, Nicolas Veyrie, Agnes Hartemann, Eckardt Treuter, Nicolas Venteclef

×

Figure 6

The SMRT-GPS2 complex represses IL-6 expression in human adipocytes through inhibition of the proinflammatory transcription factors NF-κB, AP-1, and C/EBP.

Options: View larger image (or click on image) Download as PowerPoint
The SMRT-GPS2 complex represses IL-6 expression in human adipocytes thro...
(A and B) Identification of GPS2 and SMRT-dependent inflammatory transcription factors (TF) in adipocytes using a transcription factor profiling assay. Transcription factor activation was analyzed in nuclear extracts of human adipocytes upon treatment with GPS2 siRNA or ATCM coupled with adenoviral expression of GPS2 (or GFP as control). Reporter activation was measured as relative luminescence activity (RLU). Data are derived from 4 different experiments. (C) Human IL-6 promoter with known binding sites for inflammatory transcription factors. (D and E) ChIP analysis of transcription factor binding at R1 and R2. See Supplemental Figure 12 for schematic and ChIP analysis of the nonresponsive control region R3. (F and G) Re-ChIP. Human adipocytes were infected with adenovirus HA-GPS2 or GFP (as control). ChIP (first IP) using anti-HA was followed by re-ChIP (second IP) using the indicated antibodies. Data are representative of 5 different experiments. *P < 0.05.