A proteomic analysis reveals that snail regulates the expression of the nuclear orphan receptor nuclear receptor subfamily 2 group F member 6 (Nr2f6) and interleukin 17 (IL-17) to inhibit adipocyte differentiation

Alberto Peláez-García, Rodrigo Barderas, Raquel Batlle, Rosa Viñas-Castells, Rubén A. Bartolomé, Sofía Torres, Marta Mendes, María Lopez-Lucendo, Rocco Mazzolini, Félix Bonilla, Antonio García De Herreros, J. Ignacio Casal*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)

Abstract

Adipogenesis requires a differentiation program driven by multiple transcription factors, where PPAR and C/EBP play a central role. Recent findings indicate that Snail inhibits adipocyte differentiation in 3T3-L1 and murine mesenchymal stem cells (mMSC). An in-depth quantitative SILAC analysis of the nuclear fraction of Snail-induced alterations of 3T3-L1 cells was carried out. In total, 2251 overlapping proteins were simultaneously quantified in forward and reverse experiments. We observed 574 proteins deregulated by Snail1 using a fold-change ≥1.5, with 111 up- and 463 down-regulated proteins, respectively. Among other proteins, multiple transcription factors such as Trip4, OsmR, Nr2f6, Cbx6, and Prrx1 were down-regulated. Results were validated in 3T3-L1 cells and mMSC cells by Western blot and quantitative PCR. Knock-down experiments in 3T3-L1 cells demonstrated that only Nr2f6 (and Trip4 at minor extent) was required for adipocyte differentiation. Ectopic expression of Nr2f6 reversed the effects of Snail1 and promoted adipogenesis. Because Nr2f6 inhibits the expression of IL-17, we tested the effect of Snail on IL-17 expression. IL-17 and TNF were among the most up-regulated pro-inflammatory cytokines in Snail-transfected 3T3-L1 and mMSC cells. Furthermore, the blocking of IL-17 activity in Snail-transfected cells promoted adipocyte differentiation, reverting Snail inhibition. In summary, Snail inhibits adipogenesis through a down-regulation of Nr2f6, which in turn facilitates the expression of IL-17, an anti-adipogenic cytokine. These results would support a novel and important role for Snail and Nr2f6 in obesity control.

Original languageEnglish
Pages (from-to)303-315
Number of pages13
JournalMolecular and Cellular Proteomics
Volume14
Issue number2
DOIs
Publication statusPublished - 1 Feb 2015
Externally publishedYes

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