Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) regulates glucocorticoid action in adipocytes

Abstract

Local modulation of glucocorticoid action in adipocytes regulates adiposity and systemic insulin sensitivity. However, the specific cofactors that mediate glucocorticoid receptor (GR) action in adipocytes remain unclear. Here we show that the silencing mediator of retinoid and thyroid hormone receptors (SMRT) is recruited to GR in adipocytes and regulates ligand-dependent GR function. Decreased SMRT expression in adipocytes in vivo increases expression of glucocorticoid-responsive genes. Moreover, adipocytes with decreased SMRT expression exhibit altered glucocorticoid regulation of lipolysis. We conclude that SMRT regulates the metabolic functions of GR in adipocytes in vivo. Modulation of GR-SMRT interactions in adipocytes represents a novel approach to control the local degree of glucocorticoid action and thus influence adipocyte metabolic function.

Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin

“…One of the mechanisms of transrepression of genes by GR is its interaction with SMRT (36). The latter forms a multimolecular complex with HDACs (37).…”

GPS2-mediated regulation of the adipocyte secretome modulates adipose tissue remodeling at the onset of diet-induced obesity

“…Based on structural evidences about the interplay between different corepressors in the NCoR/SMRT corepressor complex [ 120 ], we propose that compromised assembly of the NCoR/SMRT corepressor complex in the absence of GPS2 may explain the observed increase in gene expression. This provides a mechanistic explanation for failed rewiring of the exosomal cargo secreted by energy stressed adipocytes in GPS2-AKO mice exposed to a short-term dietary challenge, in a similar fashion to the derepression of inflammatory cytokines reported in GPS2-null macrophages [ 153 ], and adds to a large body of literature highlighting the importance of NCoR/SMRT corepressors and associated cofactors in the modulation of lipid metabolism, adipose tissue functions, and metabolic health [ 5 , 46 , 48 , 53 , 79 , 95 , 119 , 129 , 131 , 141 ]. Future studies investigating the extent to which this can be rescued by modulating aberrant ubiquitination activity in the absence of GPS2 may provide useful translational insights for the treatment of obesity and associated metabolic disorders.…”

A New Perspective on Thyroid Hormones: Crosstalk with Reproductive Hormones in Females

“…In the absence of ligands, GRα forms a multi-protein complex with the heat-shock protein 90 (HSP90) and HSP70, as well as other factors to prevent the migration to the nucleus to suppress transcription [ 93 ]. After binding to glucocorticoids, the glucocorticoids–GRα multi-protein complex is quickly transferred to the nucleus, where it binds to GRE and regulates the transcription of target genes [ 94 , 95 , 96 ].…”