DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Krüppel-like factor 15 gene expression

Abstract

Glucocorticoids, such as dexamethasone (Dex), have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (GR) in adipogenesis have not been well characterized yet. Here we show that inhibition of GR activity using the GR antagonist RU486 prevents human mesenchymal stem cell (hMSC) and mouse embryonic fibroblast (MEF) differentiation into adipocytes. Moreover, in MEFs isolated from GR knockout (GRnull) and GRdim mice deficient in GR DNA-binding activity, adipogenesis was blocked. We identified GRE sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation. Moreover transfection of MEFs with siRNA for KLF15 significantly attenuated the expressions of adipogenic-marker genes and the lipid accumulation. Our results provide a new mechanism for understanding glucocorticoids dependent adipogenesis and that GR promotes adipogenesis via KLF15 gene expression as a transcriptional direct target.

The Glucocorticoid Receptor and KLF15 Regulate Gene Expression Dynamics and Integrate Signals through Feed-Forward Circuitry

“…Reporters containing these regions were induced in both A549 and Beas-2B cells by dex in transfection assays (Fig. 3E); the GBR in the first intron had previously been shown to respond to GR in other cell types (34). Together these data indicate that KLF15 is directly induced by GR signaling in A549 and Beas-2B cells through two glucocorticoid response elements (GREs).…”

Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy

“…Klf15 is a direct target of the GR (32,(53)(54)(55). We found divergent epigenetic chromatin marks on the Klf15 GRE that paralleled the change in gene expression elicited by differential GC steroid dosing.…”

Krüppel-like factors in mammalian stem cells and development

“…Furthermore, it has been reported that variants in KLF7 are protective against type 2 diabetes mellitus in Japanese and Danish patient cohorts (Kanazawa et al, 2005;Zobel et al, 2009). In addition, multiple laboratories have reported that KLF15 induces mouse adipocyte differentiation by increasing the expression of PPARγ (Mori et al, 2005), which has direct implications when correlated with the glucocorticoid-induced effects on mouse adipogenesis (Asada et al, 2011). Interestingly, all of these findings are based on tissue-specific constitutive knockout murine models, highlighting specific and important roles for KLFs in development and disease.…”