Serum- and glucocorticoid-induced kinase 3 orchestrates glucocorticoid signaling to facilitate chromatin remodeling during murine adipogenesis
Qilong Chen, Jialu Guo, Yuyi Liu, Tai Du, Jiapei Liu, Yuyao Zhang, Yuming Dai, Mengdi Zhang, Ziqian Zhou, Qiyang Zhang, Caixia Wei, Qiurong Ding, Jun Qin, Qiwei Zhai, Ju Qiu, Mengle Shao, Fang Zhang, Alexander A. Soukas, Ben Zhou
Qilong Chen, Jialu Guo, Yuyi Liu, Tai Du, Jiapei Liu, Yuyao Zhang, Yuming Dai, Mengdi Zhang, Ziqian Zhou, Qiyang Zhang, Caixia Wei, Qiurong Ding, Jun Qin, Qiwei Zhai, Ju Qiu, Mengle Shao, Fang Zhang, Alexander A. Soukas, Ben Zhou
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Research Article Cell biology Metabolism

Serum- and glucocorticoid-induced kinase 3 orchestrates glucocorticoid signaling to facilitate chromatin remodeling during murine adipogenesis

Abstract

Elevated glucocorticoid levels are common in conditions such as aging, chronic stress, Cushing syndrome, and glucocorticoid therapy. While glucocorticoids suppress inflammation through the glucocorticoid receptor (GR), they also cause metabolic side effects. Investigating alternative pathways beyond GR activation is crucial for reducing these side effects. Our phosphoproteomics analysis revealed that glucocorticoid exposure promotes phosphorylation at the RxxS motifs of multiple proteins in preadipocytes, including those mediated by serum- and glucocorticoid-induced kinase 3 (SGK3). SGK3 is a key mediator of glucocorticoid-induced adipogenesis, as shown by impaired adipogenesis after SGK3 inhibition or genetic ablation. Sgk3-KO mice were resistant to obesity induced by glucocorticoid or a high-fat diet, and proteolysis targeting chimeras (PROTAC) targeting SGK3 reduced adipogenesis in both obese mice and in a thyroid eye disease cell line. Mechanistically, SGK3 translocated to the nucleus upon glucocorticoid stimulation, interacted with and phosphorylated the BRG1 subunit of the BAF complex, and prevented BRG1 degradation, promoting chromatin remodeling necessary for adipogenesis. These findings highlight SGK3 as a potential therapeutic target to mitigate metabolic side effects of elevated glucocorticoid levels.

Authors

Qilong Chen, Jialu Guo, Yuyi Liu, Tai Du, Jiapei Liu, Yuyao Zhang, Yuming Dai, Mengdi Zhang, Ziqian Zhou, Qiyang Zhang, Caixia Wei, Qiurong Ding, Jun Qin, Qiwei Zhai, Ju Qiu, Mengle Shao, Fang Zhang, Alexander A. Soukas, Ben Zhou

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Figure 6

Deficiency of SGK3 impairs chromatin remodeling during preadipocyte differentiation.

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Deficiency of SGK3 impairs chromatin remodeling during preadipocyte diff...
(A) Representative Western blot (upper) and related quantifications (lower) of BRG1, ACTL6A, SMARCC2, SMARCB1, GR, and SGK3 in SGK3 PROTAC-treated preadipocytes. n = 4 samples from different culture wells. (B) Representative images of Oil Red O staining (left) and related quantifications (right) of differentiated preadipocytes transfected with Ctrl or Brg1 siRNA and/or treated with SGK3 PROTAC on day 7. Scale bar: 200 μm. n =3 independent assays. (C) Enrichment analysis of genes near the regions of induced BRG1 occupation during preadipocyte differentiation. (D) Heatmap of BRG1 CUT&TAG (upper) and ATAC-Seq (lower) signals with or without SGK3 PROTAC treatment during preadipocyte differentiation. (E) Quantification of BRG1 CUT&TAG signals and ATAC-Seq signals in regions of induced BRG1 occupation during preadipocyte differentiation. n = 1,158 regions. (F) BRG1 CUT&TAG and ATAC-Seq signals in the Pparg and Cebpa gene locus. Data in A are represented as mean ± SEM, and unpaired 2-tailed t test was used for statistical analysis. Data in B are represented as mean ± SEM, and 2-way ANOVA was used for statistical analysis. Identical sample aliquots were loaded on separate gels for immunoblotting analysis in A. Data in E are represented as mean and 25th to 75th percentile, and 1-way ANOVA was used for statistical analysis. ns, no significance; *P < 0.05, ***P < 0.001, ****P < 0.0001.