SGK3 Orchestrates Glucocorticoid Signaling to Facilitate Chromatin Remodeling During Adipogenesis

Excessive glucocorticoid exposure is associated with significant metabolic side effects, partly attributed to the transcriptional regulation of adipogenesis by the Glucocorticoid receptor (GR). However, emerging evidence suggests the involvement of alternative pathways beyond GR activation, which are inadequately explored. Through quantitative phosphoproteomics analysis, we identified a significant enrichment of rapidly phosphorylated proteins harboring the RxxS motif following glucocorticoid exposure. Notably, a subset of these proteins undergoes phosphorylation at the RxxS motif by Serum- and glucocorticoid-induced kinase 3 (SGK3) upon glucocorticoid stimulation in preadipocytes. SGK3 emerges as a critical mediator of glucocorticoid-induced preadipocyte differentiation, supported by genetic ablation and pharmacological inhibition experiments that demonstrate impaired adipogenesis both in vitro and in vivo. Mechanistically, upon glucocorticoid stimulation, SGK3 translocates to the nucleus and directly interacts with the core ATPase subunit of the BAF chromatin remodeling complex, BRG1, leading to phosphorylation at threonine 428 and serine 1417 residues. This phosphorylation event prevents proteasomal degradation of BRG1, facilitating chromatin remodeling essential for adipogenesis. Furthermore, Sgk3 knockout mice exhibit resistance to obesity induced by either glucocorticoids or a high-fat diet (HFD). These findings illuminate novel roles of glucocorticoids beyond GR-mediated transcriptional control, highlighting SGK3 as a promising therapeutic target for mitigating metabolic side effects associated with glucocorticoid therapy. Overall design: BRG1 CUT&TAG profiling and chromatin accessibility profiling via ATAC-Seq were conducted on stromal vascular fraction (SVF) cells treated with either vehicle or SGK3 PROTAC at D-3 or D2 during adipocyte differentiation induction.