Glucocorticoid receptor signaling protects human mature adipocytes from metabolic stress and is impaired in obesity.

BACKGROUND: Obesity-associated adipose tissue dysfunction is a major contributor to metabolic disease. Although obesity is associated with increased glucocorticoid exposure, the role of glucocorticoid receptor (GR) signaling in mature adipocytes during obesity remains unclear. METHODS AND RESULTS: To investigate the direct effects of dexamethasone (Dex) on mature adipocytes, we established an ex vivo culture model of primary human white adipocytes. Dex-mediated GR activation exerted cytoprotective effects by attenuating stress-associated DNA damage, suppressing aberrant cell-cycle re-entry, and downregulating pro-inflammatory programs, thereby preserving adipocyte function. Similar protective effects were observed in adipocytes exposed to sustained high insulin concentrations. In obese human cohorts, elevated circulating adrenocorticotropic hormone levels and increased adipose expression of 11β-hydroxysteroid dehydrogenase type 1 supported the presence of increased glucocorticoid exposure. However, integrated analysis of human adipose single-nucleus RNA-sequencing datasets revealed a significantly higher proportion of GR- unresponsive adipocytes in obesity. Consistently, key GR pathway components, including glucocorticoid receptor (NR3C1), FK506 binding protein 5, and glucocorticoid-induced leucine zipper were significantly downregulated in adipose tissue and mature adipocytes in obesity. These findings were supported by analyses of bulk sequencing datasets from multiple cohorts of obese human adipose tissue. Dataset analyses showed that suppressed GR signaling in obese adipocytes was reversed following sustained weight loss after bariatric surgery. CONCLUSIONS: GR activation protects human adipocytes by restraining cellular stress responses. Obesity-related adipocyte dysfunction is associated with impaired GR signaling despite increased adipose glucocorticoid exposure. These findings support selective GR activation as a potential therapeutic strategy for obesity-related metabolic syndrome.