In humans, glucocorticoids (GCs) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GCs often lead to side effects, including diabetes and lipodystrophy. We recently reported that adipocyte glucocorticoid receptor (GR)–deficient (AdipoGR-KO) mice under corticosterone (CORT) treatment exhibited a massive adipose tissue (AT) expansion associated with a paradoxical improvement of metabolic health compared with control mice. However, whether GR may control adipose development remains unclear. Here, we show a specific induction of hypoxia-inducible factor 1α (HIF-1α) and proangiogenic vascular endothelial growth factor A (VEGFA) expression in GR-deficient adipocytes of AdipoGR-KO mice compared with control mice, together with an increased adipose vascular network, as assessed by three-dimensional imaging. GR activation reduced HIF-1α recruitment to the Vegfa promoter resulting from Hif-1α downregulation at the transcriptional and posttranslational levels. Importantly, in CORT-treated AdipoGR-KO mice, the blockade of VEGFA by a soluble decoy receptor prevented AT expansion and the healthy metabolic phenotype. Finally, in subcutaneous AT from patients with Cushing syndrome, higher VEGFA expression was associated with a better metabolic profile. Collectively, these results highlight that adipocyte GR negatively controls AT expansion and metabolic health through the downregulation of the major angiogenic effector VEGFA and inhibition of vascular network development.
Article Highlights
- Adipocyte glucocorticoid receptor (GR) deficiency protects mice from glucocorticoid (GC)–induced deleterious metabolic effects; this health improvement was associated with a massive expansion of adipose tissue (AT).
- We determined the role of GC/GR signaling in AT expansion and vascularization.
- GR suppressed adipose tissue vascularization by decreasing the vascular endothelial growth factor A (VEGFA) and its transcriptional regulator hypoxia-inducible factor 1α, wherein VEGFA abrogated beneficial impacts of GR deficiency in GC-exposed mice, and in patients with Cushing syndrome, higher VEGFA expression in AT exhibited a healthier metabolic profile.
- Selectively antagonizing adipocyte GR could prevent GC metabolic adverse effects.
