Adipocyte glucocorticoid receptor activation with high glucocorticoid doses impairs healthy adipose tissue expansion by repressing angiogenesis

In Human, glucocorticoids (GC) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GC often lead to adverse 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 to control mice. However, whether GR may control adipose development remains unclear. Here, we show a specific induction of the hypoxia-inducible factor HIF-1a and the pro-angiogenic Vascular Endothelial Growth Factor-A expression in GR-deficient adipocytes of AdipoGR-KO mice as compared to control mice, together with an increased adipose vascular network, as assessed by 3D-analysis imaging. GR activation reduced HIF-1a recruitment on Vegfa promoter resulting from Hif-1a down-regulation at the transcriptional and post-translational 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 Cushing patients, 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 down-regulation of the major angiogenic effector VEGFA and inhibiting vascular network development. (LIPOCUSH, NCT01688349)

Article Highlights

· Our previous study demonstrated that adipocyte glucocorticoid receptor (GR) deficiency protects mice from glucocorticoid (GC)-induced deleterious metabolic effects. Interestingly, this health improvement was associated with a massive expansion of their adipose tissue.

· Here we determined the role of GC/GR signaling on adipose tissue expansion and vascularization.

· GR suppresses adipose tissue vascularization by decreasing the vascular factor VEGFA and its transcriptional regulator HIF-1a. Blocking VEGFA abrogates beneficial impacts of GR deficiency in GC-exposed mice. Cushing’ patients with higher VEGFA expression in AT exhibit a healthier metabolic profile.

· Selectively antagonizing adipocyte GR could prevent GC metabolic adverse effects.