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

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posted on 2023-11-14, 22:11 authored by Anna Vali, Héloïse Dalle, Alya Loubaresse, Jérôme Gilleron, Emmanuelle Havis, Marie Garcia, Carine Beaupère, Clémentine Denis, Natacha Roblot, Karine Poussin, Tatiana Ledent, Benjamin Bouillet, Mireille Cormont, Jean-François Tanti, Jacqueline Capeau, Camille Vatier, Bruno Fève, Alexandra Grosfeld, Marthe Moldes

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.

Funding

Fondation pour la Recherche Médicale [FRM] EQU201903007868

Institut National de la Santé et de la Recherche Médicale

Ministère de l'Éducation et de l'Enseignement supérieur

Société Francophone pour le Diabète [SFD] RAK18021DDA

Sorbonne Université

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