Adipocyte Glucocorticoid Receptor Activation With High Glucocorticoid Doses Impairs Healthy Adipose Tissue Expansion by Repressing Angiogenesis

Author:

Vali Anna12,Dalle Héloïse12,Loubaresse Alya12,Gilleron Jérôme3,Havis Emmanuelle4,Garcia Marie12,Beaupère Carine12,Denis Clémentine12,Roblot Natacha12,Poussin Karine12,Ledent Tatiana1,Bouillet Benjamin12ORCID,Cormont Mireille3,Tanti Jean-François3,Capeau Jacqueline12,Vatier Camille125,Fève Bruno125,Grosfeld Alexandra12,Moldes Marthe12ORCID

Affiliation:

1. 1Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Paris, France

2. 2Sorbonne Université, INSERM, Institute of CardioMetabolism and Nutrition, Paris, France

3. 3Université Côte d’Azur, INSERM, C3M, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France

4. 4Sorbonne Université, CNRS, INSERM, Laboratoire de Biologie du Développement, Institut Biologie Paris Seine, Paris, France

5. 5Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Service Endocrinologie, CRMR PRISIS, Paris, France

Abstract

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

Funder

Ministère de l’Enseignement Supérieur

Société Francophone pour le Diabète [SFD]

Institut National de la Santé et de la Recherche Médicale

Sorbonne Université

Fondation pour la Recherche Médicale [FRM]

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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