Robin Lengton1, Mariëtte R. Boon1, Anand M. Iyer1, Mostafa Mohseni1, Jordy Renes1, Eline S. van der Valk1, Jenny A. Visser1, Elisabeth F.C. van Rossum1
1Obesity Center CGG, Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Introduction: Evidence suggests a link between increased glucocorticoid action and weight gain. Beyond serum levels, glucocorticoid action is influenced by individual differences in tissue-specific glucocorticoid sensitivity. However, the role of these differences in obesity development remains unclear. The aim of this study was to compare glucocorticoid sensitivity between subjects with obesity and lean controls using an in vitro glucocorticoid receptor (GR) sensitivity assay.
Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 68 individuals with obesity (58 females, mean BMI 39.8 kg/m2), and 16 lean individuals (8 females, mean BMI 23.4 kg/m2). PBMCs were stimulated with phytohemagglutinin and incubated with increasing concentrations of dexamethasone (DEX; 0.33-1000 nM) for 4 hours. The half maximal effective concentration of DEX mediating transactivation (EC50) of the responsive genes glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein 5 (FKBP5), and transrepression (IC50) of the responsive genes interleukin (IL)-2 and IL-6 were used as a measure of glucocorticoid sensitivity.
Results: Individuals with obesity had significantly lower EC50 values for GILZ (4.10 vs 5.93 nM, p=0.015) and FKBP5 (4.77 vs 6.75 nM, p=0.046), and lower IC50 for IL-6 (3.21 vs 5.49 nM, p=0.004) compared to lean individuals, all indicating increased glucocorticoid sensitivity. No difference was found for IL-2. Across all participants, each standard deviation (SD) increase in EC50 of GILZ was associated with lower BMI (β=-2.47, p=0.03). Similar associations were observed for IC50 of IL6 with BMI (β=-2.43, p=0.01) and weight (β=-8.18, p=0.01).
Conclusion: Individuals with obesity exhibited greater glucocorticoid sensitivity compared to lean individuals. Moreover, increased glucocorticoid sensitivity was associated with higher BMI and weight. These findings highlight the potential of targeting glucocorticoid signaling in obesity treatment and raise considerations for personalized corticosteroid dosing in individuals with obesity.
Funding: EFCvR is supported by a Vidi grant from the Netherlands Organisation for Scientific Research (NWO) (grant number: 91716453). EFCvR is also funded by the Elisabeth Foundation.
Disclosures: All authors declare that they have no relevant financial interests or disclosures to report.