Robin Lengton1, Mariëtte R Boon1, Anand I Iyer1, Mostafa Mohseni1, Ceyda Ilhan1, Jordy Renes1, Wim A Dik2, Eline S van der Valk1, Sjoerd AA van den Berg3, Jenny A Visser1, Elisabeth FC van Rossum1
(1) Obesity Center CGG, Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
(2) Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
(3) Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Introduction
Evidence suggests a link between 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 remains unclear. This study compared glucocorticoid sensitivity in individuals with obesity and lean controls using an in vitro glucocorticoid sensitivity assay.
Methods
Peripheral blood mononuclear cells (PBMCs) were collected 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 incubated with increasing concentrations of dexamethasone (DEX; 0.33-1000 nM) for 4 hours. Glucocorticoid sensitivity was assessed by calculating the half maximal effective concentration (EC50) for DEX-induced transactivation of GILZ and FKBP5, and the half maximal inhibitory concentration (IC50) for DEX-mediated transrepression of IL-2 and IL-6.
Results
Compared with lean controls, individuals with obesity displayed 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 values for IL-6 (3.21 vs. 5.49 nM, p=0.004), indicating increased glucocorticoid sensitivity. No group difference was observed for IL-2. Across all participants, each standard deviation increase in EC50 for GILZ was associated with lower BMI (β =-2.47, p=0.03); similar associations were found for IC50 of IL-6 with BMI (β =-2.43, p=0.01) and weight (β =-8.18, p=0.01).
Conclusion
Individuals with obesity exhibit greater glucocorticoid sensitivity, which is linked to higher BMI and weight. These findings suggest a role for glucocorticoid signaling in obesity pathophysiology and may have implications for personalized corticosteroid therapy.