Glucocorticoid mediated regulation of inflammation in human monocytes is associated with depressive mood and obesity

Abstract

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is observed in various conditions, including depression and obesity, which are also often related. Glucocorticoid (GC) resistance and desensitization of peripheral GC receptors (GRs) are often the case in HPA dysregulation seen in depression, and GC plays a critical role in regulation of inflammation. Given the growing evidence that inflammation is a central feature of some depression cases and obesity, we aimed to investigate the immune-regulatory role of GC-GR in relation to depressive mood and obesity in 35 healthy men and women. Depressive mood and level of obesity were assessed, using Beck Depression Inventory (BDI-Ia) and body mass index (BMI), respectively. We measured plasma cortisol levels via enzyme-linked immunosorbent assay and lipopolysaccharide-stimulated intracellular tumor necrosis factor (TNF) production by monocytes, using flow cytometry. Cortisol sensitivity was determined by the difference in monocytic TNF production between the conditions of 1 and 0 μM cortisol incubation (“cortisol-mediated inflammation regulation, CoMIR”). GR vs. mineralocorticoid receptor (MR) antagonism for CoMIR was examined by using mifepristone and spironolactone. A series of multiple regression analyses were performed to investigate independent contribution of depressive mood vs. obesity after controlling for age, gender, systolic blood pressure (SBP), and plasma cortisol in predicting CoMIR. CoMIR was explained by somatic subcomponents of depressive mood (BDI-S: β= −0.499, p= 0.001), or BMI (β= −0.466, p< 0.01) in separate models. The effects of BMI disappeared when BDI-S was controlled for in the model, while BDI-S remained a significant independent predictor for CoMIR (β= −0.369, p< 0.05). However, BMI remained the only independent predictor when BDI-T or BDI-C were controlled for in the model. Mediation analyses also revealed that the relationship between BMI and CoMIR was mediated by BDI-S. The exploratory findings of the relative GR vs. MR roles in CoMIR, using GR and MR blockers, indicated that CoMIR in our cellular model was predominantly mediated by GRs at the higher cortisol dose (1 μM). There was initial indication that greater obesity and somatic depressive symptoms were associated with smaller efficacy of the blockers, which warrants further investigation. Our findings, although in a preclinical sample, signify the shared pathophysiology of immune dysregulation in depression and obesity and warrant further mechanistic investigation.

Acute Strenuous Exercise Induces an Imbalance on Histone H4 Acetylation/Histone Deacetylase 2 and Increases the Proinflammatory Profile of PBMC of Obese Individuals

“…However, our study revealed that the higher levels of cortisol found in the obese group have no effect in acetylation-deacetylation events in PBMC of obese individuals. In fact, the immunosuppressive action of cortisol in LPS-stimulated monocytic production of TNF- α was inhibited in obese subjects [ 41 ]. Thus, the impaired cortisol action on PBMC of obese individuals may contribute to the enhancement in proinflammatory cytokine production and histone H4 hyperacetylation in obesity.…”

Anxiety independently contributes to elevated inflammation in humans with obesity

“…Thus, our results extend previous findings to a more representative cohort of adults with obesity not awaiting bariatric surgery but at high CVD risk. The abolishment of the relation between CRP and depression after adjusting for BMI suggests that obesity and depression might share overlapping pathways of inflammatory activation , whereas anxiety modulates inflammation in persons with obesity at least partly through mechanisms independent of adiposity.…”

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad

“…Greater NFκB DNA-binding concurrent with blunted glucocorticoid sensitivity has been reported in women with childhood abuse-related post-traumatic stress disorder (PTSD) (Pace, Wingenfeld et al 2012). Diminished suppression of inflammation by cortisol in monocytes was associated with increased depressive mood in patients (Cheng, Dimitrov et al 2016). Conversely, cognitive-behavioral stress management has been found to reverse anxiety-related upregulation of pro-inflammatory transcripts in leukocytes of women undergoing breast cancer treatment (Antoni, Lutgendorf et al 2012).…”