UC San Diego

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is most significantly studied via glucocorticoid (GC) receptor desensitization and has been associated with depression, inflammation, and also obesity, while various bidirectional links seem to exist also between these variables. To understand better and characterize the relationship between GC desensitization and these health variables, we recruited 36 average health participants and assayed their obesity via body mass index (BMI), depressive mood via Beck Depression Inventory (BDI-Ia), plasma cortisol via ELISA, and LPS stimulated monocyte TNF production via whole blood incubation with receptor agonists and antagonists for GC. Cortisol sensitivity was characterized as change in percent monocyte TNF production from baseline to inhibited conditions. The main findings were that % TNF+ monocytes without cortisol correlated with depressive mood (BDI-S: r= -0.336, p= 0.045), as did depressive mood with cortisol sensitivity after controlling for population demographics (BDI-S: [Beta]= - 0.289, p= 0.013). BMI also independently correlated with cortisol sensitivity (BMI:[Beta]= -0.273, p= 0.020). With demographics, BMI, BDI-S, % TNF+ monocytes without cortisol in the final multiple regression model, only BDI- S ([Beta]= -0.215, p= 0.074) and % TNF+ monocytes [Beta]= 0.546, p= 0.000) still predicted cortisol sensitivity. Secondary findings with antagonists saw that relative blocking effect of mifepristone increases with increasing concentration of cortisol inhibition, while not with spironolactone. Our results find a strong relationship between the triad of HPA dysregulation, depression, and obesity through the inflammatory potential of monocytes. This preclinical sample reinforces significance of the pathophysiological triad, though require further mechanistic exploration