Increased hypothalamo-pituitary-adrenal axis drive has been reported in obese subjects but with paradoxically low or normal levels of plasma cortisol. Our current study was designed to investigate whether glucocorticoid feedback was altered in obesity, both under basal and stressed conditions. Plasma ACTH and cortisol concentrations in male control or obese subjects (age range 20-50 yr) were measured at frequent intervals over 24 h during infusion of saline or hydrocortisone at two physiological doses (7.5 and 15 mg/d) designed to occupy predominantly mineralocorticoid rather than glucocorticoid receptors. The same subjects then underwent insulin-induced hypoglycemia either in the morning or the evening. Obese subjects had significantly higher basal ACTH and lower cortisol concentrations throughout the 24 h infusion period, compared with controls (P < 0.05, two-way ANOVA followed by Newman-Keuls posthoc analysis). Basal plasma ACTH was decreased in obese groups given low- or high-dose hydrocortisone during the day (P < 0.05) but not during the night, unlike controls who responded to hydrocortisone both during the day and at night (P < 0.05). Obese subjects also showed resistance to steroid-induced inhibition of the ACTH response to hypoglycemia, compared with controls (P < 0.05). These data clearly show that obesity is associated with a relative insensitivity to glucocorticoid feedback, which is most marked during the night, and suggest that this condition is characterized by a decreased mineralocorticoid receptor response to circulating corticosteroids.