Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss

Abstract

Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (S(I)) by frequently sampled intravenous glucose tolerance test; and adipocyte 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased S(I). Increased 11beta-HSD-1 gene expression correlated with both IAF and SQF and with decreased S(I). With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11beta-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11beta-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.

Fig. 1.

Top: linear regression analysis with 95% confidence intervals for 24-h cortisol production rates adjusted for body surface area (CPR/BSA) vs. intra-abdominal fat (IAF) (r = 0.53, P = 0.01; left) and 24-h plasma free cortisol levels vs. IAF (r = 0.45, P = 0.04; right). CPR vs. IAF, r = 0.59, P = 0.005 (graph not shown). Bottom: linear regression analysis with 95% confidence intervals for CPR/BSA vs. insulin sensitivity (S_I) (r = −0.58, P = 0.003; left) and 24-h plasma free cortisol levels vs. S_I (r = −0.50, P = 0.01; right). CPR vs. S_I, r = −0.70, P < 0.001 (graph not shown).

Fig. 2.

Mean ± SE plasma total cortisol levels sampled every 30 min over 24 h in the subjects with the least amount of IAF (1st tertile, ○; n = 7) and the subjects with the greatest amount of IAF (3rd tertile, •; n = 7). Median 24-h area under the curve (AUC): total cortisol 6,120 μg-day/dl vs. 8,330 μg-day/dl, 1st vs. 3rd tertile, P = 0.01. Lines and P values signify AUC values during 6-h time blocks that are different in the 1st vs. 3rd tertiles.

Fig. 3.

CPR in relationship to fat-free mass (FFM), fat mass (FM), and IAF before (Pre) and after (Post) a period of caloric restriction-induced weight loss.

Fig. 4.

Twenty-four-hour free cortisol levels in relationship to FFM, FM, and IAF, before (Pre) and after (Post) a period of caloric restriction-induced weight loss.