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

Abstract

Purnell JQ, Kahn SE, Samuels MH, Brandon D, Loriaux DL, Brunzell JD. Enhanced cortisol production rates, free cortisol, and 11␤-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss. Am J Physiol Endocrinol Metab 296: E351-E357, 2009. First published December 2, 2008; doi:10.1152/ajpendo.90769.2008.-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; intraabdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (SI) by frequently sampled intravenous glucose tolerance test; and adipocyte 11␤-hydroxysteroid dehydrogenase-1 (11␤-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 SI. Increased 11␤-HSD-1 gene expression correlated with both IAF and SQF and with decreased SI. 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 11␤-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 11␤-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.obesity; metabolic clearance rate; disposition index EXCESS ACCUMULATION of abdominal fat occurs in men and is a risk factor for both type 2 diabetes and cardiovascular disease (9,11,22). A number of specific mechanisms that could mediate selective uptake of fat into the visceral depot have been proposed, including both dysregulation of central pituitary hormone secretion and alterations in fat cell-and depotspecific gene and enzyme activities (6,23,27).Hypercortisolemia, or Cushing's syndrome, can lead to central obesity and type 2 diabetes. Many studies of subjects selected only for obesity have found that while cortisol production rates (CPR) are increased compared with those in lean control subjects, this difference is no longer significant after adjusting for body size (usually body surface area) and that levels of total and free cortisol are not different between lean and obese groups (29, 36 -38). Therefore, the balance of evidence does not support a role of increased cortisol secretion contributing to generalized adiposity (29, 41...

Effects of energy restriction on activity of the hypothalamo-pituitary-adrenal axis in obese humans and rodents: implications for diet-induced changes in body composition

“…These findings support a shorter-term study that showed no differences in salivary cortisol levels following 18 days on a moderately energy-restricted diet of 1000 kcal/day [54]. Also, 3 months on a moderately energy-restricted diet of 1000 kcal/day, followed by a period where participants were transitioned back to solidfoods over 2 weeks and then spent 3 months on a weight maintenance diet, had no effect on cortisol production rate, either absolute values or normalized to fat free mass [55]. However, in that study cortisol production rate normalized to fat mass or intra-abdominal fat mass increased by 40% and 100%, respectively, after weight loss [55].…”

“…Also, 3 months on a moderately energy-restricted diet of 1000 kcal/day, followed by a period where participants were transitioned back to solidfoods over 2 weeks and then spent 3 months on a weight maintenance diet, had no effect on cortisol production rate, either absolute values or normalized to fat free mass [55]. However, in that study cortisol production rate normalized to fat mass or intra-abdominal fat mass increased by 40% and 100%, respectively, after weight loss [55]. While these three studies involving moderate energy restriction showed no clear changes in HPA axis function, another study of a 90-day diet of 800 -1500 kcal/day in obese women showed decreased ACTH and cortisol levels measured during an oral glucose tolerance test [56].…”

Association of serum cortisol levels with parameters of metabolic syndrome in men and women

“…Previous studies suggested that increased serum cortisol level in men is mainly mediated through 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) activity [24,25]. 11b-HSD1is a bidirectional enzyme, located in the abdominal fat mass and omental subcutaneous tissue, and mediates the conversion of cortisone to cortisol [26,27] thermore there are gender di erences in 11b-HSD1 activity, which is greater in men [20], and 5a-reductase activity, which is greater in women [28].…”

Sex defines the age dependence of endogenous ACTH-cortisol dose responsiveness

“…In a group of 24 men and 30 women (ages 19 -70 yr, BMI 19 -64 kg/m 2 ), daily cortisol production rates ranged from 6.6 to 39 mol/m 2 based upon isotope-dilution mass spectrometry (55,56 (9,42)]. In contrast, analytically estimated ACTH efficacy (defined by asymptotically maximal ACTH-stimulated pulsatile cortisol secretion) would be 136 and 113 mol/day in men and women, respectively.…”