Enhanced circadian ACTH release in obese premenopausal women: reversal by short-term acipimox treatment

Abstract

Several studies suggest that the hypothalamopituitary-adrenal (HPA) axis is exceedingly active in obese individuals. Experimental studies show that circulating free fatty acids (FFAs) promote the secretory activity of the HPA axis and that human obesity is associated with high circulating FFAs. We hypothesized that HPA axis activity is enhanced and that lowering of circulating FFAs by acipimox would reduce spontaneous secretion of the HPA hormonal ensemble in obese humans. To evaluate these hypotheses, diurnal ACTH and cortisol secretion was studied in 11 obese and 9 lean premenopausal women (body mass index: obese 33.5 Ϯ 0.9 vs. lean 21.2 Ϯ 0.6 kg/m 2 , P Ͻ 0.001) in the early follicular stage of their menstrual cycle. Obese women were randomly assigned to treatment with either acipimox (inhibitor of lipolysis, 250 mg orally four times daily) or placebo in a double-blind crossover design, starting one day before admission until the end of the blood-sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of plasma ACTH and cortisol concentrations. ACTH and cortisol secretion rates were estimated by multiparameter deconvolution analysis. Daily ACTH secretion was substantially higher in obese than in lean women (7,950 Ϯ 1,212 vs. 2,808 Ϯ 329 ng/24 h, P ϭ 0.002), whereas cortisol was not altered (obese 36,362 Ϯ 5,639 vs. lean 37,187 Ϯ 4,239 nmol/24 h, P ϭ 0.912). Acipimox significantly reduced ACTH secretion in the obese subjects (acipimox 5,850 Ϯ 769 ng/24 h, P ϭ 0.039 vs. placebo), whereas cortisol release did not change (acipimox 33,542 Ϯ 3,436 nmol/24 h, P ϭ 0.484 vs. placebo).In conclusion, spontaneous ACTH secretion is enhanced in obese premenopausal women, whereas cortisol production is normal. Reduction of circulating FFA concentrations by acipimox blunts ACTH release in obese women, which suggests that FFAs are involved in the pathophysiology of this neuroendocrine anomaly. adrenocorticotropic hormone; spontaneous secretion; pituitary adrenal system; free fatty acids; obesity THE ENDOCRINE ENVIRONMENT is a powerful regulator of body fat storage. For example, the hypothalamo-pituitary-adrenal (HPA) ensemble profoundly affects body composition in animals and humans. Glucocorticoid administration promotes body weight gain in rodents (19,26,77), and hypercortisolism in patients with Cushing's syndrome leads in visceral depots to excess fat, which is readily reversed by lowering plasma cortisol levels (45, 70).Obese animal models are marked by an exceedingly active HPA ensemble. Genetically obese rodents have high levels of glucocorticoids (5, 6), adrenalectomy reduces body weight in these animals (12, 21), and subsequent corticosterone replacement restores the obese state (12,22,32,61,76). Adrenalectomy also attenuates diet-induced obesity. Removal of the adrenals reduces energy intake and adipose tissue weights in diet-induced obese rodents, which is reversed by glucocorticoid replacement (18,36,48,62).Various clinical studies suggest that the HPA axis is also h...

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

“…The dose used was 250 mg four times per day starting on the day before blood sampling till the end of sampling. Free fatty acids (FFAs) decreased from 0.52G0.04 to 0.40G0.03 mmol/l, PZ0.005, GH secretion increased by 70%, and ACTH secretion decrease by 30%, as reported previously (12,13). Fourteen other obese women were treated with 5 mg bromocriptine in two divided doses for 10 days in an attempt to improve the metabolic state.…”

“…There is an experimental evidence that FFAs, which are increased in obesity, enhance HPA output through their effects on neuronal control systems in brain centers at the suprapituitary level, and that circulating FFAs are involved in the activation of the HPA axis in obese humans and mammals (12). Therefore, it is interesting to note that short-term treatment with acipimox, which decreased serum FFA and reduced ACTH secretion in the obese cohort, did not impact the dose-response relationship.…”

“…The CRH-ACTH system appears to be activated in obesity, although the number of studies in which spontaneous plasma ACTH secretion patterns were analyzed is rather limited (10,12,33,39). Elevated CRH in obese subjects is likely responsible for the increased ACTH secretion.…”

No effect of free fatty acids on adrenocorticotropin and cortisol secretion in healthy young men

“…In human beings, an activation of the HPA axis was described in different states of elevated FFAs, such as obesity [8,24,25] and diabetes mellitus [26,27]. This hyperactivity of the HPA axis with enhanced responsiveness to stimulation with CRH or arginine vasopressin and to suppression with dexamethasone was particularly observed in individuals with abdominal obesity [24,25,28,29].…”

“…A dose-related increase in corticotropin (ACTH) and corticosterone levels was found after the infusion of lipid emulsion or high-fat diet in rats [5][6][7], suggesting an activation of HPA axis by FFAs. Moreover, Kok and coworkers [8] demonstrated a blunted ACTH release in obese women after reduction of circulating FFAs by acipimox treatment. One action of FFAs in rats seems to be at the hypothalamic or pituitary level of the HPA axis [5].…”