Several studies suggest that the hypothalamo-pituitary-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 +/- 0.9 vs. lean 21.2 +/- 0.6 kg/m(2), P < 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 +/- 1,212 vs. 2,808 +/- 329 ng/24 h, P = 0.002), whereas
cortisol was not altered (obese 36,362 +/- 5,639 vs. lean 37,187 +/- 4,239 nmol/24 h, P = 0.912).
Acipimox significantly reduced
ACTH secretion in the obese subjects (
acipimox 5,850 +/- 769 ng/24 h, P = 0.039 vs. placebo), whereas
cortisol release did not change (
acipimox 33,542 +/- 3,436 nmol/24 h, P = 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.