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Inhibition of cortisol biosynthesis decreases circulating leptin levels in obese humans.

Dagogo-Jack S, Tykodi G, Umamaheswaran I

Department of Medicine, University of Tennessee College of Medicine, 956 Court Avenue, Suite D334, Memphis, Tennessee 38163, USA. sdj@utmem.edu

CONTEXT: Glucocorticoids increase both appetite and leptin secretion; the hyperleptinemic effect might be a counterregulatory response to the orexigenic effect of glucocorticoids. However, the effect of glucocorticoid inhibition on leptin production has not been reported. OBJECTIVE: We tested the hypothesis that if glucocorticoid-induced hyperleptinemia plays a physiological role, then inhibition of endogenous cortisol biosynthesis should decrease leptin secretion. DESIGN: A randomized, placebo-controlled, cross-over study design was used. SETTING: The study was carried out at a General Clinical Research Center. PARTICIPANTS: Eight obese subjects (four men, four women; mean age, 30.4 +/- 1.56 yr; mean body mass index, 42.0 +/- 1.33 kg/m2) participated in the study. Intervention: The subjects were treated with metyrapone (750 mg every 4 h) or placebo for 24 h during two overnight admissions, 2 wk apart. Blood sampling for measurement of cortisol, leptin glucose, insulin, and C-peptide was performed hourly for 6 h and every 2 h for 24 h. MAIN OUTCOME MEASURE: The change in plasma leptin from baseline during metyrapone vs. placebo treatment was measured. RESULTS: Metyrapone treatment was associated with a significant decrease in plasma cortisol level; the cortisol nadir was 4.84 +/- 1.22 microg/dl during placebo and 2.80 +/- 0.65 microg/dl during metyrapone treatment (P = 0.009). Compared with placebo, metyrapone treatment was associated with a significant reduction in circulating leptin levels and marked attenuation of the nocturnal rise in plasma leptin (+28.45 +/- 11.12% vs. +55.51 +/- 5.42%; P = 0.01). CONCLUSIONS: We conclude that metyrapone-induced inhibition of cortisol biosynthesis results in hypoleptinemia, which indicates that glucocorticoids may play an important role in the physiological regulation of leptin.

Published 8 September 2005 in J Clin Endocrinol Metab, 90(9): 5333-5.
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