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Inhibition of Cortisol Biosynthesis Decreases Circulating Leptin Levels in Obese Humans

Department of Medicine and General Clinical Research Center (S.D.-J.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; and Division of Endocrinology, Diabetes and Metabolism (G.T., I.U.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Samuel Dagogo-Jack, M.D., University of Tennessee College of Medicine, 956 Court Avenue, Suite D334, Memphis, Tennessee 38163. E-mail: sdj{at}utmem.edu.

Abstract

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 µg/dl during placebo and 2.80 ± 0.65 µg/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.

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