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


METHODS
A randomized, placebo-controlled, cross-over study design was used.


METHODS
The study was carried out at a General Clinical Research Center.


METHODS
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.


METHODS
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.


METHODS
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.
Dagogo-Jack
Samuel
S
Department of Medicine, University of Tennessee College of Medicine, 956 Court Avenue, Suite D334, Memphis, Tennessee 38163, USA. sdj@utmem.edu
Tykodi
Gunjan
G
Umamaheswaran
Indira
I
D000328:Adult; D000963:Antimetabolites / Q000627:therapeutic use*; D002096:C-Peptide / Q000037:antagonists & inhibitors / Q000097:blood; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000097:blood; D008297:Male; D008797:Metyrapone / Q000627:therapeutic use*; D009765:Obesity / Q000097:blood* / Q000188:drug therapy*
D000963:Antimetabolites; D002096:C-Peptide; D020738:Leptin; D006854:Hydrocortisone; D008797:Metyrapone