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.
Department of Medicine, University of Tennessee College of Medicine, 956 Court Avenue, Suite D334, Memphis, Tennessee 38163, USA. sdj@utmem.edu
Samuel
S
Dagogo-Jack
Gunjan
G
Tykodi
Indira
I
Umamaheswaran
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