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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.
GLUCOCORTICOIDS ARE KNOWN to increase both appetite and leptin secretion (1, 2, 3, 4, 5). We had previously suggested (3, 6) that the hyperleptinemic effect might be a counterregulatory response to the orexigenic effect of glucocorticoids, thus implying physiological relevance. However, others have argued that the interaction between glucocorticoids and leptin might represent a pharmacological phenomenon of doubtful physiological significance (7). We recently showed that augmentation of endogenous leptin secretion with hydrocortisone treatment decreases voluntary caloric intake in humans (8). To further evaluate the physiological significance of glucocorticoid-leptin interaction, in the present report we have tested the hypothesis that if the glucocorticoids play a physiological role in leptin regulation, then inhibition of endogenous cortisol biosynthesis should decrease leptin secretion.
The hypothesis was tested among obese but otherwise healthy subjects whose known high levels of circulating leptin would facilitate the detection of decreases in leptin output. Moreover, obesity also is associated with hypercortisolemia, which we reasoned would be a favorable milieu to test the effects of inhibition of steroidogenesis with metyrapone. Our studies demonstrate that administration of metyrapone resulted in reduced cortisol output, which was associated with hypoleptinemia. This finding strengthens the physiological relevance of glucocorticoid-leptin interaction.
Subjects and Methods
We studied eight obese adult (four men, four women) subjects whose mean age was 30.4 ± 1.56 yr and mean body mass index was 42.0 ± 1.33 kg/m2. The subjects had no history of diabetes or current or previous use of glucocorticoids or other medications that alter appetite, body weight, or glucoregulatory physiology. No subject was enrolled in any active weight loss program. All subjects had normal fasting glucose levels and gave written informed consent before enrollment in this study, which was approved by the Washington University Human Studies Committee. Study subjects were admitted to the General Clinical Research Center after an overnight fast on two occasions, separated by 2 wk. On each occasion, the subjects received either metyrapone (750 mg orally every 4 h) or placebo for 24 h, in random fashion. The study subjects ate a standard diet (54% carbohydrate, 28% fat, and 18% protein and approximately 3000 kcal/day) consisting of three meals and snacks during each entry, and they and the investigators were masked as to the order of administration of the placebo or metyrapone treatments. An indwelling iv line for blood sampling was established in an antecubital vein and a slow iv infusion of normal saline (0.9%) was administered in the contralateral arm throughout the studies. Heart rate and blood pressure were monitored continuously during each 24-h period of study. Blood sampling for measurement of glucose, insulin, cortisol, and leptin was performed at baseline, hourly during the initial 6 h, and every 2 h for the remainder of the 24-h period of infusion.
Biochemical analyses
Plasma leptin was measured with an in-house RIA using a commercial kit (Linco Research, St. Louis, MO). Samples were assayed in duplicate and the limits of detection and linearity for the leptin RIA were 0.5 and 100 ng/ml, respectively; the intra and interassay coefficients of variation were less than 7% (9). Plasma insulin (10), C-peptide (10), and cortisol (11) levels were measured with RIAs. Plasma glucose was measured with a glucose oxidase method (Beckman Instruments, Fullerton, CA).
Statistical analysis
Data are expressed as means ± SEM. To account for individual and gender differences in baseline leptin levels, values are expressed as a percentage of baseline during metyrapone or placebo treatment. Serial plasma levels of leptin, insulin, C-peptide, cortisol, and glucose during metyrapone or placebo treatment were analyzed using repeated measures ANOVA with Dunnett’s test to confirm specific differences. Paired t tests were used to analyze differences in mean plasma values of hormones and metabolites during placebo or metyrapone treatment. Statistical analyses were run on an IBM StatView program (SAS Institute Inc., Cary, NC). P < 0.05 was accepted as significant.
Results
Metyrapone treatment was well tolerated at the dosage used; nausea was the most frequent adverse effect, and was reported by most of the study subjects. None of the subjects had hypotension or electrocardiographic abnormalities during the study. The inhibitory effect of metyrapone on plasma cortisol became evident after 6 h and was maximal at 12 h, after which a tendency to escape was noted, despite continued medication. The plasma cortisol nadir was 4.84 ± 1.22 µg/dl (133.50 ± 33.66 nmol/liter) during placebo and 2.80 ± 0.65 µg/dl (77.25 ± 17.93 nmol/liter) during metyrapone treatment (P = 0.009) (Fig. 1
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). Compared with placebo, a significant decrease in circulating leptin levels occurred within 6 h of metyrapone treatment and persisted for the remainder of the study period. Notably, the well-known nocturnal rise in plasma leptin between 2000–0200 h was markedly attenuated during treatment with metyrapone. The peak nocturnal leptin attained was 55.51 ± 5.42% above baseline during placebo treatment as compared with 28.45 ± 11.12% above baseline during metyrapone treatment (P < 0.01).
Meal-stimulated increases in plasma glucose levels were similar during metyrapone or placebo treatment (Fig. 2). This was generally mirrored by the insulin secretory pattern, as indicated by plasma C-peptide levels (Fig. 2). However, a tendency toward lower C-peptide levels was observed during metyrapone treatment as compared with placebo; the difference was significant (P = 0.04) at the 5-h study time point.
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Glucocorticoids stimulate appetite (1) and increase body weight. The orexigenic effect of glucocorticoids is mediated, at least in part, by augmentation of the hypothalamic feeding signal neuropeptide Y (11), an effect that is inhibited by leptin (12). The metabolic effects of leptin result from coordinate activation of anorexigenic pathways and inhibition of orexigenic pathways mediated by leptin-responsive neurons in the hypothalamus (13, 14). Because leptin has anorexigenic and insulin-sensitizing properties (15, 16), we hypothesized (3) that glucocorticoid-induced hyperleptinemia is a physiological (counterregulatory) mechanism designed to limit the hyperphagia, weight gain, and the insulin resistance associated with glucocorticoid excess. If indeed glucocorticoids are so involved in the physiological regulation of leptin, then inhibition of endogenous steroidogenesis should decrease leptin secretion.
The results of the present study show that treatment with metyrapone, which blocks 11-b-hydroxylase (the final enzyme in cortisol biosynthesis), results in a reduction in plasma leptin levels in humans. Numerous previous reports have observed a stimulatory effect of glucocorticoids on leptin synthesis and secretion (2, 3, 4, 5, 17). The present report documents the obverse, namely, that inhibition of steroidogenesis attenuates circulating leptin levels. This is a novel contribution that strengthens the existing body of knowledge on the regulation of leptin by glucocorticoids. Based on these data, it is likely that the glucocorticoid-leptin interaction may be of physiological relevance (18).
Clinical examples of glucocorticoid deficiency (such as patients with Addison’s disease) are associated with anorexia and weight loss. In such patients, it is physiologically appropriate for circulating levels of the anorexigenic hormone leptin to be suppressed. On the other hand, circulating leptin levels predict survival in patients with septic shock, many of whom have evidence of relative glucocorticoid deficiency (19). The present study is limited by the small sample size and high body mass index of the study subjects. It will be interesting to determine whether leaner subjects, with low baseline leptin levels, would show a similar hypoleptinemic response to metyrapone. In conclusion, our data indicate that inhibition of cortisol biosynthesis decreases plasma leptin levels, which suggests that the interaction between the two hormones may be physiologically significant.
Footnotes
This study was supported by an American Diabetes Association Clinical Research Grant and National Institutes of Health Grants MO1 RR00036 and P60 DK20579. S.D.-J. is supported in part by National Institutes of Health Clinical Research Center Grant MO1 RR00211.
First Published Online June 28, 2005
Received April 12, 2005.
Accepted June 16, 2005.
References
This article has been cited by other articles:
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  K. K. Koh, S. M. Park, and M. J. Quon Leptin and Cardiovascular Disease: Response to Therapeutic Interventions Circulation, June 24, 2008; 117(25): 3238 - 3249. [Full Text] [PDF]
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 B. Laferrere, C. Abraham, M. Awad, S. Jean-Baptiste, A. B. Hart, P. Garcia-Lorda, P. Kokkoris, and C. D. Russell Inhibiting Endogenous Cortisol Blunts the Meal-Entrained Rise in Serum Leptin J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2232 - 2238. [Abstract] [Full Text] [PDF]
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). Significant decreases in plasma cortisol and leptin occurred within 6 h. To convert cortisol from milligrams per deciliter to nanomoles per liter, multiply by 27.59. *, P < 0.05; **, P < 0.01.