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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0693
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 6 2232-2238
Copyright © 2006 by The Endocrine Society

Inhibiting Endogenous Cortisol Blunts the Meal-Entrained Rise in Serum Leptin

Blandine Laferrère, Cynthia Abraham, Marianne Awad, Stephanie Jean-Baptiste, Allison B. Hart, Pilar Garcia-Lorda, Peter Kokkoris and Colleen D. Russell

Obesity Research Center, St. Luke’s/Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York 10025

Address all correspondence and requests for reprints to: Dr. Blandine Laferrère, Obesity Research Center, St. Luke’s/Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, 1111 Amsterdam Avenue, New York, New York 10025.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Administration of glucocorticoids increases serum leptin levels in lean and obese individuals. A morning meal produces an increase in insulin, a cortisol peak, and an increase in leptin; these changes do not occur during fasting.

Objective: The objective of this study was to investigate whether inhibiting endogenous cortisol secretion with metyrapone decreases 24-h serum leptin levels and to determine whether a meal-related midmorning surge in cortisol is a prerequisite for the meal-entrained nocturnal rise in leptin.

Design: This was a randomized, cross-over study.

Setting: The study was performed at the General Clinical Research Center.

Participants: Lean males were studied.

Intervention: In study 1, seven lean men were studied for 24 h while their endogenous cortisol secretions were manipulated as follows: 1) CONTROL; 2) cortisol suppression by metyrapone (MET); and 3) MET and oral hydrocortisone (at 0900 h) (MET + CORT). Subjects were all fed a eucaloric diet (two meals at 1100 and 1700 h). In study 2, six men were studied without pharmacological intervention for 24 h on two occasions: once under a complete fast (FAST) and once in a feeding condition (one meal at 1100 h; FED).

Main Outcome Measure: The main outcome measure was serum leptin.

Results: MET significantly suppressed serum cortisol at 0800 h, midmorning, and over the 24-h period. As a result of cortisol suppression, 24-h serum leptin levels were decreased vs. control values despite similar insulin responses to meals. Administering a single dose of hydrocortisone to MET subjects potently stimulated serum leptin compared with the effect of MET alone.

Conclusions: Our data demonstrate that endogenous cortisol secretion is necessary for the maintenance of serum leptin levels over 24 h in lean, normally fed males.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LEPTIN, THE PRODUCT of the obese (ob) gene secreted by adipose tissue, circulates in the blood and acts mainly at the level of the hypothalamus to regulate energy balance (1, 2). Circulating leptin follows a diurnal pattern, with a nocturnal rise between midnight and early morning and a nadir between noon and midafternoon (3, 4, 5, 6). This nocturnal rise in leptin is influenced by daytime feeding and is prevented by fasting (7). The absolute increase in leptin levels from nadir to peak is related to insulin excursions in response to meals (8, 9). Although the underlying mechanism of the leptin rhythm is not fully understood, the available literature strongly supports the idea that the leptin rhythm is more closely dependent on meal-related timing than on the circadian clock or sleep cycles (6, 10).

Glucocorticoids play a key role in the positive regulation of energy balance (11). Hypercortisolism or hypersensitivity to glucocorticoids has a permissive effect on the development of obesity with central distribution of fat (12). The secretion of cortisol is the result of the complex interaction between the hypothalamo-pituitary-adrenal axis, the central nervous system, and nutritional status. Serum cortisol levels follow a nycthemeral variation dependent on the day-night cycle (10, 13). However, the midday cortisol surge is directly related to meal intake (14, 15, 16, 17). The variation in cortisol concentration that normally occurs over a 24-h period has been shown to have both immediate and delayed effects on glucose metabolism (18) or lipolysis (19). In parallel to these experiments, our in vivo data showed a delayed stimulatory effect of administration of the synthetic glucocorticoid dexamethasone on serum leptin. We reported an interaction between exogenous glucocorticoids and insulin in the up-regulation of serum leptin in human subjects (20, 21). Food or insulin, if given with dexamethasone, stimulates a 50–100% rise in leptin, occurring 5–10 h later (20, 22). The stimulation of serum leptin by glucocorticoid seems to require either a positive feeding state (17) or a hyperglycemic hyperinsulinemic state, however transient (1–2 h) (22).

Food intake in the morning produces an acute increase in insulin, a spike in cortisol at midday (14, 15, 16, 17), and an increase in leptin levels at night (9). During fasting, insulin levels are low, cortisol levels do not peak in the midmorning, and leptin levels do not rise at night (7). Manipulation of circulating insulin levels by fasting (7), food intake (20), or insulin administration (22, 23) clearly shows the stimulatory role of insulin on leptin. Similarly, glucocorticoid administration has shown to have a positive effect on leptin (24, 25, 26). However, it is unclear whether endogenous glucocorticoids exert a physiological effect on leptin secretion (27). Specifically, it is unclear whether the physiological, meal-related, midday cortisol surge is a prerequisite for the nocturnal meal-entrained rise in leptin.

The goals of this study were to investigate 1) whether manipulating endogenous cortisol levels affects serum leptin concentration, and 2) whether the midmorning cortisol surge is necessary for the meal-related insulin effect on leptin. We hypothesized that by blocking the adrenal production of cortisol with metyrapone, 24-h leptin levels would be lower. In particular, we believed the nocturnal rise in serum leptin levels in response to daytime food intake would be blunted in subjects receiving metyrapone. It therefore follows that the administration of hydrocortisone should simulate the morning surge and restore the nocturnal leptin response to the meal in subjects receiving metyrapone.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A total of 13 men (nonobese, healthy, nonsmoking, not taking any medications, aged 18–27 yr, stable body weights for at least 3 months, normal blood chemistry, thyroid function, and oral glucose tolerance test) completed the study. Seven men participated in study 1 and six in study 2. None was depressed, with Beck scores less than 5 (28). Total body fat (13 ± 2%) was measured by plethysmography (29) (study 1) or dual x-ray absorptiometry (30) (study 2). The study protocol was approved by the institutional review board of St. Luke’s Hospital, and informed written consent was obtained.

Study 1

Twenty-four-hour leptin levels were tested under three conditions: 1) CONTROL: no pharmacological intervention; 2) MET: a dose of 500 mg metyrapone was given orally every 4 h starting at midnight on the morning of the experiment for a total of eight doses to suppress 24-h serum cortisol levels; and 3) MET+CORT: 25 mg hydrocortisone was given orally at 0900 h to simulate a midmorning cortisol surge in subjects receiving metyrapone. Feeding and/or insulin are strong regulators of leptin. To single out the influence of endogenous glucocorticoids on leptin, subjects were required to eat two meals (at 1100 and 1700 h) with fixed caloric content and identical food items to ensure a similar insulin response between the CONTROL and MET conditions. Therefore, under all three conditions, subjects were fed the same eucaloric diet with two fixed meals at 1100 and at 1700 h. In CONTROL, no placebo pill was administered.

Each study was separated by at least 14 d, and the order was randomized. Subjects came to the General Clinical Research Center before 2100 h the night before the experiment. An iv catheter was inserted into an antecubital vein the following morning at 0800 h, and the iv line was kept open with 0.45% sodium chloride to allow for blood sampling at 30-min intervals starting at 0800 h on the morning of the experimental day. Lights were turned off at 2300 h and on at 0700 h. Subjects were asked to remain in the recumbent position, except for bathroom privileges. Blood samples were kept on ice before centrifugation, and the serum was frozen at –20 C for later hormonal assessments.

Cortisol level manipulations

The goal of this experiment was to determine whether 24-h serum leptin levels are altered when endogenous cortisol levels are reduced. Metyrapone, an adrenal 11-hydroxylase blocker (31), was the tool used to block the endogenous adrenal production of cortisol and to put subjects into an artificial state of reduced cortisol secretion. Cortisol levels were further manipulated through oral hydrocortisone administration (25 mg) 2 h before the meal (at 0900 h) to mimic the morning cortisol surge (32) in subjects who were given metyrapone. During a preliminary experiment, the administration of a 750-mg metyrapone dose was very poorly tolerated in three lean subjects, who experienced headache, nausea, and vomiting, and the administration of metyrapone had to be discontinued. Therefore, the better-tolerated 500-mg dose of metyrapone was employed for study 1.

Diet

All subjects were given a diet based upon a calculation of 35 kcal/kg·d to prevent caloric restriction that could impair leptin secretion. The diet was split into a 1500-kcal fixed meal at 1100 h and a dinner at 1700 h consisting of the remaining calories. The midday mixed meal composition was as follows: English muffins with butter, macaroni and cheese, yogurt, apple juice, cereal bar, and ice cream. The breakdown of this meal consisted of 55% carbohydrate (CHO), 15% protein (PROT), and 30% fat. Subjects were instructed to eat all the food served. Platters were weighed before and after meals to ensure compliance. Nutritionist IV software was used for nutritional analysis (Nsquared Computing, Salem, OR). The diet was identical for each condition.

Study 2

Six other subjects were studied under two 24-h conditions: fasting (FAST) and feeding (FED). In FED, subjects received a single fixed 1700-kcal meal (55% CHO, 15% PROT, and 30% fat) at 1100 h with similar food items as in experiment 1. During FAST, only ad libitum tap water was allowed orally. The total length of the fast was 35 h (overnight fast plus 24-h fast). Detailed methods and partial results for insulin and leptin from this study were previously published (21). The data for cortisol levels during FAST and FED reported in this study have not been previously published.

Analytical methods (studies 1 and 2)

Glucose was measured with a glucose analyzer (Beckman Instruments, Inc., Fullerton, CA). Serum insulin and leptin were measured by RIAs (Linco Research, Inc., St. Charles, MO) and cortisol (Diagnostic Products Corp., Los Angeles, CA), with intra- and interassay coefficients of variations of 6% and 8% for leptin and cortisol and of 7% and 10% for insulin, respectively. All samples were assayed in duplicate and analyzed simultaneously.

Statistical analysis (studies 1 and 2)

Outcome variables were serum leptin, cortisol, and insulin levels. Raw leptin values were log transformed. Areas under the curve (AUC) for different variables were also calculated using the trapezoidal method to determine changes over time for each condition. The 24-h period was divided into time intervals for ease of analysis. A general linear model with repeated measures was used to detect hormonal changes over time and between conditions (CONTROL, MET, and MET+CORT). Paired t tests were used to compare data between FED and FAST conditions in study 2. Data are expressed as the mean ± SEM. Significance was assumed for P < 0.05. Statistical analyses were performed with programs from SPSS, Inc. (version 11.5, Chicago, IL) (33).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Subject characteristics for studies 1 and 2 are shown in Table 1Go.


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  		TABLE 1. Subject characteristics

 
Study 1

No side effects were observed with the 500-mg dose of metyrapone.

Food intake

Subjects ate 1487 ± 51 kcal (6222 ± 213 kJ) during the fixed 1100 h meal and 937 ± 231 kcal [3920 ± 966 kJ; range, 834-1040 kcal (3489–4351 kJ)] during the 1700 h meal. Food intake at each meal and total 24-h food intake were not different between each condition for each subject (data not shown).

Cortisol

In MET (compared with CONTROL), baseline serum cortisol levels at 0800 h were decreased by 32.6 ± 14.1% (P = 0.034), the midmorning peak of cortisol (AUC 0800–1400 h) was decreased by 47.6 ± 5.6% (P = 0.002), and the mean 24-h AUC of cortisol was decreased by 20 ± 6% (P = 0.016; Table 2Go and Fig. 1AGo).


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  		TABLE 2. Study 1: changes in serum cortisol, insulin, and leptin during CONTROL, MET, and MET + CORT conditions

 

Figure 1
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  		FIG. 1. Study 1: serum cortisol (A), insulin (B), and leptin (C) levels and leptin change from baseline (D) during control ({blacksquare}), MET ({blacktriangleup}), and MET+CORT (•) conditions in seven subjects. The two arrows indicate meal times at 1100 and 1700 h. In MET ({blacktriangleup}), metyrapone (500 mg) was administered orally every 4 h starting at 2400 h before beginning sampling at 0800 h. In CORT (•), metyrapone was administered similarly to MET, and hydrocortisone (25 mg) was administered once orally at 0900 h, 2 h before the first meal.

 
When endogenous cortisol was suppressed by metyrapone (MET), a single replacement dose of hydrocortisone (MET+CORT), given orally, significantly increased midmorning serum cortisol levels by 187.3 ± 48% (P = 0.002) and 24-h serum cortisol by 126 ± 20% (P = 0.008) compared with CONTROL (Table 2Go and Fig. 1AGo).

Insulin

The administration of metyrapone altered neither the food-related insulin response to the meal (measured as the AUC between 1100 and 2000 h) nor the 24-h insulin levels (MET vs. CONTROL, not significant; Table 2Go and Fig. 1BGo). With MET+CORT, 24-h insulin and midmorning insulin secretion increased by 42 ± 17% (P = 0.028) and 56 ± 24% (P = 0.031), respectively, compared with CONTROL (Table 2Go and Fig. 1BGo).

Leptin

There was a positive time effect (P < 0.001) and a time x condition effect (P = 0.027) on 24-h serum leptin levels (Fig. 1Go). Serum leptin decreased by 22.6 ± 7.4% (P = 0.01) in controls and by 30 ± 5% (P = 0.02) in the MET group from 0800 to 1230 h. In the MET group, leptin levels declined to 60 ± 5% of baseline values at 0800 h the next day (P < 0.001). The amplitude of leptin changes was lower in the MET group compared with CONTROL (51 ± 5% vs. 75 ± 11%; P = 0.056; Table 2Go). In MET+CORT, 24-h AUC leptin increased by 33 ± 12% compared with MET (P = 0.028; Table 2Go).

Correlations

In CONTROL, the insulin peak and 24-h AUC insulin correlated with the amplitude of leptin secretion (r = 0.910; P = 0.012 and r = 0.803; P = 0.054 respectively). Morning cortisol secretion correlated with the ratio of peak leptin/0800 h leptin (r = 0.767; P = 0.044). No correlation was found between insulin and leptin or between cortisol and leptin in MET and MET+CORT conditions.

Study 2

Cortisol. Feeding increased midmorning serum cortisol levels with a characteristic surge that was not observed during fasting [FED, 15.6 ± 1.5 ng/dl (430 ± 41 nmol/liter); FAST, 7.1 ± 1.0 ng/dl (196 ± 28 nmol/liter); P = 0.004; Fig. 2AGo).


Figure 2
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  		FIG. 2. Study 2: serum cortisol (micrograms per deciliter; upper panel) and leptin (nanograms per milliliter; lower panel) levels during FAST (•) and FED ({circ}) conditions in six subjects. The arrow represents the mealtime (1700 kcal) at 1100 h.

 
Leptin

Feeding significantly increased serum leptin levels over the baseline value 6 h after the meal (P < 0.03), with a maximal increase of 123 ± 12% between 2100 and 2400 h (10–13 h after the meal; P < 0.02) and a return to baseline levels between midnight and 0800 h. FAST decreased serum leptin levels from baseline over 23 h (P = 0.008) and prevented the occurrence of the nocturnal peak. Compared with FAST, the meal fed at 1100 h increased serum leptin by 215 ± 24% between 2100 and 2400 h, as previously shown (P < 0.02) (18).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study we asked whether normal levels of endogenous cortisol are required for the maintenance of circulating leptin patterns, particularly the meal-entrained nocturnal leptin peak, in lean, healthy individuals. We report that when cortisol synthesis was suppressed by administration of the adrenal 11-hydroxylase blocker, metyrapone, 24-h serum leptin levels were decreased, and the amplitude of changes in leptin levels was dampened, blunting the nocturnal peak of leptin compared with controls. By administering a single midmorning bolus of hydrocortisone to subjects given metyrapone, a pulse of serum cortisol was replaced, 24-h leptin levels were increased, and the nocturnal leptin peak was reinstated.

Over the past several years since leptin was discovered, a distinct pattern of peaks and troughs in its circulating levels has emerged. Careful studies have revealed that this pattern is not a simple diurnal rhythm, but is ultradian and, more importantly, is entrained to meals (10). The nocturnal peak in serum leptin, occurring 5–7 h after the evening meal, has been hypothesized to play a role in appetite control (34) and is blunted in obesity (5). Daytime meal intake, particularly CHO intake (9), may up-regulate nighttime leptin, although the mechanisms by which this happens are poorly understood. One obvious candidate is insulin (23).

In humans, insulin administration increases leptin levels dose-dependently (23). Moreover, physiological nocturnal leptin levels seem directly related to the amount of insulin secreted in response to daytime meals (8). The 24-h profile of leptin can be manipulated by varying the diet from high CHO (with higher insulin response) to high fat content (low insulin response), which, respectively, increases or decreases 24-h circulating leptin levels (9).

Our study (study 2, FED vs. FAST) clearly shows that a physiological insulin secretion in response to daytime feeding is key to obtaining a normal profile of leptin secretion. During both MET and FAST, the midmorning cortisol surge is blunted, and leptin levels are lower. However, the pattern of 24-h leptin levels with MET vs. FAST is quite different. In fed subjects, metyrapone dampens, but does not fully obliterate, the normal physiological profile of leptin peaks and troughs. In contrast, fasting decreases leptin levels and prevents the nocturnal rise. An important difference between these conditions is the level of insulin. In contrast to the normally elevated insulin level in response to a meal in the MET condition, insulin levels are very low in the FAST condition.

However, our study also indicates that in the absence of normal endogenous cortisol (i.e. MET), the physiological insulin response to the meal is insufficient to maintain normal leptin levels at night. Although meal intake and insulin levels were perfectly matched between MET and CONTROL, the suppression of cortisol levels in MET was accompanied with a blunting of nocturnal leptin secretion. This suggests that the maintenance of the diurnal pattern and the nocturnal increment in leptin requires the presence of adequate food intake and insulin secretion. The morning rise in cortisol levels can be considered permissive for insulin’s subsequent effect on leptin. Insulin is therefore necessary, but not sufficient, to stimulate peak nocturnal leptin secretion, and normal endogenous cortisol secretion is necessary to potentiate the effect of insulin on leptin.

In addition to its more acute effects, cortisol is an important player in the development and maintenance of a positive energy balance, particularly in central obesity (35, 36, 37, 38). The effects of cortisol are complex and dose dependent (39). Glucocorticoid receptors have long been identified in adipose tissue (40). Additionally, dysregulation of glucocorticoid receptors (41) and 11ß-hydroxysteroid dehydrogenase (42, 43, 44), key determinants of glucocorticoid actions, have been found in obesity. Although cortisol has traditionally been considered to be a counterregulatory hormone by antagonizing the actions of insulin (45), low to moderate concentrations of glucocorticoid in combination with insulin potentiate the up-regulation of several adipogenic factors, such as glucose transporter 4 (46) and lipoprotein lipase (47).

We have previously shown that the combination of insulin and dexamethasone (a synthetic glucocorticoid) up-regulates leptin in vivo (22) and in vitro (48). Glucocorticoids (alone) up-regulate leptin levels via increases in gene expression (26, 48), whereas insulin (alone) appears to work predominantly through posttranscriptional mechanisms (49, 50). In human adipose tissue in vitro, even with both of these mechanisms working in concert, there is a lag of 5–7 h before the combination of insulin and dexamethasone increases leptin levels (48). Similarly, in vivo, the administration of dexamethasone with food (20) or insulin (22) increases serum leptin levels by 5–6 h in humans. With MET+CORT, a similar time course of leptin up-regulation was achieved. Furthermore, our carefully controlled conditions in the present study demonstrate that both glucocorticoid and insulin are necessary for the physiological nocturnal rise in leptin occurring several hours later.

In many studies, the increased leptin levels resulting from in vivo administration of exogenous glucocorticoid have been deemed a pharmacological effect and, therefore, of limited physiological relevance. We blocked cortisol synthesis with the drug metyrapone to suppress endogenous circulating cortisol. Our data demonstrate that when endogenous cortisol levels were suppressed, hypoleptinemia occurred. Because lean subjects have low levels of circulating leptin, this effect was most apparent during the nocturnal rise of leptin, which was blunted with metyrapone compared with the control value. Supporting our findings, another study recently obtained similar results; Dagogo-Jack et al. (51) reported that metyrapone (750 mg) significantly suppressed 24-h leptin levels in obese individuals.

Under the MET condition, not only were 24-h cortisol levels lower, but the midmorning cortisol surge was abolished. As a result, nocturnal leptin secretion was blunted. Replacing the meal-induced spike in cortisol (MET+CORT) at midmorning reinstated the nocturnal leptin peak. This administration of one dose of hydrocortisone, before the morning meal, induced a delayed (4–6 h) increase in leptin over 24 h. This shows the importance of the midmorning cortisol secretion, rather than the morning fasting level of cortisol, to the subsequent increase in leptin. This is also in concordance with our previous data (20, 22) and data from others (24, 25, 26, 52) showing clearly and consistently that administering glucocorticoids results in a potent stimulation of leptin across gender, races, ages, and body mass indexes.

The design of our experiment (24-h suppression) does not allow us to distinguish whether it is the absence of the morning surge of cortisol per se, the decrease in morning cortisol, the overall 24-h decrease in cortisol levels, or some combination of these that is responsible for the nocturnal leptin decrease. Nonetheless, these data provide strong evidence that normal endogenous cortisol secretion is necessary to trigger the rise in leptin that occurs several hours after a meal. Future studies should address the relationship between the timing of hydrocortisone replacement in metyrapone-suppressed individuals to distinguish and better understand the role of basal cortisol secretion vs. the meal-related peak of cortisol.

The administration of higher doses of metyrapone (750 mg) in our preliminary studies induced nausea and vomiting, preventing us from testing the effect of a more pronounced cortisol suppression under a normal fed condition. Although we observed no side effects with the 500-mg dose of metyrapone, the suppression of endogenous cortisol was not complete and varied between subjects. Nevertheless, the partial blockade of endogenous cortisol significantly affected serum leptin levels despite similar insulin levels. When administering a higher dose of metyrapone (750 mg) to obese subjects, Dagogo-Jack et al. (51) recently reported greater cortisol suppression as well as lower postprandial insulin levels. Their subjects experienced nausea, which potentially may have decreased food intake and insulin secretion while they were taking metyrapone. Although intakes were not significantly different between conditions, we must accept that some element of food restriction may have occurred with our own diet, explaining the lower than baseline leptin levels at 0800 h at the end of the 24-h observation period in CONTROL and MET+CORT.

Our study group included only men; thus, it is unclear whether our findings would also apply to women. Lean men have lower leptin levels than women; therefore, it would not be surprising if the hypoleptinemia induced by cortisol suppression were more pronounced in women, especially in obese women, who have even higher circulating leptin levels (51).

In summary, our data show that pharmacological manipulations to suppress endogenous cortisol levels in fed subjects have a significant negative impact on 24-h leptin levels. These results confirm our hypothesis that cortisol, at physiological concentrations, plays a stimulatory role in the control of leptin. The morning levels of cortisol and/or the meal-related cortisol surge potentiate the effect of insulin on nocturnal leptin. Future studies should address whether the meal-related cortisol-leptin pathway is dysregulated in obese individuals.


   Footnotes
 
This work was supported by National Institutes of Health Grants DK-62939-01, RR-00645, and DK-26687.

First Published Online March 14, 2006

Abbreviations: AUC, Area under the curve; CHO, carbohydrate; CORT, hydrocortisone; FAST, fasting condition; FED, feeding condition; MET, metyrapone; PROT, protein.

Received March 30, 2005.

Accepted March 6, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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