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Dexamethasone Increases Leptin Expression in Humans in Vivo

Department of Nutritional Sciences (S.P-R., R.N.P., S.K.F.) Rutgers University; Division of Endocrinology (S.H.S.), Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08903

Address all correspondence and requests for reprints to: Susan K. Fried, Ph.D., Department of Nutritional Sciences, Rutgers University - Cook College, New Brunswick, New Jersey 08903.

	Abstract

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The effect of 2 days of oral dexamethasone administration (0.75 mg twice daily) on leptin expression in healthy volunteers was tested. Dexamethasone increased the relative abundance of leptin messenger RNA in abdominal and gluteal adipose tissues by approximately 70% (P < 0.05). Dexamethasone also significantly increased serum leptin (+ 80%) and insulin concentration (+ 83%) but did not affect serum glucose. We conclude that a hypercortisolemic/hyperinsulinemic state up-regulates leptin expression at the messenger RNA level in humans.

	Introduction

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THE ADIPOCYTE hormone leptin is thought to serve as a signal to the central nervous system reflecting the status of fat stores. Serum levels of leptin and adipocyte leptin messenger RNA (mRNA) levels are clearly increased in obesity (1, 2). However, the factors regulating leptin production in obesity are not yet understood. Hyperinsulinemia is a logical candidate, and indeed, insulin appears to be a long-term regulator of leptin expression in humans (3, 4). Obesity is also associated with increased cortisol turnover (5, 6). In combination with insulin, glucocorticoids increase the expression of genes important in regulating lipid deposition in the adipocyte, including lipoprotein lipase (LPL) (7, 8). Glucocorticoids also increase leptin expression in rodents, in vivo and in vitro (9, 10, 11).

The primary objective of the present study was to determine the effects of in vivo administration of the synthetic glucocorticoid dexamethasone on levels of adipose tissue leptin mRNA and serum leptin in humans. A dose of dexamethasone was chosen to produce a high physiological level of glucocorticoid activity. Because glucocorticosteroids induce insulin resistance (12, 13, 14), we assessed effects of dexamethasone administration on serum insulin levels. Additionally, to gain insight into metabolic effects of elevated glucocorticoids in humans, expression of lipoprotein lipase (LPL) was determined.

	Materials and Methods

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Subjects and procedures

Subject characteristics are shown in Table 1. Six healthy, nonsmoking, weight-stable, overweight volunteers were subjects in Study 1. They were free of metabolic disease and not taking medications (except for one subject on a stable dose of Prozac whose results did not differ from the rest of the group). Subjects reported for medical screening and baseline determinations of weight and height after a 12 h overnight fast. Blood was drawn for determination of serum insulin, cortisol, glucose, and leptin. Subcutaneous adipose tissue was aspirated from the abdominal and gluteal regions under local lidocaine anesthesia, as previously decribed (15). Subjects were instructed to ingest tablets containing a total of 1.5 mg dexamethasone per day (0.75 mg, 2 x daily with breakfast and dinner) on two consecutive days. They returned on the following morning after an overnight fast for a second blood sample and adipose tissue aspirations (on the contralateral side of the body from the first sample). Subjects were also instructed to keep food records on one control day (a weekday without the drug) and during the treament period. They were not given any instructions on diet composition or daily intake. Unfortunately, serum samples for all but one subject in Study 1 were not available for insulin, glucose, or leptin determinations. Thus, in Study 2, eight healthy subjects were recruited for serum sampling before and after dexamethasone administration using the same protocol, excluding the adipose tissue aspirations. One male subject in Study 2 was a light smoker and continued this behavior throughout the study. His results were included as they did not differ from the rest of the group. These studies were approved by the Institutional Review Board of the University of Medicine and Dentistry of New Jersey and Rutgers University.

Statistics

After log-transformation of the data, the effect of dexamethasone on serum parameters, and the relative abundance of mRNAs (ratio to 28S ribosomal RNA) were determined by two-tailed (unless indicated) paired t-tests (Excel, Microsoft). Probabilities less than 0.05 were considered statistically significant.

	Results

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As indicated by the mean body mass indices (BMI), subjects were on average overweight (Table 1). The range of values, however, was wider in Study 2 than Study 1. As expected, dexamethasone (dex) administration suppressed endogenous cortisol in all subjects (Table 2), indicating good compliance with the protocol. Serum insulin levels also increased by an average of 83 ± 29% over control values, but serum glucose did not change (Table 2).

Two days of dexamethasone treatment increased the relative abundance of leptin mRNA by 70 ± 28% in the abdominal depot and 68 ± 25% in the gluteal depot (n = 6, P < 0.05). A typical autoradiograph of a Northern blot and a densitometric quantitation of leptin/28S are illustrated in Fig. 1.

View larger version (81K): [in this window] [in a new window]   Figure 1. Effect of dexamethasone on leptin mRNA levels. Bars represent means ± SEM of the 6 subjects in Study 1 before (day 0) and after (day 2) dexamethasone administration for 48 h. Representative autoradiograph of a Northern blot shown above the bars. *P < 0.05.

Serum leptin

In Study 2, serum leptin levels increased by 80 ± 17%, n = 9, after two days of dexamethasone (P < 0.005; Fig. 2).

View larger version (21K): [in this window] [in a new window]   Figure 2. Effect of dexamethasone administration on serum leptin levels. Lines connect individual values before and after dexamethasone administration in men (----) and women (———). Square symbols represent the mean ± SEM (n = 9). * P < 0.01.

	Discussion

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The stimulatory effect of glucocorticoid on serum insulin that we observed is consistent with several previous reports (12, 13, 14), although one study using methylprednisolone found no effect (18). A recent study showed that a dose of 2 mg/day dexamethasone did not influence glucose tolerance whereas higher, pharmacological doses did (12). Thus, it is likely that we were successful in inducing a moderately hypercortisolemic state, in which hyperinsulinemia compensated for mild peripheral insulin resistance.

It is possible that the doubling of fasting insulin induced by dexamethasone contributes to the increase in leptin expression that we observed. Kolaczynski et al. (3) reported that serum leptin levels were not increased until the final 48–72 h period of a hyperinsulinemic-euglycemic clamp in lean subjects. Preliminary observations in two lean female subjects showed that levels of serum leptin and insulin had already doubled after 30 h of dexamethasone administration. Additional studies of the time course of glucocorticoid and insulin effects during clamped conditions are needed to resolve whether dexamethasone stimulates leptin without concomitant hyperinsulinemia, how rapidly this effect occurs, and whether there are gender or obesity-related differences in responsiveness to these hormones.

The permissive or synergistic effects of insulin and glucocorticoids in regulating leptin mRNA expression are supported by our recent studies of human adipose tissue from obese subjects in organ culture (19). The combination of insulin and dexamethasone, but not insulin or dexamethasone alone, consistently stimulated leptin mRNA relative abundance in subcutaneous adipose tissue.

Gender-specific depot differences in the expression of glucocorticoid receptor mRNA levels have been observed between abdominal (abd) and gluteal (glu) adipose tissues (men: abd < glu; women abd > glut) (20). Thus, we expected a depot difference in the expression of leptin and responsiveness to glucocorticoids. However, both depots responded similarly.

In addition to increasing leptin expression, dexamethasone administration also increased the expression of LPL mRNA in the gluteal depot. The moderate increase in mRNA level was not accompanied by a statistically significant rise in LPL activity, as we would have predicted from our in vitro studies (7). The time course of induction of LPL may lag behind the induction of message.

Increases in serum leptin would be expected to lead to a suppression of food intake. However, we did not observe any effects of dexamethasone treatment on spontaneous food intake, as indicated from diet records (unpublished observation). A recent study by Tataranni et al. (13) found an increase in food intake as a consequence of administration of the glucocorticoid methylprednisolone. However, a preliminary report indicated that they found no change in serum leptin after 4 days of treatment (21). Discrepancies with the present study may be explained by the higher dose (40 mg methylprednislone is equivalent to 7.5 mg dexamethasone), time-dependent effects, the use of exclusively lean male subjects, or more accurate measures of food intake in an inpatient study. However, it is possible that the rise in leptin that occured at the lower dose of glucocorticoids in our subjects may have offset any stimulatory effects on appetite (6, 21). Alternatively, we speculate that glucocorticoids may decrease sensitivity to leptin’s inhibitory effects on food intake, leading eventually to an increased body weight "set point". Whether this mechanism contributes to the obesity that occurs clinically in hypercortisolemic patients remains to be determined. Because the balance between insulin and glucocorticoid is thought to be crucial in regulating energy balance (6), in future studies it will be important to undertake careful measurements of food intake during administration of varying doses of glucocorticosteroids in lean compared with obese men and women.

In conclusion, a moderate elevation in serum insulin and glucocorticoids increased leptin mRNA levels in subcutaneous adipose tissues and serum leptin levels in humans within 48 h. The concommitant hyperinsulinemia and increased cortisol turnover associated with the obese state may be important modulators of the degree of hyperleptinemia.

	Note Added in Proof

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After submission of this manuscript, Larsson and Ahren (J Clin Endocrinol Metab 81:4428–4432, 1996) also reported that dexamethasone (3 mg/day for 48 h) increased plasma leptin.

	Acknowledgments

 
We thank Yim Dam and Dr. F. Xavier Pi-Sunyer, New York Obesity Center, St. Luke’s Roosevelt Hospital Center, New York for insulin determinations.

Received November 4, 1996.

Accepted January 22, 1997.

	References

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