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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 4 1492-1496
Copyright © 2003 by The Endocrine Society

Interleukin-1 Receptor Antagonist Is Associated with Fat Distribution in Endogenous Cushing’s Syndrome: A Longitudinal Study

T. Ueland, C. Kristo, K. Godang, P. Aukrust and J. Bollerslev

Section of Endocrinology (T.U., C.K., K.G., J.B.), Research Institute for Internal Medicine (T.U., C.K., P.A.), and Section of Clinical Immunology and Infectious Diseases (P.A.), Medical Department, National University Hospital, N-0027 Oslo, Norway

Address all correspondence and requests for reprints to: Thor Ueland, M.D., Research Institute for Internal Medicine, National University Hospital, Sognsvannsveien 20, 0027 Oslo, Norway. E-mail: thor.ueland{at}klinmed.uio.no.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The weight gain and visceral obesity associated with Cushing’s syndrome (CS) has been linked to elevated plasma leptin levels, although the mechanism behind a central leptin resistance in these patients is unknown. Several studies describe interactions among the hypothalamic-pituitary-adrenal axis, leptin, and the IL-1 system. To investigate these interactions, we have evaluated changes in regional fat distribution, by DEXA, and the role of circulating cortisol, leptin, IL-1ß, and IL-1 receptor antagonist (IL-1Ra), in relation to these changes, in 27 (19 DEXA; 27 serum measurements) patients with CS, before and after surgical treatment (mean follow-up, 31 months; range, 5–80), and compared them with measurements of age-, sex-, and body mass index-matched healthy controls (also obtained longitudinally). We found that surgical treatment caused a decrease in all fat parameters, without changing lean body mass, and these changes were significantly larger than the so-called natural changes occurring in control subjects. These changes in CS patients were paralleled by decreases in cortisol, leptin, and IL-1Ra, whereas IL-1ß increased. Stepwise linear regression showed that serum IL-1Ra was strongly associated with regional fat distribution, and especially truncal fat mass, both at baseline and during treatment. In conclusion, the present study shows that treatment significantly changes body composition in CS patients by decreasing fat mass, especially in the truncal region, without major effects on lean body mass. We also show that circulating IL-1Ra is strongly associated with these changes, signifying a relationship among the hypothalamic-pituitary-adrenal axis, IL-1 system, and regional fat distribution in these patients.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PATIENTS WITH ENDOGENOUS Cushing’s syndrome (CS) are characterized by weight gain and visceral obesity, but the underlying mechanisms have not been fully clarified. Leptin, the ob gene product, is a peptide hormone derived from adipocytes and involved in the regulation of food intake and energy expenditure (1, 2, 3, 4). It is released into the circulation in proportion to percentage of body fat in human and experimental models (5) and acts both peripherally and in the brain (6). A variety of hormones have been shown to regulate leptin production both in vitro and in vivo, including insulin and cortisol (7, 8, 9, 10). Thus, the fat distribution associated with CS (11, 12, 13, 14) has been linked to elevated plasma leptin levels (11, 15, 16), although the pathophysiological significance of leptin overproduction in these patients is, at present, unclear. Different mechanisms have been proposed for this apparent leptin resistance, including reduced efficiency of brain leptin transport and increased levels of soluble leptin receptor acting as a decoy for ligand signaling (17). Recently, it was shown, in experimental models, that the hypothalamic effects of leptin on food intake are mediated by IL-1; and several studies describe interactions between the hypothalamic-pituitary-adrenal (HPA) axis and the IL-1 system (18, 19, 20). Moreover, enhanced activity of inflammatory cytokines, such as IL-1, has been related to both increased leptin release from adipocytes and to leptin resistance, suggesting important interactions between leptin and the IL-1 system.

Only few studies have investigated fat distribution after surgical treatment in CS patients (21, 22, 23). The aim of this study was to investigate: 1) regional fat distribution after treatment in these patients; and 2) the role of cortisol, leptin, and the IL-1 system, in relation to these changes.


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

Twenty-seven consecutive recruited patients with recently diagnosed CS were included in the study and evaluated before and after surgical treatment and were compared with 27 age-, sex-, and body mass index (BMI)-matched healthy controls without any underlying endocrine or metabolic disorder (Table 1Go). Body composition was evaluated in 19 patients and all controls, whereas biochemical measurements were performed in all participants. The 19 patients in which body composition data were available did not differ from the other CS patients or controls, with regard to age, gender, or BMI. All patients with CS had a typical history and clinical signs. The diagnosis was confirmed by elevated 24-h urinary cortisol, abnormal diurnal rhythm of cortisol, and serum cortisol resistance to the 2-day low-dose (2 mg) dexamethasone suppression test. Pituitary adenoma was identified by a magnetic resonance imaging scan and/or inferior petrosal sinus sampling combined with CRH test. In CS with suppressed ACTH levels, an adrenal tumor was visualized by computed tomographic analysis. After treatment, the short dexamethasone suppression test was repeated in 24 patients, showing that 18 had a normal suppression of cortisol (mean, 32 ± 5 nM), whereas 6 had not (mean, 139 ± 18 nM). Mean follow-up time after removal of pituitary tumor was 30 months (range, 5–80 months), whereas adrenal tumors were removed after 34 months (range, 8–68 months). Controls were reanalyzed after 50 months (range, 26–56 months). Written informed consent was obtained from all participants. The study was approved by the local ethical committee and conducted according to the declaration of Helsinki II.


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  		Table 1. Clinical characteristics of the study group before and after surgical treatment in CS patients (PO) or during longitudinal follow-up in controls (FU)

 
Methods

Biochemical measurements. Peripheral venous blood was drawn into pyrogen-free blood collection tubes, without any additives (Becton Dickinson and Co., San Jose, CA), after an overnight fast. The tubes were allowed to clot, they were centrifuged for 10 min at 1000 x g, and serum was stored in multiple aliquots at -80 C until analyzed. Cortisol (Orion Diagnostica, Epsoo, Finland), leptin (Linco Research, Inc., St. Charles, MO), and C-peptide and insulin (DPC, Los Angeles, CA) were analyzed by RIA. IL-1ß and IL-1 receptor antagonist (IL-1Ra) were measured by enzyme immunoassays (R&D Systems, Minneapolis, MN). Intraassay coefficients of variation were less than 10% for all assays. All samples from a given patient were analyzed at the same time to minimize the run-to-run variability.

Body composition. Total body composition was measured by DEXA (DPX-L, software version 1.31; Lunar Corp., Madison, WI) in 19 of the patients (12 women and 7 men) and in all controls. All subjects were weighed and measured without shoes and while wearing light clothing. Total body scan was accomplished and analyzed by one person as previously described (24). Lean tissue and fat mass was determined in the truncal, arm, and leg regions, as well as in the total body.

Statistics. Changes in variables during follow-up were calculated as absolute changes (follow-up/treatment – baseline). Differences between and within groups were compared by appropriate t tests for unpaired and paired data. To examine the relationship between regional fat distribution and biochemical parameters, we used simple linear (bivariate) regression analysis and, subsequently, a linear regression analysis with stepwise addition of the variables that had P values < 0.2 in our a priori analysis and on bivariate regression. The percentage of variation explained by the regression model is presented as adjusted R2, whereas data in parentheses represent the unstandardized coefficients with SE and the P value (B ± SE, P value). P values < 0.05 were regarded as statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics are detailed in Table 1Go. As expected, marked decreases in serum levels of cortisol, insulin, and C-peptide were found after surgical treatment. Furthermore, surgical treatment caused a significant decrease in fat mass at all measured sites, and these changes were significantly larger than the time-dependent changes occurring in control subjects (Table 2Go). In contrast, no changes were found for lean body mass.


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  		Table 2. Body composition before (baseline) and after surgical treatment (END) in patients with endogenous CS and age-, sex-, and BMI-matched controls

 
IL-1 parameters and leptin in CS patients and controls

When analyzing cytokine levels, baseline leptin and IL-1Ra were significantly increased in CS patients, and notably, surgical treatment induced a significant decrease not only in leptin (~36%) but also in IL-Ra levels (~26%) (Fig. 1Go). In contrast, we found a significant increase in IL-1ß (~100%) after therapy (Fig. 1Go). As for healthy controls, a quite different pattern was observed during follow-up, with an increase in leptin, a decrease in IL-1ß, and no changes in IL-1Ra levels (Fig. 1Go). Interestingly, leptin and IL-1Ra, but not IL-1ß, were significantly correlated in CS patients (r = 0.45, P = 0.02), but not controls, at baseline. This relationship was not present during longitudinal testing.



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  		Figure 1. Changes in serum levels of (A) leptin, (B) IL-1ß, and (C) IL-1Ra after surgical treatment (Post OP) in 27 patients with CS, compared with 27 controls (CTR) who had been followed for a similar period of time (see Patients and Methods). a, P < 0.05; b, P < 0.01 vs. controls; c, P < 0.05; d, P < 0.01; e, P < 0.001 vs. baseline; #, ng/ml; §, pg/ml. Data are given as mean ± SEM.

 
Relationships among IL-1 parameters, leptin, cortisol, and body composition

To further determine the relationships between body composition and cortisol, leptin, IL-1ß, and IL-1Ra, we performed correlation analysis between these parameters at baseline and between changes in these parameters after follow-up. At baseline, we found highly significant correlations between leptin and truncal and total body fat mass in both patients and controls, whereas IL-1Ra was significantly correlated with these fat parameters only in the patient group (Table 3Go, Fig. 2Go). We further found that in CS patients, the same relationships were found when correlating the changes in these parameters during treatment (Table 3Go, Fig. 2Go). In addition, changes in 24-h urinary cortisol were significantly positively correlated with changes in truncal and total body fat mass. No relationships were found between fat parameters and insulin, IL-1ß, or cortisol in either population at baseline.


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  		Table 3. Pearson correlations (r) between fat mass and biochemical parameters at baseline and changes during treatment (parentheses) in Cushing patients (CS) and controls (CTR)

 


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  		Figure 2. Correlations (r) between truncal fat mass and IL-1Ra and leptin at baseline (left), and between changes ({Delta}) in these parameters (right) during treatment in 27 patients with CS (•), compared with 27 controls (CTR, {circ}) who had been followed for a similar period of time (see Patients and Methods). a, P < 0.05; b, P < 0.01; c, P < 0.001. Regression lines: solid, CS; broken, CTR.

 
Based on these findings, we then performed stepwise linear regression analysis to further characterize which of the measured biochemical parameters could best explain body composition, restricting our regression analysis to truncal and total body fat mass. Data in parentheses represent the unstandardized coefficients (B) with SE and P value. In CS patients we found that at baseline, IL-1Ra explained 34% of the variation in truncal fat (B = 6.8 ± 2.1, P = 0.005), with no contribution from leptin, whereas leptin explained 48% of the variation in total body fat mass (B = 293 ± 92, P = 0.006), with IL-1Ra contributing 12% (B = 6.0 ± 2.5, P = 0.028). During treatment, linear regression showed that 24-h urinary cortisol explained 34% of the decrease in truncal fat mass (B = 3.7 ± 1.1, P = 0.004), with IL-1Ra contributing 21% (B = 4.1 ± 1.5, P = 0.015). The same relationships of approximately the same magnitude were found for total body fat mass. In controls, leptin alone explained 43% of the variation in total body fat mass (B = 372 ± 82, P < 0.001) and 70% of the change in this compartment (B = 377 ± 98, P < 0.001). Leptin contributed to 46% of the change in truncal fat mass (B = 96 ± 25, P = 0.002) in controls, with IL-1ß contributing 15% (B = -1323 ± 501, P = 0.019), but none of these parameters were significant determinants of truncal fat at baseline. Notably, and in marked contrast to the finding in CS patients, IL-1Ra was not associated with truncal or total fat, either at baseline or during follow-up, in healthy controls. Similar results were obtained with both forward and backward stepwise regression.

When comparing men and women, we found that men were generally characterized by higher lean body mass, and women by higher fat mass. Sexual dimorphism was also found when comparing leptin levels within the groups, with higher levels in women; however, no differences were found in changes during longitudinal testing in any of the measured parameters, with respect to sex, origin of the adenoma (pituitary or adrenal), suppression of cortisol with the dexamethasone suppression test after treatment (cured or not-cured), or duration of follow-up (i.e. <12 months, >12 months).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The importance of glucocorticoids in regulating body fat distribution is well known, and many studies have described the central obesity associated with CS. However, only few describe longitudinal changes in these patients after treatment, and none using longitudinal sampling of controls as well as patients (23, 25). Our findings are in agreement with a recent study describing body composition in CS using total body potassium and bioelectrical impedance counting, showing a normalization of fat mass, without changes in lean body mass up to 6 months after surgery (23). However, in the present study, we also show that these changes in fat were associated with a decrease in leptin and particularly with a decrease in IL-1Ra levels. Notably, this association between IL-1Ra and body fat was only seen in CS patients and not in healthy controls, suggesting that this cytokine antagonist may play a pathogenic role in CS.

The underlying pathogenic mechanisms responsible for the abnormal fat distribution in CS have been linked to increased leptin levels, as also found in obese subjects (16, 26). Leptin gene expression is enhanced by both glucocorticoids and insulin in adipose tissue cultures in vitro (7, 9, 16, 26), and which of these factors is the most determining factor of leptin expression has also been the subject of extensive research in vivo (26). These populations seem to be insensitive to endogenous leptin production, and several mechanisms have been proposed for this resistance (17, 27). The findings in the present study may suggest that enhanced IL-1Ra levels could contribute to the leptin resistance in CS, and the involvement of IL-1Ra in the pathogenesis of acquired leptin resistance has also been supported by others (28).

Our baseline data may suggest that factors other than cortisol regulate fat distribution when this hormone is in excess, and that the influence of these hormones and cytokines differ, depending on fat compartment. Experimental models show that IL-1 mediates the hypothalamic effects of leptin on food intake, and that IL-1Ra, which acts as a natural antagonist of IL-1 by competitive binding to IL-1 type I receptor, abolishes the effects of the leptin-induced reduction in food intake (18). Thus, the central resistance to leptin in obesity could be mediated by IL-1Ra; and accordingly, markedly enhanced levels have been found in obese subjects, compared with nonobese (28). The present study extends these findings by showing that IL-1Ra levels are increased in CS patients as well, significantly correlated with leptin levels, suggesting that IL-1Ra could contribute to the leptin resistance also in CS. Furthermore, whereas leptin was associated with total fat mass in both patients and controls, IL-1Ra was associated with total and, in particular, with truncal fat mass in CS patients, but not in healthy controls. The fact that that this association between IL-1Ra and fat mass was restricted to CS patients may suggest a direct link between IL-1Ra and the development of central obesity in this population. Moreover, the decreases in both cortisol and IL-1Ra were significant determinants of changes in both truncal and total body fat mass during treatment, substantiating a relationship among the HPA axis, the IL-1 system, and regional fat distribution (20).

Treatment of CS was accompanied by an increase in IL-1ß levels, and one possibility might be that this increase in IL-1ß is related to weight loss in obese individuals. However, we found no relationships between IL-1ß and fat or lean body mass in this study. Moreover, although high IL-1ß levels have been related to cachexia in AIDS patients (29), obese alcoholics (30) and obese patients with non-insulin-dependent diabetes mellitus (31) had high, rather than low, IL-1ß levels, comparing nonobese patients with these disorders.

Granulocytes and monocytes are major cellular sources of IL-1Ra. However, because glucocorticoids decrease IL-1Ra expression in these cells (32, 33), it is possible that other sources, such as the central nervous system, could contribute to the increased serum levels of IL-1Ra found in the present study. In fact, we did find a trend toward a larger decrease in IL-1Ra levels in patients that removed pituitary, compared with adrenal, adenomas (P = 0.06, data not shown); and in vivo release of IL-1Ra from corticotroph adenomas, using measurements in the cavernous sinus plasma, has been shown in CS patients (34). Also, the expression of IL-1Ra has been demonstrated in human pituitary adenomas, both in vitro and in vivo (35, 36). However, whereas glucocorticoids impair IL-1Ra expression in monocytes, leptin has been found to directly induce the secretion of IL-1Ra in these cells (37), possibly contributing to the enhanced IL-1Ra levels in CS. Thus, a possible mechanism for leptin resistance could be that cortisol increases leptin release from adipocytes, leptin increases IL-1Ra release from mononuclear cells or expression in the pituitary, and IL-1Ra antagonizes leptin induced IL-1ß signaling in the hypothalamus, representing a pathogenic loop in CS, contributing to the abnormal fat distribution in this disorder, as suggested in obesity (28).

In conclusion, the present study shows that treatment significantly changes body composition in CS patients by decreasing fat mass, especially in the truncal region, without major effects on lean body mass. We also show that circulating IL-1Ra is strongly associated with these changes, signifying a relationship among the HPA axis, IL-1 system, and regional fat distribution in these patients.


   Footnotes
 
Abbreviations: B, Unstandardized correlation coefficient; BMI, body mass index; CS, Cushing’s syndrome; HPA, hypothalamic-pituitary-adrenal; IL-1Ra, IL-1 receptor antagonist.

Received July 3, 2002.

Accepted December 20, 2002.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals