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IL-1 Receptor Antagonist Serum Levels Are Increased in Human Obesity: A Possible Link to the Resistance to Leptin?

Divisions of Endocrinology and Diabetes (C.A.M.), Therapeutic Teaching (E.B., A.G.), Rheumatology (C.G.), and Immunology and Allergy (J.-M.D.), Department of Internal Medicine, University Hospital Geneva; and Department of Medical Biochemistry, Centre Médical Universitaire (F.A.-J.), CH-1211 Geneva, Switzerland

Address all correspondence and requests for reprints to: Dr. Christoph A. Meier, Endocrine Unit, Division of Endocrinology and Diabetes, University Hospital Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. E-mail: . cameier{at}bluewin.ch

Abstract

We have recently shown that human monocytic cells express functional leptin receptors and that leptin is capable of inducing the expression and secretion of the IL-1 receptor antagonist (IL-1Ra). Although IL-1Ra has anti-inflammatory and possibly anti-atherogenic properties, it has also been shown to antagonize the action of leptin at the hypothalamic level in rodents, thereby inducing leptin resistance. We have therefore examined whether IL-1Ra levels are increased in human hyperleptinemic conditions, such as obesity.

To this end, we measured serum IL-1Ra levels in 20 morbidly obese nondiabetic subjects [body mass index (BMI), 45 ± 6 kg/m²; serum leptin, 52 ± 20 ng/ml] as well as in 10 age- and sex-matched lean controls (BMI, 22 ± 2 kg/m²; serum leptin, 7 ± 4 ng/ml). Serum IL-1Ra concentrations proved to be elevated 6.5-fold in the obese subjects, and they were positively correlated in a linear manner with the leptin levels (r² = 0.34; P = 0.01), although lean body mass (LBM) and the insulin resistance index were even better predictors of IL-1Ra levels (r² = 0.45 and 0.58, respectively; P < 0.01). Six months after 15 of the 20 obese subjects had undergone bypass surgery for their morbid obesity, their mean BMI and leptin levels decreased to 33 ± 7 kg/m² and 18 ± 12 ng/ml, respectively. This change in leptin concentrations was associated with a significant reduction in IL-1Ra levels (P < 0.02). However, there was a better correlation between the decrease in IL-1Ra level and the change in LBM than with the reduction in leptin levels, indicating that leptin is not the sole determinant of circulating IL-1Ra in obesity.

In summary, we demonstrate that IL-1Ra levels are highly elevated in human obesity and that its concentrations decrease after weight loss from bypass surgery. However, LBM and insulin resistance are better predictors of serum IL-1Ra concentrations than are leptin levels, suggesting that additional metabolic factors control the secretion of this cytokine antagonist. Although the immunological consequences of this alteration remain unknown, it is tempting to speculate that the obesity-related increase in IL-1Ra might contribute to the central resistance to leptin in obese patients, similar to the inhibition of the hypothalamic signaling of leptin by IL-1Ra in rodents.

WE HAVE RECENTLY demonstrated that leptin exhibits direct effects on monocytes, resulting in the increased expression and secretion of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra). In contrast, leptin has a weaker effect, or none at all, on IL-1 secretion (1). However, whether the levels of IL-1Ra are increased in human obesity, characterized by high leptin levels, remains unknown.

IL-1Ra is a natural antagonist to the proinflammatory cytokine IL-1, and it is commonly thought to play an important role in the regulation of inflammatory responses, as corroborated by the enhanced sensitivity of IL-1Ra knock-out mice to septic shock and their predisposition to the spontaneous development of inflammatory disorders (2, 3, 4, 5). Based on the findings of Luheshi et al. (6), it can be hypothesized that IL-1Ra also plays a regulatory role in energy homeostasis. These authors have demonstrated that the hypothalamic effects of leptin depend heavily on the action of IL-1 and that the injection of IL-1Ra into the cerebral ventricles inhibited the leptin-induced reduction in food intake as well as the concomitant increase in body temperature by more than 60%. It is thus tempting to speculate that the leptin-induced increase in IL-1Ra secretion is capable of antagonizing the hypothalamic effects of IL-1 on food intake. Because the central resistance to leptin, rather than its deficiency, is the hallmark of most cases of human obesity, a better understanding of the factors involved in the regulation of the hypothalamic sensitivity to leptin is important. Although earlier studies in humans have demonstrated that the transfer of leptin from the blood into the cerebrospinal fluid may be a limiting step, the relative importance of this mechanism remains unknown, and it is likely that other metabolic factors contribute to a functional defect in leptin signaling (7).

In the present study, we investigated the putative relationship between IL-1Ra serum concentrations and leptin levels, as well as other metabolic parameters in lean and obese subjects before and after gastric bypass surgery. IL-1Ra levels were found to be dramatically increased in obese subjects, with a positive correlation with serum leptin concentrations, whereas additional metabolic parameters also appear to determine the serum levels of this cytokine antagonist.

Patients and Methods

Patients

Three groups of subjects were analyzed for this study: A) a group of 20 morbidly obese nondiabetic women, and B) a group of 10 normal women matched for weight, age, and height to group A. IL-1Ra serum levels were also measured in a third group (C) of five moderately obese patients with a BMI of 30–35 kg/m². Fifteen of the obese subjects from group A underwent gastric bypass surgery, which consisted in separating a small stomach pouch from the distal stomach and then connecting a Y-shaped section of the small intestine to this gastric pouch to bypass the duodenum and part of the jejunum (8).

The patients gave their informed consent to the study protocol approved by the Ethical Committee of the Department of Internal Medicine of the Geneva University Hospital. All measurements detailed below were performed at baseline after an overnight fast. The obese patients having undergone gastric bypass were examined a second time 6 months after surgery.

Analysis of body composition, energy expenditure, and serum analytes

Body composition [lean body mass (LBM)] was determined from bioelectrical impedance measurements as described by Segal et al. (9). Rates of O₂ consumption and CO₂ production were determined as previously described using a ventilated hood (Deltatrac, Datex Corp., Helsinki, Finland) (10). After a 15-min equilibration period, gas exchanges were measured for 30 min and used to calculate the respiratory quotient and glucose and lipid oxidation rates, according to Lusk (11). Protein oxidation was calculated as 6.235 x N, where N is nitrogen excretion (milligrams per minute) in urine. Resting energy expenditure was calculated from the rates of substrate oxidation. As previously reported, the intraindividual coefficients of variability were 6.0% for glucose, 7.4% for lipid oxidation, 1.3% for the respiratory quotient, and 2.4% for the resting energy expenditure (12).

Plasma glucose was enzymatically determined on an Automated Glucose Analyzer (Beckman Coulter, Inc., Fullerton, CA) (13). Insulin and leptin levels were measured by RIA (Herbert and Linco Research, Inc., St. Charles, MO, respectively). The insulin resistance index (IRI) was calculated from fasting insulinemia and glycemia according to Matthews et al. (14) by multiplying the insulin (milliunits per liter) by the glucose serum level (millimoles per liter) and dividing the product by 22.5. The serum levels of IL-6 and IL-1Ra were measured by the Quantikine Immunoassays from R \|[amp ]\| D Systems (Minneapolis, MN).

Statistical methods

Results are expressed as means ± 1 SEM. We used the t test (paired and unpaired, two-tailed) for comparison of specified conditions. Multiple forward and backward stepwise linear regression analysis was performed with SYSTAT 10.01 (SPSS, Inc., Chicago IL).

Results

Patient characteristics

Table 1 summarizes the anthropometric and metabolic parameters examined. The obese group had significantly increased LBM, insulin, and leptin levels, as well as an augmentation in the IRI. All of these variables were significantly reduced 6 months after the bypass surgery.

Increased levels of IL-1Ra in morbid obesity

As shown in Fig. 1A, serum IL-1Ra concentrations were increased 6.5-fold in obese subjects (P < 0.001), with a significant decrease 6 months after bypass surgery (P < 0.02). Because leptin is a direct regulator of IL-1Ra production by monocytes, and because leptin levels decreased by 66% after the bypass operation, the correlation between the concentrations of leptin and IL-1Ra was examined (Fig. 1B). Although this correlation was statistically significant (r² = 0.34; P = 0.01), the variations in leptin levels accounted for only one third of the variability in IL-1Ra concentrations. Hence, we performed stepwise multiple regression analysis using the forward and backward entry of variables. Both types of analyses resulted in an identical model in which the IRI and LBM emerged as the most important determinants of IL-1Ra levels (r² = 0.58 and 0.45, respectively; P 0.001). Although IL-1Ra levels were correlated in a linear manner with the IRI (Fig. 2A), the relationship to the LBM was exponential, with a dramatic increase in the slope above a LBM of 50 kg (Fig. 2B). It can thus be speculated that a possible regulator is serum insulin, which is significantly correlated with baseline IL-1Ra levels in our total study population (r² = 0.53; P < 0.001; n = 30; data not shown).

View larger version (13K): [in this window] [in a new window]   Figure 1. IL-1Ra levels are reversibly increased in human obesity and correlated with leptin levels. A, The serum levels of IL-1Ra are markedly increased in obese subjects at baseline (Obese T0; n = 20) compared with age- and sex-matched lean controls (n = 10), whereas the concentrations significantly decrease (P < 0.02) 6 months after gastric bypass surgery (Obese T6; n = 15). B, The serum levels of leptin are significantly correlated with IL-1Ra concentrations in lean and obese subjects (linear regression, r2 = 0.34; P = 0.01; n = 30).

View larger version (13K): [in this window] [in a new window]   Figure 2. Insulin sensitivity and LBM are correlated with IL-1Ra serum levels. A, The IRI is the best predictor of IL-1Ra serum levels (linear regression, r2 = 0.58; P < 0.001). The LBM exhibits an exponential relationship [B, lean and obese subjects combined; exponential regression (y = b·e a·x + c), r2 = 0.45, P 0.001; n = 30].

Although the mean serum concentrations of IL-1Ra were significantly decreased 6 months after bypass surgery, they failed to reach the level of the lean control group (Fig. 1A), which might be due to the persistence of an elevated BMI (33 ± 7 kg/m²) and leptin levels (18 ± 12 ng/ml) in this group. Therefore, we measured IL-1Ra concentrations in an additional group (C) of moderately obese patients with a BMI of 30–35 kg/m². The IL-1Ra levels in this group were significantly lower (410 ± 125 pg/ml; data not shown) than in the patients after bypass surgery (1,147 ± 196 pg/ml) (Fig. 1A).

Although all patients showed a uniform reduction in their BMI (Fig. 3A), marked interindividual differences existed in the response of IL-1Ra levels after bypass surgery (Fig. 3B). As is apparent from Fig. 3B, the obese patients can be divided into two groups of moderately increased (<1,500 pg/ml) and markedly increased (>1,500 pg/ml) basal levels of IL-1Ra. Indeed, the basal concentration of IL-1Ra is a good predictor of its postoperative decrease (correlation analysis of basal IL-1Ra vs. fractional decrease in IL-1Ra, r² = 0.48, P < 0.005; data not shown). Nevertheless, more than 50% of the variability in the decrease in IL-1Ra concentrations remains unexplained, suggesting that additional factors are involved in the control of IL-1Ra secretion, as was already apparent from the analysis of the baseline parameters. Although baseline leptin serum levels showed a relatively weak, but statistically significant, correlation with IL-1Ra concentrations (Fig. 1B), the fractional decrease in leptin (leptin level at 6 months/leptin level at baseline in the obese patients undergoing gastric bypass surgery) did not correlate with the fractional decrease in IL-1Ra (r² = 0.006; P > 0.8; data not shown). In contrast, and similar to the analysis of the baseline data, stepwise (backward and forward) multiple regression revealed that, other than the impact of the basal level of IL-1Ra itself (r² = 0.25, p = 0.06; data not shown), LBM was the best predictor of postbypass IL-1Ra levels.

View larger version (16K): [in this window] [in a new window]   Figure 3. Interindividual differences in the decrease in IL-1Ra levels. A, All 15 subjects examined demonstrated a homogeneous decrease in their BMI. However, the patients with the highest baseline serum IL-1Ra concentrations before bypass surgery generally had the most pronounced decrease 6 months postoperatively (B).

We have shown that IL-1Ra levels are increased nearly 7-fold in morbid human obesity. However, a marked variability in the increase in IL-1Ra exists (mean concentration in the obese group, 1,740 pg/ml with a SD of 1,370 pg/ml), with about 25% of the patients having normal IL-1Ra concentrations (<500 pg/ml), half having moderately elevated levels (500–2,500 pg/ml), and the last having 25% highly elevated levels (3,000–5,000 pg/ml). For comparison, IL-1Ra concentrations in normal individuals range between 100–400 pg/ml, whereas increased levels are found in rheumatoid arthritis (usually <2,500 pg/ml), as well as in polymyositis, systemic lupus erythematosus, and sepsis (5,000–10,000 pg/ml) (5).

Although we have previously demonstrated that leptin also has direct effects on monocytes, resulting in the selectively increased expression and secretion of IL-1Ra, the present data show that serum leptin levels are only one of the determinants of IL-1Ra serum concentrations. Indeed, LBM and the IRI are much better predictors of basal IL-1Ra levels, as well as of its response to weight loss. Moreover, the preoperative IL-1Ra concentration is in itself a good predictor of its fractional decrease after bypass surgery (Fig. 3B). It is at present unclear which signals mediate the relationship among LBM, insulin sensitivity, and IL-1Ra secretion, although serum insulin is a likely candidate, considering its action on the liver, which is the other main source of secreted IL-1Ra besides monocytes and macrophages (5, 15). However, other than leptin, none of these metabolic factors is currently known to regulate IL-1Ra secretion, and in vitro experiments in our laboratory have failed to show a stimulatory effect of insulin THP-1 monocytes (Meier, C. A., and J.-M. Dayer, unpublished data). Because the known stimulators of IL-1Ra secretion are cytokines (IL-3, IL-4, TNF, granulocyte-macrophage colony-stimulating factor, and interferon-ß), it could be speculated that the observed increase in IL-1Ra in obese patients is simply due to an inflammatory condition (16). However, the blood samples in the group of nondiabetic obese patients was taken before the gastric bypass surgery as part of the preoperative work-up. Hence, all patients were afebrile at that time, with normal white blood cell counts and not taking any nonsteroidal anti-inflammatory drugs or antibiotics. More importantly, the serum levels of IL-6 (3.6 ± 0.5 pg/ml in the 20 obese patients) were below the lower limit of the normal range (10–40 pg/ml), thereby excluding an underlying inflammatory disorder. Nevertheless, these levels of IL-6 were slightly higher than in the 10 lean control patients (2.0 ± 1.1 pg/ml). Although such a small increase in the serum levels of IL-6 has been reported previously in obese patients, the functional detection limit of the IL-6 assay used in our study is approximately 5 pg/ml, thereby rendering the interpretation of this minor difference difficult (17). Moreover, if a hypothetical inflammatory state would explain the markedly elevated serum concentrations in our group of obese patients, the IL-6 levels would also be expected to be several-fold above the upper limit of the normal range (40 pg/ml in our laboratory).

The pathophysiological relevance of the increased levels of IL-1Ra in obese patients remains a matter of conjecture. Although the increased levels of this IL-1 antagonist may protect obese patients from inflammatory disorders, there are currently no data substantiating such a concept. However, we hypothesize that the increased levels of circulating IL-1Ra in the obese may contribute to the central resistance to leptin, which is characteristic of the vast majority of obese patients. Although a limited capacity transport system for leptin into the cerebrospinal fluid and abnormalities in the intracellular signaling by the leptin receptor have been proposed, the pathophysiological relevance of these findings remains unclear. Intriguingly, leptin has been found to induce IL-1ß immunoreactivity in the hypothalamus of rodents, where this cytokine is required for the lowering of food intake by leptin as corroborated by the resistance to leptin in IL-1 receptor knock-out animals (6). Similarly, the central administration of IL-1Ra in rodents was shown to inhibit the leptin-induced suppression of food intake, as well as to abolish the leptin-induced increase in body temperature (6). Because IL-1Ra readily passes the blood-brain barrier (18), it is likely that the increased IL-1Ra serum levels also result in higher local levels within the leptin-responsive hypothalamic nuclei. In addition, some of the neurons involved in the regulation of appetite are even located outside the blood-brain barrier, and these nuclei are directly exposed to the circulating levels of IL-1Ra. Hence, it can be speculated that the marked elevation in IL-1Ra serum levels in obese patients, which are associated with an augmentation in the LBM, IRI, and leptin levels, contributes to the central resistance to leptin, thereby reinforcing a vicious cycle of the mutual enforcement of progressive obesity and resistance to leptin.

The prediction would be that obese patients with low levels of IL-1Ra (about 25% in our study population) are less resistant to the hypothalamic effects of leptin than their peers with IL-1Ra concentrations above the upper limit of the normal range (500 ng/ml). Although no data in humans are yet available, the observation that knock-out mice lacking the IL-1Ra gene are significantly lighter than the wild-type littermates is compatible with such a model (4).

In summary, we have shown that IL-1Ra levels are markedly and reversibly increased in human obesity. Although leptin may be one of the regulatory factors, our data suggest that additional parameters, such as LBM and insulin levels, predict with greater precision the variations in IL-1Ra. It remains to be determined whether in the human system this increase in IL-1Ra levels has a relevant impact on the immune system and/or the central sensitivity to leptin.

Acknowledgments

We are grateful to Dr. Isabelle Ruffini and Dr. Roswitha Rem for their expert assistance in preparing the manuscript.

Footnotes

This work was supported by the Swiss National Science Foundation Grants 3231-51957.97/2 and 3200-064078.01 (to C.A.M.) and 3231-054954.98 and 3200-054955.98 (to C.G.), as well as a grant from the Wilsdorf Foundation (to C.A.M.).

Abbreviations: BMI, Body mass index; IL-1Ra, IL-1 receptor antagonist; IRI, insulin resistance index; LBM, lean body mass.

Received August 6, 2001.

Accepted December 12, 2001.

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