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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Unexplained weight loss is common in patients with chronic obstructive pulmonary disease (COPD).
Since leptin, an obesity gene product, is known to play important roles in the control of body weight
and energy expenditure, we investigated serum leptin levels, along with circulating tumor necrosis
factor-
(TNF-) and soluble TNF receptor (sTNF-R55 and -R75) levels, in 31 patients with COPD and
15 age-matched healthy controls. The body mass index (BMI) and percent body fat (%fat) were significantly lower in the COPD patients than in the healthy controls (BMI = 18.1 ± 2.7 kg/m2 versus
22.8 ± 2.2 kg/m2 [mean ± SD]; p < 0.0001; %fat = 16.9 ± 5.8% versus 24.3 ± 4.9%; p < 0.001). Serum leptin levels were significantly lower in the COPD patients than in the healthy controls (1.14 ± 1.17 ng/ml versus 2.47 ± 2.01 ng/ml; p < 0.05). In contrast, serum TNF- levels (6.59 ± 1.92 pg/ml
versus 5.41 ± 1.60 pg/ml; p < 0.05), plasma sTNF-R55 (1.16 ± 0.47 ng/ml versus 0.67 ± 0.13 ng/ml;
p < 0.0001) and sTNF-R75 (3.65 ± 1.29 ng/ml versus 2.25 ± 0.43 ng/ml; p < 0.0001) levels were significantly higher in the COPD patients than in the healthy controls. Importantly, circulating leptin levels (log transformed) did correlate well with BMI and %fat, but not with TNF- or with sTNF-R levels in the COPD patients. These data suggest that circulating leptin is independent of the TNF- system and is regulated physiologically even in the presence of cachexia in patients with COPD.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Unexplained weight loss commonly occurs in patients with chronic obstructive pulmonary disease (COPD) (1, 2). That these findings are clinically important is indicated by their adverse relation to physical performance and survival in COPD (3), independent of the severity of airflow obstruction. Although the increased work of breathing in COPD could be partly responsible for excessive energy expenditure (4), this hypothesis is still controversial (5, 6). In either case, it does not by itself explain weight loss, and other mechanisms have been considered.
Leptin, an adipocyte-derived hormone, plays an important role in an energy homeostasis by signaling the brain about the amount of adipose tissue stored in the body (7, 8). After interaction with specific receptors located in the central nervous system and in peripheral tissues, leptin induces a complex response, including control of body weight and energy expenditure (9). Improvements in lipid metabolism and glucose homoeostasis, and increased thermogenesis, are considered to be some of the important metabolic effects of leptin (7, 8). Administration of recombinant leptin to ob/ob mice, which have a genetic defect in leptin production, reduces food intake, increases energy expenditure, and decreases body weight (7, 8). Circulating leptin levels are reported to correlate with the body mass index (BMI) in humans (10, 11). In pathologic conditions such as chronic renal insufficiency (12) and bacterial endotoxemia (13), and with exposure to high-dose glucocorticoids (14), inappropriately increased levels of leptin are thought to induce excessive metabolic effects underlying anorexia and loss of body weight.
Recently, cytokine-mediated metabolic derangements have
begun to be considered as among the candidates responsible
for cachexia in COPD patients (15, 16). It has been suggested
that tumor necrosis factor- (TNF-), a pleiotropic cytokine
causing cachexia (17, 18), plays a part in metabolic changes associated with chronic wasting diseases such as cancer (19), cystic fibrosis (20), congestive heart failure (CHF) (21), and COPD
(15, 16). It was shown that both circulating levels of TNF-
and TNF- production by peripheral blood monocytes were
increased in weight-losing COPD patients (15, 16), suggesting
that activation of the TNF- system was associated with the
cachexia observed in COPD patients. Importantly, administration of endotoxin or cytokines including TNF- or IL-1
produced a prompt and dose-dependent increase in serum
leptin levels in both experimental animals (13, 22) and in humans (23). This suggests that increased levels of circulating
leptin may contribute to anorexia and weight loss in pathologic conditions including COPD.
Against this background, we conducted the present study
to elucidate two questions. First, whether circulating leptin
levels are inappropriately increased in patients with COPD.
Second, whether circulating levels of leptin are related to
those of TNF- or soluble TNF receptors (sTNF-Rs) in patients with COPD. Two kinds of soluble TNF receptor have
been shown to be sensitive markers of activation of the TNF-
system (24). We felt that answering these two questions might
provide new insights into the pathophysiology of cachexia in
COPD patients.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Study Population
Thirty-one patients with COPD (all male) were diagnosed according
to the criteria of the American Thoracic Society (25). Their irreversible chronic airflow obstructions were confirmed. The patients had
been clinically stable for at least 3 mo and lacked clinical signs of exacerbation, such as infection or heart failure. Patients who had conditions known to affect serum leptin or TNF- levels, such as corticosteroid use, cancer, collagen vascular disease, smoking, cardiac failure,
or infection were strictly excluded (13, 14, 19, 21, 22, 26, 27). The patients were not receiving nutritional support therapy.
Fifteen age-matched healthy males were also studied as control subjects. These control subjects had no medical illnesses, had normal physical examinations, blood counts, chemistries, and showed no symptoms or signs of infection at the time of study.
After an overnight fast, all subjects had anthropometric measurements and were tested for body composition with bioelectric impedance analysis (HBF-301; Omron Corp., Tokyo, Japan). Percent of normal body weight (% normal BW) was calculated using the 1995 National Nutritional Assessment by the Japanese Ministry of Health and Welfare. Informed consent was obtained from all subjects in the study.
Measurement of Body Composition by Bioelectric Impedance Analysis
The basic principles of bioelectric impedance analysis were described by Lukaski and colleagues (28). Using the HBF-301 instrument, we calculated fat-free tissue mass (FFM) as follows:
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where Ht is height (in centimeters), weight is in kilograms, age is in
years, and bioelectric impedance, Z, in ohms (
) measured between
both palms. This equation was applied for male subjects in the standing position.
Pulmonary Function Test
FVC and FEV1 were measured with standard spirometric techniques (CHESTAC-25 part II EX; Chest Corp., Tokyo, Japan). The highest value from at least three spirometric maneuvers was used. Reference values were those proposed by Quanjer and coworkers (29). Arterial blood gas was analyzed with the subject in the sitting position and breathing air (280 Blood Gas System; Ciba Corning Diagnostics Corp., Medfield, MA).
Determination of Serum Leptin and TNF Levels
Blood samples were drawn between 8:00 and 9:00 A.M. from subjects
who had been fasting since 8:00 P.M. the previous night. Both serum and
plasma were separated from blood cells by centrifugation at 1,000 × g
for 5 min. All samples were stored at 
70° C until analyzed.
Serum leptin concentrations were measured in duplicate with a highly sensitive radioimmunoassay (RIA) (Linco Res, Inc., St. Louis, MO) (30). The antibody used in the RIA was a polyclonal antibody raised in rabbits against a highly purified recombinant human leptin. Both the calibrators (0.5, 1, 2, 5, 10, 20, 50, and 100 µg/L) and 125I-labeled tracer for the RIA were prepared with a recombinant human leptin. Calibrators or specimens (100 µl) in duplicate were mixed with 125I- labeled leptin and incubated overnight at 4° C with the leptin antibody. Antirabbit IgG was added to all samples, which were then incubated for 20 min at 4° C to precipitate the antibody-antigen complex. After then centrifuging the samples for 15 min at 2,000 × g and 4° C, the supernates were decanted and the radioactivity in the pellets was counted to determine bound radioactivity. The log values of the calibrators were plotted against the unknown bound counts/zero calibrator bound counts (B/B0) to generate a curve for the calculation of unknowns.
Serum TNF- and plasma sTNF-R55 and sTNF-R75 concentrations were measured in duplicate with enzyme-linked immunosorbent
assay (ELISA) kits (Quantikine; R&D Systems, Minneapolis, MN)
(31). Briefly, a microtiter plate was coated with a murine monoclonal antibody specific for TNF-, sTNF-R55, or sTNF-R75. Standards and
samples were added to individual wells. After several washes to remove unbound proteins, an enzyme-linked (conjugated to alkaline phosphatase for TNF- and to horseradish peroxidase for sTNF-Rs) polyclonal antibody specific for TNF-, sTNF-R55, or sTNF-R75 was
added to the wells. Following another several washes to remove unbound antibody-enzyme reagent, a substrate solution (lyophilized nicotinamide adenine dinucleotide phosphate [NADPH] for TNF-, hydrogen peroxide and tetramethylbenzidine for sTNF-Rs) was added. For the measurement of TNF-, amplifier solution (lyophilized amplifier enzymes) was added (high-sensitivity kit). The reaction was
stopped with 2N sulfuric acid. The color generated was determined with a spectrophotometric microtiter plate reader (Model 450; Bio-Rad, Richmond, CA) by measuring the optical density at 490 nm and
450 nm for TNF- and the sTNF-Rs, respectively.
Statistical Analysis
Because the normality hypothesis was not always fulfilled for most of the variables except for height, statistical analysis was performed with the Mann-Whitney U test for nonparametric data to analyze differences between the two groups. The relations between continuous variables were evaluated with Spearman's rank correlation technique. Results were expressed as mean ± SD. Significance was determined at the 5% level. Statistical analysis was done with the Statview Statistical Package (Statview, Inc., Berkeley, CA).
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RESULTS |
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DISCUSSION
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Clinical characteristics of both the COPD patients and the healthy controls are shown in Table 1. Patients with COPD had significantly lower BW, BMI, and percent body fat (%fat) than did the control subjects. The COPD patients had severe airflow limitation, decreased arterial PO2, and increased arterial PCO2 values. The control subjects had normal %FVC and %FEV1 on spirograms.
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We first analyzed serum leptin levels in patients with COPD and then in the healthy controls. The levels of leptin (Table 2) in the COPD patients were significantly lower than in the healthy controls (1.14 ± 1.17 ng/ml versus 2.47 ± 2.01 ng/ml; p < 0.05). We found significant correlations between serum leptin levels (log transformed) and BMI (r = 0.706; p = 0.0001; Figure 1) as well as %fat (r = 0.554; p < 0.005; Figure 2) in COPD patients. Similar results were achieved for the control subjects (BMI: r = 0.874; p < 0.005; Figure 1; %fat: r = 0.713; p < 0.01; Figure 2).
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In light of the ability of TNF- to increase leptin levels in
humans (23), we next examined serum TNF- and plasma
sTNF-R55 and -R75 levels in both the COPD patients and
healthy controls. We found that serum TNF- and plasma
sTNF-R55 and sTNF-R75 concentrations in COPD patients
were significantly higher than those in the healthy controls.
This was in contrast to decreased leptin levels in the COPD
patients as compared with the healthy controls (Table 2). Importantly, serum leptin levels did not correlate with either serum TNF- or with plasma sTNF-R levels in either the COPD
patients or the healthy controls.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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This study was done to evaluate circulating leptin levels and
the possible association between leptin and the TNF- system in the regulation of energy expenditure, body composition,
and metabolic effect in COPD patients. Against expectation,
we found that serum leptin levels in COPD patients were not
elevated over those in healthy controls, although serum TNF-
levels were significantly increased in the COPD patients. Furthermore, we were unable to find any relationship between
circulating leptin and TNF- levels. These observations suggest that leptin is not primarily under the control of the TNF-
system, and it seems not to play an important role in weight
loss in patients with COPD. The positive correlation between
serum leptin levels and BMI in patients with COPD confirms that circulating leptin levels remain regulated even in patients in the cachexic status seen in COPD. Similar physiologic regulation of leptin is also noted in other malnutritional states such
as anorexia nervosa (32) and acquired immune deficiency syndrome (AIDS) (33).
The physiologic relevance of the slightly but significantly
increased TNF- levels in the COPD patients in the present
study is difficult to explain, but several speculations warrant
further discussion. First, inflammation is not the only source
of activation of the TNF- system; hypoxia, for example, can
induce TNF- and sTNF-R release in a human macrophage
cell line, THP-1 (34). Hypoxemia observed in COPD patients
might contribute to the activation of the TNF- system independently of airways inflammation. Second, although TNF-
exerts its effect at least partly in a paracrine/autocrine fashion
in each tissue, there is no significant correlation between TNF-
levels at local sites and in the systemic circulation (35). It may
be possible that circulating TNF- is spilled from the lung tissue of COPD patients (36, 37). Third, we have previously reported that circulating TNF-, sTNF-R55, and sTNF-R75
were increased in patients with CHF (21) to levels similar to
those observed in our COPD patients. Since the levels of both
sTNF-R55 and sTNF-R75 were affected in close proportion to
the disease severity and hemodynamic variables in patients
with CHF (21), the increased levels of circulating TNF- and
sTNF-Rs found in our study would be related to the pathophysiology of right-sided heart failure associated with COPD.
Additionally, as shown by Francia and colleagues (15), serum
levels of TNF- were much higher in weight-losing COPD patients than in COPD patients of normal weight. Less marked but persistent elevation of circulating levels of TNF- may
have unknown effects on metabolic abnormalities, independent of leptin, in patients with COPD.
Our data showed significantly increased levels of circulating sTNF-R55 and -R75 in clinically stable patients with
COPD. Two kinds of TNF--binding proteins are known as
extracellular fragments of TNF-R55 and -R75 (38). The endogenous formation of TNF- and other inflammatory stimuli
leads to the shedding of TNF-Rs, which interfere with the
binding of TNF- to TNF-Rs on the cell surface, and sTNF-Rs
therefore act as regulatory components of the TNF- system
(24). The increased levels of circulating sTNF-Rs in COPD
patients may reflect activation of the TNF- system or other
pathophysiologic activities (24).
The lower levels of circulating leptin in the COPD patients in our study may have some clinical significance for the following reasons. First, hypoxemic COPD patients were found to have impaired glucose tolerance, which cannot be readily explained by changes in known glucoregulatory hormones (39). Lower leptin levels, such as those observed in our study, might contribute to this phenomenon, since leptin is known to improve glucose homeostasis (7, 8). Second, sexual impotence and atrophy of the testes associated with reduced serum testosterone levels have been found in hypoxemic male patients with COPD (40). Although there is a negative correlation between serum leptin and testosterone in healthy men (27), this relationship may not exist in patients with COPD, because serum leptin levels in our study were extremely low. However, reduced levels of circulating leptin, independently of testosterone, might contribute to the sexual disturbances seen in patients with COPD, since leptin has an important function in stimulating the reproductive system (7, 8). Third, although growth hormone (GH) levels are normal in COPD patients (39, 43), administration of recombinant human growth hormone (rhGH) has been attempted in an effort to improve nitrogen balance and increase muscle strength in patients with COPD (44, 45). Since serum GH levels are inversely correlated with circulating levels of leptin (27), this rhGH treatment for COPD patients may aggravate the lower levels of leptin. Additionally, leptin has recently been reported to have been involved in T-cell-mediated immunity (46). Since administration of leptin to mice reverses the immunosuppressive state in starvation, the lower leptin levels in patients with COPD might contribute to a higher frequency of pulmonary infection in COPD patients.
In summary, we evaluated serum levels of leptin, TNF-,
and sTNF-Rs in patients with COPD and in age-matched
healthy controls. We found that circulating levels of leptin
were significantly lower in patients with COPD than in the
healthy controls. In addition, there was no relationship between circulating leptin levels and the activated TNF- system
in patients with COPD. However, circulating leptin levels correlated well with BMI and %fat in COPD patients, as also
demonstrated in the healthy controls. We conclude that the
physiologic regulation of leptin is maintained despite weight loss in patients with COPD, and that circulating levels of leptin are not controlled by the TNF- system. However, decreased levels of circulating leptin may have some pathophysiologic roles in patients with COPD.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Noriaki Takabatake, M.D., c/o Hidenori Nakamura, M.D., First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2, Iida-Nishi, Yamagata 990-9585, Japan.
(Received in original form June 23, 1998 and in revised form October 22, 1998).
Acknowledgments: The authors thank the Cosmic Corporation (Tokyo, Japan) for technical assistance and critical discussion.
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References |
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REFERENCES
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