Departments of 1 Pediatrics, 2 Pathology, and 3 Medical Biochemistry, University of Geneva Medical School, 1211 Geneva 4, Switzerland
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ABSTRACT |
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Leptin, a cytokine
involved in the regulation of food intake, has been reported to be
decreased in lung diseases such as chronic obstructive pulmonary
disease and cystic fibrosis and increased in critically ill patients
with sepsis. We investigated the role of leptin during hyperoxia in
mice, which results in alveolar edema, severe weight loss, and death
within 3-4 days. In oxygen-breathing mice, serum leptin was
increased six- to sevenfold and its mRNA was upregulated in white
adipose tissue. Leptin elevation could not be attributed to changes in
circulating tumor necrosis factor- but was completely dependent on
endogenous corticosterone elevation because adrenalectomized mice did
not exhibit any increase in leptin levels. Using leptin-deficient mice
and wild-type mice treated with anti-leptin antibody, we
demonstrate that weight loss was leptin independent. Lung damage
was moderately attenuated in leptin-deficient mice but was not
modified by anti-leptin antibody or leptin administration, suggesting
that leptin does not play an essential role in the direct and
short-term effects of oxygen-induced injury.
oxygen toxicity; ob/ob mouse; lung
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INTRODUCTION |
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OXYGEN EXPOSURE IS A
MODEL of acute lung injury due to a direct lung insult by oxygen
free radicals and to an indirect insult generated by a secondary
inflammatory process. Hyperoxia has been associated with the rise of
several cytokines such as platelet-derived growth factor and
intercellular adhesion molecule-1 or their receptors and of chemokines
such as interleukin (IL)-8 (7). Leptin, the cytokine
product of the ob gene that is secreted by adipocytes, is an
important regulator of food intake and energy expenditure in rodents
(37). Serum leptin levels correlate positively with body
fat stores in rodents as well as in humans (11).
Regulation of leptin secretion by adipocytes is fairly complex, with
several positive [tumor necrosis factor (TNF)-, IL-1,
glucocorticoids, and insulin] or negative (catecholamines) signaling
pathways (for a review, see Ref. 21).
More recently, leptin has been shown to play an important role in
inflammation and seems necessary for the induction of the T helper type
1 response (22). Acute inflammation elicited with endotoxin or by TNF- injection is known to raise leptin levels (30). On the other hand, leptin has been shown to protect
against the toxicity exerted by TNF-
because mice deficient for the
ob gene [leptin deficient (ob/ob)] or its
receptor are more sensitive to TNF-
or endotoxin (13,
33). High levels of leptin are related to a better survival rate
in critically ill septic patients (8). Another study
(9) performed in septic patients showed that serum leptin
concentrations were significantly correlated with plasma cortisol but
not with sepsis.
Several lung diseases (acute and chronic) are associated with severe
weight loss, anorexia, and inflammation. Patients suffering from
chronic lung disease such as chronic obstructive pulmonary disease
(COPD) or cystic fibrosis are underweight and exhibit high levels of
circulating TNF- and low levels of leptin (1, 32).
However, leptin levels are not reported yet in nonseptic patients with
acute lung injury. Weight loss in these patients has often been related
to increased caloric loss due to high respiratory work
(2). Intensivists are often confronted with patients
ventilated for acute lung disease in whom it is very difficult to avoid
weight loss even with adequate caloric support.
Taking this background into account, we have first examined circulating leptin levels and leptin gene expression during hyperoxia in mice because exposure of mice to high oxygen concentrations leads to an acute lung injury that is accompanied by severe and rapid weight loss (3, 5). Then, we tested whether leptin might be involved in oxygen-induced lung damage.
We report that during hyperoxia, leptin blood levels increase, probably
because its synthesis is upregulated in adipose tissue. Serum leptin
elevation is not mediated by circulating TNF- but is secondary to
increased levels of circulating corticosterone because adrenalectomized
(ADX) mice do not increase their leptin levels during hyperoxia.
Wild-type (WT) and ob/ob mice treated with anti-leptin
antibody lose weight during hyperoxia, indicating that body weight loss
is mainly leptin independent. We show that oxygen toxicity in
ob/ob mice was attenuated, an effect that could not be
reproduced with anti-leptin antibody administration in WT mice. The
protective effect observed during oxygen toxicity in ob/ob
mice could not be attributed to constitutive high corticosterone levels, whereas injection of hydrocortisone 21-acetate (HCS) aggravates rather than delays hyperoxia-induced lung injury. Rather, it is due to
subtle metabolic and immunologic changes occurring in obese mice
secondary to the lack of leptin.
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MATERIALS AND METHODS |
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Mice. C57BL/6 female mice were purchased from Iffa Credo (Labresle, France) and bred in our animal facility for two generations. ob/ob mice and their littermates (C57BL/6 background) were purchased from Taconic Farms. ADX or sham-operated mice (C57BL/6 females) were purchased from Iffa Credo. Experiments were performed with 2- to 3-mo-old mice. The animals were killed with an intraperitoneal injection of pentobarbital sodium and bled through the abdominal aorta. The thorax was opened, and the lungs were removed, weighed, frozen, and prepared for DNA or mRNA extraction. Pulmonary edema was evaluated by measuring the weight as previously described (4, 6). The white adipose tissue was removed from the periovarian region and frozen.
Reagents.
Leptin blood level was assessed by RIA (mouse leptin RIA kit, Linco
Research, St. Charles, MI). Corticosterone was determined by RIA with
125I-labeled corticosterone (Diagnostic Systems
Laboratories, Webster, TX) as previously described
(35). Mouse TNF- and mouse IL-6 were determined by
DuoSet ELISA (R&D Systems, Minneapolis, MN).
Hyperoxic exposure and in vivo treatment. The mice were placed in a sealed Plexiglas chamber and exposed to 100% oxygen or room air in the same conditions as previously described (6). Food and water were available ad libitum. All mice were weighed daily. The mice were killed at 72 h or between 84 and 96 h of exposure when the temperature dropped below 32°C, an event followed by death within 2 h. The Ethical Committee on Animal Experiments (Office Vétérinaire Cantonal of Geneva) approved this study protocol.
Anti-mouse TNF-RNA analysis.
After removal, the lungs and adipose tissue were immediately frozen in
liquid nitrogen and stored at 80°C. Total lung RNA was isolated
with TRIzol reagent (GIBCO BRL), and total adipose tissue RNA was
isolated with a RNeasy protocol with small modifications specific for
adipose tissue (QIAGEN). Leptin mRNA was detected by Northern blot. The
complete coding sequence of mouse leptin cDNA was labeled with the
random-primer labeling system (Rediprime II, Amersham Pharmacia
Biotech, Little Chalfont, UK). Northern blots of total RNA were
hybridized with the complementary mouse leptin
-32P-labeled dCTP DNA probe (specific activity 3,000 Ci/mmol; Amersham International) (26). Mouse TNF-
mRNA
was detected with a TNF-
32P-labeled dUTP riboprobe
(specific activity 400 Ci/mmol) containing the 696 TaqI-EcoRI fragment isolated from
pAT153-trp-mTNF85 as previously described (10).
Quantification was achieved by phosphorimager analysis (Molecular
Dynamics, Sunnyvale, CA) with ImageQuant software (Molecular Dynamics).
To evaluate gel loading and membrane transfer, the blots were stained
with methylene blue. These blots were analyzed by densitometry, and
small differences in loading were normalized by the density of the 18S
rRNA bands. The results of mRNA abundance are expressed in arbitrary
units ± SD as a ratio of the intensity of the signal to that of
the 18S rRNA signal.
Detection of internucleosomal DNA fragmentation. The lungs were homogenized by polytronic disruption in phosphate-buffered saline-10 mM EDTA (10 mg of tissue in 0.5 ml). The homogenate was then centrifuged at 13,000 rpm for 20 min at 4°C. The supernatant was kept and treated for 30 min at 37°C with 20 µg/ml of RNase A and for another 30 min with 200 µg/ml of proteinase K. After three phenol-chloroform extractions, 3 M sodium acetate (pH 4.8) was added (1:10), and DNA was precipitated with 1 volume of isopropanol. The pellet was centrifuged at 13,000 rpm for 10 min at 4°C, washed with 70% ethanol, dried, and resuspended in 10 mM Tris-0.1 mM EDTA, pH 8.0. The samples were run on a 1% agarose gel, and DNA fragmentation was revealed with ethidium bromide.
Statistical analysis. The values for all animals within each experimental group were averaged, and the SD of the mean was calculated. The significance of differences between different groups was determined by Kruskal-Wallis test with Dunn's multiple comparison test. The significance between the survival of two groups was determined by Kaplan-Meier test. The significance between the values of one control group and one experimental group was determined by the unpaired Student's t-test. Correlations were calculated with the Spearman correlation test. The significance level was set at P < 0.05.
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RESULTS |
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Hyperoxia increases plasma leptin levels and mRNA expression in
adipose tissue.
Oxygen exposure is known to provoke an acute lung injury that leads to
mouse death in 3-4 days, concomitant with a body weight loss of
10-15%. Plasma leptin levels did not change until 60 h of
oxygen exposure and then markedly increased to reach levels that were
six- to sevenfold higher than those measured in control mice
(P < 0.05; Table 1). We
then analyzed the expression of leptin mRNA in adipose tissue. At
72 h of hyperoxia, the oxygen-exposed mice showed a fourfold
upregulation in leptin mRNA level compared with that in control animals
(P < 0.003; n = 5; Fig.
1). Leptin mRNA was mildly expressed and
unchanged during hyperoxia in the skeletal muscle and was not
detectable in the lungs (data not shown).
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Role of leptin in weight loss induced during oxygen-induced lung
injury.
Although it is known that the plasma leptin concentration correlates
positively with body fat percentage and body mass index, the body
weight did not diminish significantly until 48 h and was
significantly decreased after 72 h (P < 0.05)
when the leptin level was significantly elevated (Fig.
2). To determine whether the leptin
increase was responsible for weight loss, we exposed ob/ob
mice to hyperoxia. Because the initial body weight of ob/ob mice was very different from that of WT mice (45.6 ± 2.1 g
vs. 20.4 ± 0.5 g), comparison of weight loss is not
straightforward. Indeed, it is known that oxygen toxicity not only
depends on the strain but also on the age of the animal, and
ob/ob mice weighing ~20-25 g would be only 4-5
wk old (19). Daily weight loss, expressed in grams, was
equal in WT and ob/ob mice (Fig. 2) but was significantly different when measured in percent of initial body weight (10.4 ± 2.9% in WT vs. 4.2 ± 1.3% in ob/ob mice;
P < 0.05).
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Role of leptin in hyperoxia-induced lung injury. We attempted to decipher the participation of leptin in hyperoxia-induced injury by using 1) ob/ob mice, 2) WT mice treated with anti-leptin antibody, and 3) WT mice treated with recombinant leptin.
First, the lung weight, reflecting alveolar edema and capillary leak after 72 h of oxygen exposure, was significantly higher in WT compared with ob/ob mice (P < 0.05; n = 10; Fig. 3A). We also compared the survival of ob/ob and WT mice. ob/ob mice survived slightly but not significantly longer than WT mice; mean survival was 92.7 ± 11 vs. 84.5 ± 6.1 h (95% confidence interval of the ratio = 0.57-1.25; n = 10). We and others have shown that oxygen toxicity was related to apoptosis of lung cells (5); we then analyzed lung DNA fragmentation by gel electrophoresis. Figure 4 illustrates that WT but not ob/ob mice exhibit DNA fragmentation at 72 h of hyperoxia, whereas in ob/ob mice, nucleosomal ladders occurred only at 90 h (around the time of death; n = 3). In air-breathing mice, no DNA fragmentation was observed. These results might suggest that leptin aggravates pulmonary lesions. Second, we administered anti-leptin antibody to WT mice, which did not prevent hyperoxia-induced lung injury as measured by lung weight (n = 15; Fig. 3B). Third, we treated WT mice with recombinant leptin and found no statistical difference in total lung weight at 72 h of exposure (Fig. 3B). The data obtained with anti-leptin antibody or leptin administration do not argue in favor of an important role for leptin in the lesions of WT mice and suggest that the increased resistance to oxygen seen in ob/ob mice might be due not to the absence of leptin but to the indirect nutritional or immunologic long-term effects of leptin deficiency.
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TNF- does not account for leptin upregulation.
TNF-
as well as other cytokines has been shown to regulate leptin
levels (30). To determine whether the increase in leptin was due to an increase in circulating TNF-
, we measured the plasma TNF-
concentration with ELISA. Compared with control mice, no change
was seen in active TNF-
during hyperoxic exposure (Table 1). The
TNF-
concentration was <50 pg/ml when measured by ELISA. Blocking
TNF-
in vivo has been shown to decrease leptin production in an
endotoxin model (25). To evaluate whether TNF-
plays a
role in the leptin elevation seen in the oxygen-exposed mice, we
injected anti-TNF-
or control IgG on days 1 and
3 of hyperoxia at a dose that was effective in other models
of lung injury in mice (28). No decrease in leptin levels
was observed after this treatment (data not shown).
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IL-6 plasma levels and leptin production. IL-6 plasma levels were undetectable in air-breathing mice (WT; <0.1 pg/ml) and were markedly increased in mice exposed to hyperoxia for 84 h (n = 3; Table 1). ob/ob air-breathing mice exhibited higher and dissimilar IL-6 levels compared with WT mice but did not show any increase during hyperoxia (20.5 ± 3.5 pg/ml; n = 5 air-breathing mice vs. 12.7 ± 6.4 pg/ml; n = 3 hyperoxic mice).
Corticosterone is responsible for leptin increase during hyperoxia.
Because corticosterone has been shown to be regulated by leptin or,
conversely, to regulate leptin levels (12, 20), we measured corticosterone levels in WT and ob/ob mice.
Corticosterone increased gradually and significantly over time during
hyperoxia in WT mice (Fig. 6). The
correlation between corticosterone and the leptin level was highly
significant as calculated by the Spearman correlation test
(P < 0.0001). As already described (18),
ob/ob mice exhibited a higher basal level of corticosterone
than WT mice (253 ± 87 ng/ml in ob/ob mice compared
with 98 ± 37 ng/ml in WT mice). The corticosterone level did not
change significantly during hyperoxia in ob/ob mice (Fig. 6)
and in anti-leptin antibody-treated WT mice.
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DISCUSSION |
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In this study, we report that circulating leptin increases dramatically during oxygen-induced lung injury, most likely by an increased synthesis in adipose tissue as suggested by an increase in the mRNA level. In contrast, the leptin mRNA level in the skeletal muscle, also detectable in accord with Friedman and Halaas (15), was unchanged. We failed to find detectable leptin mRNA within the lungs and did not find any upregulation of leptin receptor mRNA within the lung (data not shown).
Body weight loss in grams was similar in WT and ob/ob mice. However, when measured in percent of initial body weight, weight loss was clearly different and less important in ob/ob mice. How to interpret these results is debatable and still controversial in human studies (Golay A, unpublished observations). The percent of weight loss being different between ob/ob and WT mice could have been in favor of a leptin participation to weight loss. However, the similar weight loss (in grams and in percent) seen in WT mice treated with anti-leptin or control antibody argues against a leptin-dependent weight loss. Interestingly, the leptin increase seems specific to acute lung injury because bleomycin-induced lung injury (data not shown), a more chronic disease occurring in 7-14 days also accompanied by severe weight loss, or COPD was not followed by plasma leptin elevation (32).
The fact that leptin is produced mainly by adipose tissue during
hyperoxia suggests that hyperoxia could either exert a direct effect on
adipose tissue via oxygen toxic metabolites or exert an indirect effect
via other mediators secreted by the lung or other organs. Different
hypotheses can be envisioned to explain the effects of hyperoxia on
adipose tissue. 1) Hyperoxia-derived signals could act on
the hypothalamus and in this way alter the adrenocortical axis (for
example, sympathetic tone is known to regulate the adrenocortical
axis). This possibility has been ruled out by the same level of leptin
increase in mice exposed to hyperoxia and treated with nadolol.
2) Hyperoxia could differently upregulate other hormones or
cytokines such as TNF- and IL-6, insulin, and corticosterone in the
lung or other tissues that might be responsible for the increase in
leptin. We have explored several of the candidate molecules that might
be relevant for lung diseases.
TNF- is one of the proinflammatory cytokines known to regulate
leptin production when injected into mice (30). Barazzone et al. (6) have previously shown that TNF-
mRNA was upregulated within the lungs only during the terminal phase of
oxygen toxicity. In patients, the levels of circulating leptin are not
always correlated with circulating TNF-
. Underweight patients
suffering from COPD and cystic fibrosis exhibit, in opposite ways, high
TNF-
and soluble TNF receptor levels and lower levels of plasma
leptin than control patients (1, 32). Therefore, we tried
to determine by different approaches whether TNF-
could be
responsible for the increase in leptin synthesis. We could not measure
any change in TNF-
blood levels during hyperoxia. Moreover,
administration of anti-TNF-
antibody had no effect on the plasma
leptin levels. Because leptin production by adipocytes is inhibited by
TNF-
in vitro (36), we explored whether TNF-
from
adipose tissue could influence local leptin production as during
diabetes (17). For that reason, we measured TNF-
mRNA
expression within the adipose tissue. We observed a decrease in TNF-
mRNA during hyperoxia, suggesting that the downregulation of TNF-
might favor leptin production. Taken together, our data do not argue
for a significant role of circulating TNF-
in leptin upregulation
but are consistent with the possibility that TNF-
produced in the
adipose tissue might participate in leptin production. IL-6 can be
produced by several organs, including adipose tissue, and is also one
of the mediators that might be implicated in mice (23).
The serum level of this circulating cytokine has been shown to be
elevated during obesity (21), and this was confirmed by
our results in ob/ob mice. In contrast to TNF-
, IL-6
blood levels increase dramatically during oxygen-induced injury,
raising the possibility that this cytokine contributes to leptin
production and weight loss.
The presence of leptin receptors in the lungs indicates that this
tissue can be a target for leptin. Although the in vivo effects of
leptin in the lungs are not reported, a study (34) has
shown that this hormone acts as a proliferative factor for tracheal
epithelial cells in vitro (34). Leptin might exert pro- or
anti-inflammatory effects. On one hand, the circulating leptin level is
increased in response to inflammatory agents such as lipopolysaccharide
or cytokines and, furthermore, when injected leptin increases vascular
permeability. On the other hand, leptin also protects against toxicity
exerted by TNF- because ob/ob mice are less resistant to
TNF-
(33).
The role of leptin in alveolar damage was investigated by three
separate approaches with different results. In overweight ob/ob mice, alveolar damage was delayed compared with that
seen in WT mice. In contrast, blockade of leptin in WT mice did not alter the course of lung injury. Accordingly, leptin administration had
no effect on the course of hyperoxic injury in WT mice. These observations suggest that the chronic or acute absence of leptin does
not have similar effects on the course of an alveolar inflammation. This interpretation is in accord with that made during the study of the
response of ob/ob mice to TNF- or lipopolysaccharide
discussed above. The peculiar response observed in ob/ob
mice cannot be attributed to increased circulating steroid levels
because corticosterone administration before the appearance of the
injury did not protect the mice but even worsened the lesions. One
possibility could be that obesity itself and its consequences such as
changes in lipoproteins could be responsible for this small protective
effect. Indeed, high levels of high-density lipoprotein (HDL) and
cholesterol have been reported in ob/ob mice secondary to a
defect in HDL catabolism by the liver (31). Because HDLs
are able to protect endothelial cells from oxidative stress and
apoptosis (29), it might be possible that the
acute inflammatory response during hyperoxia in ob/ob mice
is attenuated by high levels of circulating HDLs. In conclusion, we
think that the acute elevation of leptin does not play an essential
role in the development of hyperoxia-induced lung injury and that the
effect of hyperoxia in ob/ob mice might be due not only to
the absence of leptin but also to its related long-term consequences
such as changes in biochemical, nutritional, and immunologic status
compared with those in WT animals. Our data also underline that the
long-term defect of a single gene might lead to complex modifications
that are not comparable to acute blockade with the use of antibodies.
Corticosterone has been shown to stimulate leptin production in vitro and in vivo (11, 12, 24). Corticosterone increased up to fivefold during hyperoxia in WT mice, whereas in ob/ob mice in which the basal level is higher than in WT mice, (18), the corticosterone level did not further increase markedly during hyperoxia. We demonstrate a clear relationship between corticosterone elevation and leptin levels. ADX mice showed no change in leptin levels during hyperoxia compared with sham-operated mice. Furthermore, preliminary results suggest that glucocorticoids might contribute to aggravate the lesions of hyperoxia.
The present study demonstrated that hyperoxia stimulates leptin production via the stimulation of the adrenal gland but that leptin itself does not play a major role in oxygen-induced alveolar injury.
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ACKNOWLEDGEMENTS |
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We thank Anne Scherrer and Anne F. Rochat for technical assistance and Dr. Cem Gabay (Division of Rheumatology, University of Geneva, Geneva, Switzerland) for advice and helpful discussions.
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FOOTNOTES |
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This work is supported by Fonds National de la Recherche Scientifique (Swiss National Foundation) Grants 3200-056949.99 (to C. Barazzone-Argiroffo) and 31-56839.99 (to P.-F. Piguet) and the Wolfermann-Nägeli Foundation.
Address for reprint requests and other correspondence: C. Barazzone-Argiroffo, Dept. of Pathology, Centre Médical Universitaire, 1211 Geneva 4, Switzerland (E-mail: constance.barazzone{at}medecine.unige.ch).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 14 June 2000; accepted in final form 3 July 2001.
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