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Department of Animal Sciences, University of Illinois at Urbana-Champaign, 390 Animal Sciences Laboratory, Urbana, Illinois 61801
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Tumor necrosis factor
(TNF)-
stimulates the secretion of the adipocyte-derived hormone
leptin. However, the cellular mechanisms by which TNF- influences
leptin production are poorly understood. To examine this issue,
epididymal fat pads were isolated from mice and cultured in recombinant
murine TNF- (100 ng/ml). Compared with medium-treated controls,
steady-state leptin expression was increased in TNF--treated
explants. Culture with inhibitors of translation (cycloheximide) or
transcription (actinomycin-D) abrogated the induction of leptin
following TNF-. Explants were also cultured in the presence of the
anti-inflammatory p38 mitogen-activated protein kinase inhibitor
(SB-203580) or PG J2 metabolite
[15-deoxy-
12,14-PG J2 (PGJ)] and then
exposed to TNF-. Both compounds completely abolished TNF--induced
increases in leptin production. To test the relevance of this in vivo,
mice were pretreated with PGJ and then given TNF-. PGJ treatment
markedly blunted the TNF--induced increase in leptin, TNF-, and
interleukin-6 gene expression in epididymal adipose tissue.
Collectively, these data indicate that TNF- acutely activates leptin
expression and that anti-inflammatory agents can abrogate
TNF--induced hyperleptinemia.
endocrine-immune interaction; 15-deoxy-12,14-prostaglandin J2; SB-203580
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ALTHOUGH ORIGINALLY IDENTIFIED for its role in regulating energy balance, the adipocyte-derived hormone leptin is also an important immunoregulatory factor. From studies using mice that lack leptin, it is apparent that leptin is necessary for complete immunocompetence (18, 21). Cells of the immune system express functional leptin receptors (2), and leptin promotes the development of hematopoietic cells (2, 11). Furthermore, evidence is emerging that immunosuppression caused by malnourishment can be reversed by leptin administration (18).
Cytokines such as tumor necrosis factor- (TNF-) increase the
expression and secretion of leptin from adipocytes in rodents (9,
15, 25) and humans (34). Because leptin is
important in the regulation of food intake and body weight,
TNF--induced hyperleptinemia was initially thought to
play a role in cytokine-induced anorexia and the negative energy
balance and weight loss that accompany chronic infection and
disease. Leptin, therefore, was a potential target for therapeutic
intervention in wasting patients. Unfortunately, subsequent studies
suggested that hyperleptinemia is not involved in the pathogenesis of
the wasting syndrome (14). However, this does not discount
the importance of cytokine-induced hyperleptinemia. In fact, when this
response is absent, as in ob/ob mice, the lethal
effects of high doses of TNF- are significantly enhanced
(28). This enhanced sensitivity to TNF- can be reversed by pretreatment with recombinant leptin, suggesting that the activation of this endocrine response by TNF- is an adaptive mechanism that prevents septic shock and death.
Despite the emerging importance of this endocrine-immune interaction,
little is known concerning the cellular mechanisms by which TNF-
increases leptin secretion. In the present study, it was found that
TNF- treatment increased steady-state leptin mRNA levels in isolated
fat pads and that the resultant secretion of leptin could be blocked
with cycloheximide (CHX) or actinomycin-D (ACTD). Furthermore,
pretreatment with agents that inhibit proinflammatory cytokine
production abrogated the induction of leptin gene expression and
inflammatory hyperleptinemia.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental Animals
Male C3H/HeOuJ (OuJ) mice (26-32 g) were obtained from a breeding colony maintained at the University of Illinois. Male Balb-C mice (26-32 g) were obtained as above and used for all in vivo studies. Mice were housed under a reverse 12:12-h light-dark cycle (lights on at 2100) with ad libitum access to water and rodent chow. All housing conditions and procedures were approved by the University of Illinois Laboratory Animal Care Advisory Committee.Reagents
Recombinant murine TNF- was purchased from Pharmingen
(San Diego, CA) and was certified by Pharmingen to contain <0.1 ng endotoxin per 1 µg TNF- as assessed by Limulus
amoebocyte assay. CHX, ACTD, and dexamethasone (Dex) were purchased
from Sigma Chemical (St. Louis, MO). The p38 mitogen-activated protein
kinase (MAPK) inhibitor, SB-203580 HCl, was purchased from Calbiochem
(San Diego, CA). 15-Deoxy-12,14-prostaglandin
J2 (PGJ) was obtained from Biomol Research Labs (Plymouth
Meeting, PA). Reagents were diluted in sterile Krebs Ringer phosphate
(KRP) for cell culture experiments and sterile PBS (0.9% NaCl; Sigma
Chemical) for intraperitoneal injection.
Adipose Culture Preparation
Tissue explant isolation.
At the onset of the dark phase, when leptin levels are at their nadir
(8), mice were euthanized by CO2 gas
asphyxiation. Epididymal fat pads were excised, carefully weighed, cut
into 250-mg pieces, and minced using sterile scissors. In each well of
a 24-well plate, 250 mg of adipose tissue were cultured in 1 ml of KRP.
To control for individual differences in leptin expression between
mice, explants from each mouse were paired and one was cultured in KRP,
whereas another was exposed to TNF-.
Measurements
Leptin RIA. Leptin levels were determined using a commercially available RIA specific for murine leptin (Linco Research, St. Charles, MO) as previously described (7-9). The sensitivity of the assay was <0.2 ng/ml. The average intra-assay variation was 8.3%.
RNase protection assay. Total cellular RNA was isolated using the TRI-REAGENT protocol (Sigma Chemical) with an additional centrifugation step to remove lipid. RNA integrity was confirmed by denaturing agarose gel electrophoresis, and RNA concentration was determined by spectrophometric absorbency at two dilutions.
[-32P]UTP-labeled anti-sense RNA probes were generated
by in vitro transcription using murine cDNAs for leptin
(9), interleukin-6 (IL-6) (31), TNF-
(generated by RT-PCR-based cloning), 18s (Ambion, Austin, TX), and
-actin (Ambion). RNase protection assays were performed using the
RPA III (Ambion) protocol as previously described (9). The
relative radioactive intensity of protected fragments was subsequently
quantified by phosphorimaging analysis (Molecular Dynamics/Amersham
Pharmacia, Piscataway, NJ).
Cytokine ELISAs.
Plasma TNF- and IL-6 levels were determined using commercially
available ELISAs specific for each cytokine (R&D Systems, Minneapolis, MN).
Experimental Protocol
Experiment 1.
To determine if TNF- increased leptin mRNA expression in vitro,
adipose tissue explants from OuJ mice were isolated and then cultured
in the presence or absence of murine TNF- (100 ng/ml). After 2, 4, and 8 h of incubation, supernatants were collected for leptin RIA
and tissue was collected for RNA isolation.
Experiment 2.
To irreversibly inhibit protein synthesis, freshly isolated explants
from OuJ mice were incubated in the presence or absence of CHX (250 µM) for 30 min. Then TNF- (0 or 100 ng/ml) was added to the
medium. Explants were subsequently incubated for an additional 8 h. Then supernatants and tissue were collected for analysis.
Experiment 3.
Freshly isolated explants were cultured for 30 min in ACTD (1 µg/ml)
and then in the presence of TNF- (0 or 100 ng/ml) for 8 h. At
that time, supernatants were removed and frozen for determination of
leptin concentration.
Experiment 4.
Fat pad explants were isolated and cultured in the presence or absence
of the p38 MAPK inhibitor SB-203580 (15 µM) for 1 h. Then murine
TNF- (0 or 100 ng/ml) or Dex (0 or 125 ng/ml) was added for 8 h. At that time, supernatants and tissue were collected.
Experiment 5.
Epididymal fat pads were isolated and cultured in the presence of
vehicle (0.4% ethanol) or 15 µM PGJ. One hour later, 0 or 100 ng of
recombinant murine TNF- was added to each well. Eight hours after
the addition of TNF-, tissue and supernatants were collected for analysis.
Experiment 6.
Adult male Balb-C mice were fasted for 12 h to reduce plasma
leptin levels and then injected intraperitoneally with vehicle (PBS
with 0.4% ethanol) or PGJ (5 mg/kg). One hour later, mice were given a
second intraperitoneal injection of vehicle (PBS with 0.2% BSA) or
recombinant murine TNF- (1 µg/mouse). Mice were killed 2 h
after TNF- injection. Blood was aseptically collected by
venipuncture of the inferior vena cava into EDTA-coated syringes, centrifuged, and the plasma was stored at 
80°C until assayed for
leptin or cytokine concentration. Epididymal fat pads were collected
using RNase-free instruments, quick frozen in liquid nitrogen, and
stored at 80°C until RNA isolation.
Statistical Analysis
All data were analyzed using General Linear Model procedures (26). Data were subjected to one- or two-way ANOVA to determine the significance of main factors and main factor interactions. When ANOVA revealed a significant effect of a main factor or an interaction between main factors, differences between treatment means were tested using least squared differences. All data are presented as means ± SE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TNF- Increased Steady-State Leptin mRNA Levels in Isolated Fat
Pads
acts directly on
adipose tissue to increase leptin gene expression. To determine whether
TNF- increased leptin expression in isolated fat pads, explants were
cultured in the presence of recombinant murine TNF- (0 or 100 ng/ml)
for 2, 4, or 8 h. Consistent with previous reports (7), TNF- increased supernatant leptin content in a
time-dependent fashion after 4 and 8 h of culture (Fig.
1). In a similar time course,
steady-state leptin mRNA levels were increased in TNF--treated explants compared with explants cultured in medium alone (Fig. 1).
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CHX and ACTD Inhibit TNF--Induced Leptin Secretion
regulated leptin production, explants
were treated with the protein synthesis inhibitor CHX for 30 min and
then exposed to TNF- for 8 h. CHX was found to completely block
the increase in supernatant leptin levels following TNF- exposure
(Fig. 2A). Interestingly, the
release of leptin into the culture supernatant by explants treated with
CHX was still quite substantial. This suggests that some portion of the
spontaneous release of leptin into the supernatant is
posttranslationally regulated or may be due to cell breakage. Although
CHX inhibited the TNF--induced increase in leptin secretion, it did
not affect leptin mRNA accumulation. Rather, in the absence of
translation, leptin mRNA accumulated faster in explants treated with
TNF- (Fig. 2A). TNF--induced increases in supernatant
leptin content were also prevented by the RNA polymerase inhibitor ACTD
(Fig. 2B). Collectively, the analyses of steady-state mRNA
levels and the data obtained using pharmacological inhibitors of
transcription and translation suggest that TNF--induced increases in
leptin are mediated in a transcriptional fashion.
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TNF--Induced Increases in Leptin Expression Are Blocked by p38
MAPK Inhibitor SB-203580
-induced leptin expression
(9). In the present study, SB-203580 prevented the
induction of leptin gene expression and secretion after 8 h of
exposure to TNF- (Fig. 3). Unlike
TNF-, Dex induces its effects through a nuclear receptor complex and
stimulates leptin gene expression via a noninflammatory pathway. As
expected, RNase protection assays revealed that increased leptin
expression following Dex treatment was not attenuated by SB-203580
(Fig. 3). Therefore, SB-203580 is not a general inhibitor of leptin
secretion.
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PGJ Inhibits TNF--Induced Leptin Expression
-induced leptin production in isolated fat pads was also tested.
At doses that inhibit phorbol 12-myristate 13-acetate-induced cytokine
production by monocytes (19), PGJ significantly abrogated TNF--induced leptin expression and secretion by isolated fat pads
(Fig. 4). Together, these results
indicate that inhibiting inflammatory pathways, either via inhibition
of p38 MAPK or PGJ administration, blocks TNF--induced leptin
secretion.
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TNF--Induced Leptin Production Is Inhibited in Mice by PGJ
Pretreatment
. Consistent with a previous study (9),
TNF- treatment increased steady-state leptin mRNA levels in adipose
tissue and caused an increase in circulating leptin levels 2 h
postinjection (Fig. 5). However, plasma
leptin levels were not elevated in response to TNF- in
PGJ-pretreated mice. Furthermore, the increased expression of leptin in
epididymal adipose tissue following TNF- was completely abolished by
PGJ pretreatment.
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PGJ also markedly reduced the circulating levels of both IL-6 and
TNF- following TNF- injection (Fig. 5). Adipose tissue is a
significant source of proinflammatory cytokines (17).
Accordingly, the expression of TNF- and IL-6 in epididymal fat pads
was increased following TNF- treatment (Fig. 5). However, consistent
with lower circulating cytokine levels, the induction of TNF- and
IL-6 expression was diminished following PGJ pretreatment.
Collectively, these data suggest that by inhibiting the inflammatory
response with PGJ or via inhibition of p38 MAPK, TNF--induced
hyperleptinemia is prevented.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TNF--induced hyperleptinemia is an important endocrinologic
response to inflammatory challenge. However, the mechanisms by which
TNF- induces leptin production are poorly understood. In the present
study, by evaluating mRNA levels and by employing protein synthesis and
RNA polymerase inhibitors, it was found that TNF--induced
hyperleptinemia is likely mediated via transcriptional activation of
the leptin gene. Furthermore, use of two anti-inflammatory compounds
revealed that reducing inflammatory pathway activation diminished the
induction of leptin gene expression. However, evidence is emerging that
leptin is an immunomodulatory cytokine important to complete
immunocompetence and that TNF--induced hyperleptinemia is an
important adaptive response. The clinical implications of the present
findings should therefore be further studied.
TNF- administration to fasted rodents and humans has been shown in
several studies to induce transient hyperleptinemia (9, 15, 25,
34). However, in vitro studies aimed at delineating the
interaction between TNF- and leptin synthesis provided conflicting results. Although some studies showed that TNF- exposure caused cultured adipocytes to secrete leptin (7, 9, 32), others found that TNF- actually reduced leptin production (13, 23, 30). More thorough time course experiments reported that TNF- acutely (4, 8, or 24 h) increased leptin secretion, but it reduced leptin production at later time points (24 h or greater) (12, 20,
33). This time course of induction and subsequent inhibition may
be explained by the finding that prolonged treatment with TNF-
causes adipocyte dedifferentiation (24, 33), which could affect leptin gene expression because preadipocytes do not synthesize leptin (22).
Several previous studies demonstrated that TNF- actually reduced
leptin mRNA expression in a single-cell suspension of adipocytes (12, 20). Although the time course issue discussed above
probably plays a role in this, the use of adipose tissue explants in
this study may also explain our differing results by a number of
mechanisms. 1) Paracrine mediators produced by nonadipocytes
present in adipose tissue may be necessary for TNF- to stimulate
leptin gene expression. However, the finding that CHX did not inhibit
TNF--induced leptin mRNA expression argues against de novo synthesis
of another adipose-derived factor. 2) The explant system and
the preservation of the extracellular matrix may provide a more natural
environment that allows adipocytes to respond to TNF- as they would
in vivo. 3) Collagenase digestion or culture conditions may
select for a subset of adipocytes or preadipocytes that respond to
TNF- in a different fashion than do mature fat cells. Thus
this culture system is a useful tool for dissecting this
interaction. Indeed, the results obtained above closely parallel
the response to systemic TNF- injection. Alternatively, unlike many
other in vitro approaches, this system did not employ exogenous
insulin, which is known to stimulate leptin production
(22). TNF- counteracts many effects of insulin in
adipocytes (17). Thus, the apparent TNF--induced
reduction in leptin expression may actually be inhibition of
insulin-stimulated leptin secretion.
Recent work from this lab revealed that the p55 TNFR mediates the
induction of leptin by TNF- (9). Because p38 MAPK is rapidly activated by p55 TNFR stimulation and mediates other responses to TNF- in adipocytes (29), we hypothesized that p38
MAPK pathways could couple p55 TNFR stimulation to leptin gene
expression. We found that SB-203580 treatment suppressed
TNF--induced leptin expression, suggesting that the induction of
leptin is dependent on the activity of p38 MAPK. In contrast, leptin
expression induced by treatment with the synthetic glucocorticoid Dex
was not inhibited by SB-203580, indicating that Dex activates leptin
expression via a noninflammatory and p38 MAPK-independent
pathway. This is consistent with previous findings that Dex stimulates
leptin expression via a nonclassical mechanism (5).
The inhibition of TNF--induced leptin expression may also be
mediated by the anti-inflammatory properties of SB-203580 and PGJ.
Endogenous proinflammatory cytokine production is critical to
endotoxin-induced hyperleptinemia (6, 7). SB-203580
was originally identified for its ability to inhibit proinflammatory cytokine production (3), and PGJ inhibited cytokine
production in this and other studies (19). PGJ is also an
endogenous ligand for the peroxisome proliferator-activated
receptor-
(PPAR-) (10). PGJ (27) and
other PPAR- ligands (4, 16) have been shown to inhibit
leptin gene expression in adipocytes, raising the possibility that PGJ
is acting via PPAR- in adipose tissue to repress leptin gene
expression, independent of its anti-inflammatory effects.
Perspectives
In conclusion, the present study demonstrated that TNF--induced
leptin production is likely mediated by an increase in leptin gene
expression and that anti-inflammatory agents essentially abolished
TNF--induced leptin expression. If cytokine-induced hyperleptinemia
was still thought to be pertinent to the etiology of disease cachexia,
these interventions might be therapeutic to cachectic patients.
However, recent studies suggest that this endocrine-immune interaction
is an important adaptive response to inflammation and that leptin is
essential for proper immune function in malnourished patients. This
suggests that further studies are warranted to examine whether
preventing inflammatory hyperleptinemia might impact the patient's
ability to adapt to an inflammatory challenge and to ward off
opportunistic pathogens.
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ACKNOWLEDGEMENTS |
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The authors thank S.-M. Ye, J. R. Heyen, and E. L. Bruno for helpful discussions and assistance in data collection.
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FOOTNOTES |
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This research was supported by National Institutes of Health (NIH) Grants DK-51576 and DK-49311 and the Illinois Council on Food and Agricultural Research. B. N. Finck was supported by a NIH training fellowship (GM-007143).
Address for reprint requests and other correspondence: B. N. Finck, Washington Univ. School of Medicine, 660 S. Euclid Ave., Box 8086, St. Louis, MO 63110 (E-mail: bfinck{at}im.wustl.edu).
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.
10.1152/ajpregu.00569.2001
Received 18 September 2001; accepted in final form 11 January 2002.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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