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in the Induction of Leptin by Lipopolysaccharide1
Laboratories of Integrative Biology (B.N.F., R.W.J.) and Immunophysiology (K.W.K.) Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801; and the Laboratory of Integrative Neurobiology, INRA-INSERM, U-934 (R.D.), 33077 Bordeaux, France
Address all correspondence and requests for reprints to: Dr. R. W. Johnson, 390 Animal Sciences Laboratory, University of Illinois, 1207 West Gregory Drive, Urbana, Illinois 61801. E-mail: rwjohn{at}uiuc.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) in mediating
leptin secretion during an immunological challenge, we studied the
effects of lipopolysaccharide (LPS) and TNF on leptin secretion in
endotoxin-sensitive C3H/HeOuJ (OuJ) mice, endotoxin-insensitive C3H/HeJ
(HeJ) mice, and primary adipocytes cultured from both. Intraperitoneal
injection of LPS increased plasma concentrations of TNF and leptin
in OuJ mice, but not in HeJ mice, suggesting a causal relationship
between the induction of TNF and leptin. Consistent with this idea,
ip injection of recombinant murine TNF increased plasma leptin in
both OuJ and HeJ mice. To determine whether TNF induces leptin
secretion by acting directly on fat cells, primary adipocytes from OuJ
and HeJ mice were cultured in the presence of TNF or LPS. Whereas
LPS was without effect on leptin secretion by adipocytes, TNF
induced a marked increase in the cell supernatant leptin concentration.
These data demonstrate that TNF plays a role in regulating the
increase in leptin caused by LPS. Moreover, they show that TNF can
act directly on adipocytes to stimulate leptin secretion. Our results
are consistent with the emerging view that leptin is a key hormone
coupling immune system activity to energy balance. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a number of autoimmune, infectious, and neoplastic diseases, there
is a decrease in motivation for food and a number of metabolic
irregularities that precipitate degradation of body protein and fat.
This shift toward negative energy balance is generally attributed to
proinflammatory cytokines, particularly tumor necrosis factor-
(TNF). The plasma TNF concentration, however, is poorly
correlated with anorexia and cachexia. If TNF is involved in
anorexia and cachexia, as evidence suggests, it probably acts in a
paracrine fashion and, thus, interacts with the central nervous system
indirectly, via a mechanism that is yet unknown. TNF has long been
known to alter the metabolism of fat cells (12), and recent studies
indicate a strong positive association between the activity of the
TNF system and plasma leptin (13, 14, 15). Therefore, it is possible
that at least part of the shift toward negative energy balance in sick
animals is mediated by the induction of leptin by TNF.
Grunfeld et al. (16) and Sarraf et al. (17) were
the first to report increased leptin gene expression in rodents after
ip injection of lipopolysaccharide (LPS) or recombinant cytokines
(e.g. TNF and interleukin-1). It has recently been
reported that TNF increases leptin secretion in humans as well (18).
These results clearly indicated that immunological challenge can
increase plasma leptin and, therefore, suggested that leptin may be an
important hormone regulating food intake and metabolism in sick
animals. However, these important findings do not preclude the
possibility that LPS induces leptin production independent of
cytokines, nor do they establish that cytokines act directly on
adipocytes to induce leptin gene expression. This is particularly
important because LPS and TNF induce a variety of physiological
responses, such as secretion of insulin (19) and adrenal
corticosteroids (20, 21), that have been shown to stimulate leptin
production.
To address these issues, we measured plasma leptin in food-deprived
C3H/HeOuJ (OuJ) and C3H/HeJ (HeJ) mice after the injection of LPS or
recombinant murine TNF. These mouse strains are genetically similar
except for a mutation in a single gene that has rendered macrophages
from HeJ mice relatively insensitive to LPS (22, 23, 24, 25). HeJ mice,
therefore, are relatively resistant to LPS responses that are dependent
upon proinflammatory cytokines (26, 27, 28). We also cultured primary
adipocytes from OuJ and HeJ mice to determine whether LPS and TNF
induce leptin directly. The results of the present study indicate that
LPS induces leptin via a cytokine-dependent mechanism, and that TNF
can act directly on adipocytes to stimulate leptin secretion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Treatment solutions and reagents
LPS from Escherichia coli serotype 0128:B8 (phenol
extracted) was purchased from Sigma Chemical Co. (St. Louis, MO) and
dissolved in Krebs-Ringer phosphate (KRP) for in vitro
experiments or in sterile PBS (0.9% NaCl; Sigma Chemical) for ip
injection. Recombinant murine TNF purchased from Endogen (Woburn,
MA) had a biological activity of 1.0 x 108 U/mg and
was specified by Endogen to contain less than 0.1 ng/µg endotoxin.
Murine TNF was dissolved in sterile PBS with 1% BSA (detoxified
tissue culture grade; Stem Cell Technologies, Vancouver, Canada) for ip
injection or in KRP for in vitro studies. Bovine insulin
(cell culture grade; Sigma Chemical Co.) was dissolved in sterile
KRP.
Measurements
Leptin. The plasma or cell supernatant leptin concentration
was measured using a commercially available, RIA specific for murine
leptin (Linco Research, St. Charles, MO). The assay was conducted as
specified by the manufacturer, except that all reagents were used at
half the recommended volume. To validate this modification, pooled
plasma samples from fasted mice and mice given ad libitum
access to food [i.e. mice that had low (3.0 ng/ml) and high
(6.9 ng/ml) plasma levels of leptin, respectively) were assayed using
the recommended volumes and half the recommended volumes. Parallelism
between the recommended and amended protocols was demonstrated.
Cross-reactivity with insulin and glucagon was reported by Linco to be
undetectable. The sensitivity of the assay was less than 0.2 ng/ml. The
intraassay variation was 6.2%, and the interassay variation was less
than 6.0%.
Plasma TNF. The plasma TNF concentration was measured
using a commercially available, solid phase, enzyme-linked
immunosorbent assay (Genzyme Corp., Cambridge, MA) employing the
multiple antibody sandwich principle. All samples were measured in one
assay, and the intraassay variation was less than 4.7%.
Glycerol. The glycerol content of adipocyte supernatants was determined using the GPO-Trinder method (Sigma Chemical Co.). In brief, glycerol was phosphorylated to form glycerol-1-phosphate, which was oxidized to create dihydroxyacetone phosphate and peroxide. In the presence of 4-aminoantipyrine and sodium N-ethyl-N-(3-sulfopropyl)-m-anisidine, peroxide was cleaved by peroxidase to produce quinoneimine dye and water. The glycerol concentration was determined by comparing the spectrophotometric absorbance (540 nm; Gilford, Medfield, MA) of the sample to that of a glycerol standard.
Experimental protocol
Effect of LPS on plasma leptin in C3H/HeOuJ and C3H/HeJ
mice. Food was removed at 2100 h, and 12 h later, at the
onset of darkness (i.e. 0900 h), OuJ mice were injected
ip with 0.3 ml PBS containing 0 or 100 µg LPS. Before and 2, 4, and
8 h after injection, mice were killed by CO2 gas
asphyxiation, and blood was collected into heparinized syringes by
venipuncture of the inferior vena cava. Plasma obtained after
centrifugation was stored at -80 C until it was assayed for leptin. A
total of 40 mice were used in 2 separate, but identical, trials (n
= 5). In the second experiment, HeJ and OuJ mice were injected ip with
0.3 ml PBS containing 0 or 100 µg LPS. Four hours postinjection, mice
were killed by CO2 gas asphyxiation, and plasma was
collected and stored as described above until it was assayed for leptin
and TNF. A total of 36 mice were used in 3 separate, but identical,
trials (n = 9).
Effect of recombinant murine TNF on plasma leptin in C3H/HeOuJ
and C3H/HeJ mice. After a 12-h fast, HeJ and OuJ mice were
injected ip with 0.3 ml vehicle (PBS with 1% BSA) or vehicle
containing 500 ng recombinant murine TNF. Four hours postinjection,
mice were killed by CO2 gas asphyxiation, and plasma was
collected and stored as described above until it was assayed for
leptin. A total of 24 mice were used in 2 separate, but identical,
trials (n = 6).
Effect of LPS and recombinant murine TNF on leptin secretion
by primary adipocytes. Adipocytes were isolated as previously
described (29) with slight modification. Mice were fasted for 2 h
and then killed by cervical dislocation at the onset of the dark phase,
when circulating leptin levels were anticipated to be at their nadir
(17). Epididymal fat pads were excised and minced into small pieces,
and adipocytes were dissociated by a 35-min collagenase (1 mg/ml;
Sigma) digestion in a 37 C shaking water bath. The resulting cell
suspension was filtered through a 140-µm mesh screen to remove any
remaining tissue. Cells were then washed 4 times by centrifugation
(500 x g) in KRP containing 2 mg/ml dextrose (Sigma
Chemical Co.) and 33 mg/ml BSA (fraction V; cell culture grade; Sigma)
to remove contaminating cells. Adipocytes were counted, adjusted to
2 x 106 cells/ml, and then plated in 0.5 ml KRP in
24-well plates. Adipocytes from OuJ mice were cultured with KRP,
insulin (300 ng/ml), or LPS (10, 100, or 1000 ng/ml; n = 6) for a
period of 24 h. In a separate experiment, adipocytes from both OuJ
and HeJ mice were cultured with KRP, insulin (300 ng/ml), or TNF (1,
10, or 100 ng/ml; n = 10) for 24 h. In both studies, medium
was removed from beneath the floating monolayer and assayed for leptin
and glycerol concentrations. To determine whether TNF induced cell
atrophy, adipocytes from OuJ mice cultured with KRP or TNF (100
ng/ml) for 24 h were size fractionated by forward light scatter
using an EPICS XL MCL flow cytometer (Coulter Electronics, Hialeah, FL)
and EPICS Elite Workstation Software. A minimum of 10,000 events were
analyzed for each treatment.
Statistical analysis
All data were analyzed using general linear model procedures.
Data were subjected to one-way (treatment) or two-way (LPS x
time; treatment x genotype) 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 paired
t tests. All data are presented as the mean ±
SE.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and leptin in C3H/HeOuJ mice, but not in C3H/HeJ
mice
). These data are consistent with a
previous report that also showed LPS to increase plasma leptin in mice
(17).
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. OuJ and HeJ mice were subjected to
a 12-h fast and injected with PBS or 100 µg LPS. Because in the first
experiment plasma leptin was maximally increased 4 h after
injection of LPS, plasma was collected at this time point and assayed
for leptin and TNF. As anticipated, two-way ANOVA of plasma TNF
and leptin levels revealed a significant effect of LPS
(P < 0.01), genotype (P < 0.02), and
a LPS x genotype interaction (P < 0.01). Whereas
LPS increased the plasma TNF concentration in OuJ mice, it did not
in HeJ mice (Fig. 2). Consistent with the
first study, OuJ mice receiving LPS had significantly higher plasma
leptin levels than saline controls (Fig. 3). However, plasma leptin levels in HeJ
mice injected with LPS were not different from those in saline controls
(Fig. 3). Thus, LPS increased neither TNF nor leptin in the plasma
of HeJ mice.
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induces leptin in both C3H/HeJ
and C3H/HeOuJ mice and leptin. To test this
possibility, OuJ and HeJ mice were injected ip with saline or 500 ng
TNF, and plasma collected 4 h postinjection was assayed for
leptin. Two-way ANOVA of plasma leptin levels revealed a significant
effect of TNF (P < 0.01), but not genotype
(P < 0.40). Both OuJ and HeJ mice injected with TNF
had significantly higher plasma leptin levels than saline controls
(Fig. 4). Therefore, HeJ mice were
refractory to LPS, but not TNF.
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induces lipolysis and leptin secretion by primary
adipocytes interacts directly with adipocytes to
induce leptin secretion, primary adipocytes from OuJ and HeJ mice were
cultured in the presence of LPS or TNF. In an initial study,
adipocytes cultured from OuJ mice were incubated in the
presence of insulin (300 ng/ml) or LPS (0, 10, 100, or 1000 ng/ml) for
24 h. Supernatants were removed and assayed for leptin
concentration. On the one hand, insulin, which was employed as a
positive control (19), induced a marked increase in the supernatant
leptin concentration. On the other hand, LPS did not affect leptin
secretion in cultured adipocytes (Fig. 5). Similarly, one-way ANOVA of glycerol
revealed that LPS did not induce lipolysis, as measured by the
supernatant glycerol content (data not shown). In a subsequent study,
OuJ and HeJ adipocytes were cultured in the presence of insulin (300
ng/ml) or TNF (0, 1, 10, or 100 ng/ml) for 24 h. One-way ANOVA
of the leptin concentrations of supernatants from OuJ and HeJ
adipocytes revealed significant effects of TNF (P <
0.01). With regard to increased leptin secretion, adipocytes from HeJ
mice responded to TNF in a dose-dependent fashion (Fig. 6). Adipocytes from OuJ mice responded
similarly, but maximal leptin secretion was achieved at a lower
concentration of TNF (10 ng/ml; Fig. 6). Both OuJ and HeJ adipocytes
secreted leptin in response to insulin. As TNF is well known for its
lipolytic effects, we also determined the cell supernatant
concentration of glycerol. One-way ANOVA of the glycerol concentrations
of supernatants from OuJ and HeJ adipocytes revealed significant
effects of TNF (P < 0.01). Consistent with previous
studies, TNF increased glycerol content in supernatants from both
OuJ and HeJ adipocytes (Table 1). Despite
being lipolytic, however, flow cytometric analysis indicated that
TNF did not significantly alter the size distribution of adipocytes
(data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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by LPS is involved in the increased
plasma leptin levels after challenge with LPS, we measured plasma
leptin in OuJ and HeJ mice injected ip with LPS or recombinant murine
TNF. The results of the present study confirm that LPS increases
plasma levels of TNF and leptin in LPS-sensitive OuJ mice. However,
the important finding is that in LPS-insensitive HeJ mice, LPS induced
neither TNF nor leptin, suggesting a causal relationship between the
induction of TNF and leptin. This relationship was confirmed in a
subsequent study in which administration of TNF induced a similar
increase in leptin in both OuJ and HeJ mice. Moreover, in
vitro studies with primary adipocytes cultured from OuJ and HeJ
mice showed that TNF, but not LPS, increased supernatant leptin
levels. These data suggest that the secretion of TNF is important
for the increase in plasma leptin caused by LPS and show that TNF
can act directly on adipocytes to stimulate leptin secretion.
In the present study the secretion of leptin was compared in OuJ and
HeJ mice injected with LPS or TNF. HeJ mice are genetically similar
to OuJ mice, but, due to a defect in a single gene (Lps) on
chromosome 4, are notably insensitive to LPS (26, 27, 28). Because previous
studies concerning the mechanisms underlying the resistance of HeJ mice
to LPS indicate that their macrophages secrete relatively low amounts
of cytokines upon stimulation (22, 23), they were an ideal model for
determining the importance of cytokines in the induction of leptin by
LPS. It is important to note that in HeJ mice, LPS can induce
splenocyte proliferation (30, 31), initiate complement activation (32),
induce shedding of p55 and p75 soluble TNF receptors (33), and activate
neutrophils (34). Thus, LPS resistance in HeJ mice is not
comprehensive. The results from the present study are consistent with
recent studies that found LPS to increase leptin gene expression in
LPS-responsive mice (16, 17). In those studies it was also predicted,
but not proven, that the induction of leptin by LPS was mediated by
inflammatory cytokines. Although cytokines were not measured in plasma
after LPS challenge, this idea was supported, as the injection of
recombinant TNF, IL-1ß, and leukemia inhibitory factor increased
plasma leptin levels (17). The present results provide strong support
for this hypothesis, particularly because 1) LPS increased plasma
leptin and TNF levels in OuJ mice; 2) in HeJ mice, in which LPS did
not increase plasma TNF, it did not increase plasma leptin; and 3)
injection of recombinant murine TNF increased plasma leptin in both
HeJ and OuJ mice.
Although these results suggested that the induction of leptin by LPS
involved the secretion TNF, they did not establish a direct
relationship between the cytokine and the adipocyte. Whether TNF
acted on fat cells to induce leptin secretion is an important question,
as the hypothalamic-pituitary-adrenal axis is an early target for
TNF (35), and glucocorticoids have been shown to stimulate leptin
secretion (20, 21). To answer this very specific question, the effects
of LPS or TNF on in vitro secretion of leptin by
adipocytes cultured from OuJ and HeJ mice were assessed. Consistent
with the idea that induction of leptin by LPS is dependent upon
cytokines, adipocytes from neither OuJ nor HeJ mice secreted more
leptin in response to LPS. However, adipocytes from both mouse strains
responded to TNF with increased secretion of leptin. Therefore,
these results clearly indicate that TNF can induce leptin secretion
by direct interaction with the adipocyte.
Because leptin regulates food intake and energy expenditure in healthy
animals, it is reasonable to postulate that it does so in sick animals
as well. Supporting this idea, db/db mice, which lack a
functional leptin receptor (36, 37) and are obese, are somewhat
resistant to the anorectic properties of LPS (38). In contrast,
ob/ob mice that are obese because they carry a mutation that
prevents leptin secretion are as responsive as normal littermates to
the anorectic effects of LPS. Thus, the role of leptin in the anorexia
induced by LPS or TNF is not at all clear. Because cytokines and
their receptors are present in the brain, it would be more surprising
if leptin alone explained the anorexia. Indeed, ciliary neurotropic
factor, a cytokine that activates a similar pattern of STAT (signal
transducer and activator of transcription) factors as leptin, was found
to reduce adiposity, hyperphagia, and hyperinsulinemia in
ob/ob mice, db/db mice, and mice with
diet-induced obesity, which are insensitive to leptin (39). The finding
that db/db mice, but not the ob/ob mice, are
resistant to LPS-induced anorexia led Faggioni and colleagues (38) to
hypothesize that other cytokines that share significant structural and
sequential homology with leptin (40, 41) may signal through the
functional leptin receptor in the ob/ob mouse. Leptin
receptor density has been found to be increased in ob/ob
mice compared with that in nonobese controls (42).
Although leptin was first described for its role in regulating energy
balance, the primary purpose for the induction of leptin by TNF need
not be to regulate food intake and energy expenditure. Perhaps the
purpose of the induction of leptin by TNF is to direct or modulate
immune function. For example, irradiated ob/ob mice
replenished leukocytes more slowly than lean controls (43), which
implies that leptin plays a role in hematopoeisis. Several other
studies provide evidence for this hypothesis, as primitive
hematopoietic stem cells express some forms of the leptin receptor
(44), and addition of recombinant leptin to cultures of erythrocytic
and myelopoietic cells induces their differentiation and proliferation
(45). Gainsford and co-workers (46) found that addition of leptin to
culture medium enhanced cytokine production and phagocytosis of
Leishmania parasites by murine peritoneal macrophages.
Furthermore, the phagocytic activity of liver macrophages is decreased
in obese Zucker rats (fa/fa), which lack functional leptin
receptors (47). Collectively, these data suggest that leptin might also
function within the immune system to stimulate hematopoeisis and aid in
the clearance of infectious organisms.
In summary, our results suggest that TNF plays a role in regulating
the increase in leptin caused by immunological challenge with LPS.
Moreover, the present results show that TNF can act directly on
adipocytes to stimulate leptin secretion. Our results, therefore, are
entirely consistent with the emerging view that leptin is a key hormone
coupling immune system activity to energy balance. Understanding the
mechanism by which inflammatory stimuli regulate leptin may provide new
insights into the prevention of the anorexia and cachexia of
disease.
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Footnotes |
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Received November 7, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene Nco I polymorphism influences the relationship
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levels. Diabetes 46:1468–1472[Abstract]
system in humans. J Clin Endocrinol Metab 82:3408–3413 gene: metabolic consequences in obese and
nonobese mice. Diabetes 46:1526–1531[Abstract]
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G. N. Luheshi, J. D. Gardner, D. A. Rushforth, A. S. Loudon, and N. J. Rothwell Leptin actions on food intake and body temperature are mediated by IL-1 PNAS, June 8, 1999; 96(12): 7047 - 7052. [Abstract] [Full Text] [PDF]
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C. A. Mastronardi, W. H. Yu, V. K. Srivastava, W. L. Dees, and S. M. McCann Lipopolysaccharide-induced leptin release is neurally controlled PNAS, December 4, 2001; 98(25): 14720 - 14725. [Abstract] [Full Text] [PDF]
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C. H. Lang, R. A. Frost, A. C. Nairn, D. A. MacLean, and T. C. Vary TNF-alpha impairs heart and skeletal muscle protein synthesis by altering translation initiation Am J Physiol Endocrinol Metab, February 1, 2002; 282(2): E336 - E347. [Abstract] [Full Text] [PDF]
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