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From the Clinical Research Centers |
Inhibits Leptin Production in Subcutaneous and Omental Adipocytes from Morbidly Obese Humans1
Division of Endocrinology and Metabolism, Departments of Medicine (L.B.W., R.L.F., A.S.W., Z.P., R.L., R.V.C.) and Surgery (R.M.J.), Indiana University School of Medicine, Indianapolis, Indiana 46202; and the Department of Surgery, St. Vincent’s Hospital Carmel (R.M.J., M.I., J.H.), Carmel, Indiana 46032
Address all correspondence and requests for reprints to: Robert V. Considine, Ph.D., Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 455, Indianapolis, Indiana 46202-5111. E-mail: rconsidi{at}iupui.edu
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Abstract |
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(TNF).
Adipocytes were isolated from adipose tissue obtained during bariatric
surgical procedures (17 women and 3 men; body mass index, 52.5 ±
2.4 kg/m2; age, 40 ± 3 yr) and cultured in
suspension. Leptin release from SC adipocytes was inhibited 17.7
± 5.2% (P < 0.01), 21.6 ± 4.3%
(P < 0.005), and 37.1 ± 7.2%
(P < 0.05) by 1, 10, and 100 ng/mL TNF,
respectively, after 48 h in culture. At 100 ng/mL, significant
inhibition of leptin release (25.8 ± 9.7%; P
< 0.05) was detected by 24 h. TNF (10 ng/mL) had no effect on
dexamethasone (0.1 µmol/L)-stimulated leptin production in sc
adipocytes. In omental adipocytes TNF inhibited leptin release
21.0 ± 9.6% and 40.8 ± 6.3% at 10 and 100 ng/mL by
48 h (P < 0.05). Significant inhibition of
leptin release from omental adipocytes was observed at 24 h with
100 ng/mL TNF (P < 0.05). Anti-TNF antibody
completely blocked TNF inhibition of leptin release. The
ob messenger ribonucleic acid was significantly reduced
(23.6 ± 5.9%) after 48 h of TNF (100 ng/mL) treatment
(P < 0.025). TNF had no effect on glucose
uptake or lactate production in SC and omental adipocytes. The data
suggest that the direct paracrine effect of adipose-derived TNF is
inhibition of leptin production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) is an
inflammatory cytokine produced by macrophages (6) and in adipose tissue
(7). Adipose tissue-derived TNF has been implicated in the
development of insulin resistance in both muscle and adipose tissue
(7, 8, 9, 10). TNF messenger ribonucleic acid (mRNA) is significantly
elevated with increasing adiposity and is reduced after weight loss in
both rodents (11) and humans (12, 13). TNF alters adipose tissue
lipoprotein lipase activity, fatty acid synthesis, and lipolysis
(7, 8, 9, 10, 14). As described below, the cytokine has also been reported to
influence leptin production in animal models, primary cells, and
cultured cell lines.
The effect of TNF on leptin production is complex. The ob
mRNA expression and circulating leptin were increased within several
hours (7–8 h) after the administration of TNF to hamsters (15) and
mice (16, 17, 18), but returned toward baseline 18 h after cytokine
administration (16). A transient rise in leptin, occurring 12 h
after TNF infusion, was also observed in humans with solid tumors,
but again serum leptin levels returned to baseline by 24 h after
administration of the cytokine (19). It was concluded from these
experiments that TNF could acutely increase serum leptin in animals
and humans, and it was suggested that leptin may play a role in the
anorexia associated with infection (15). However, it was not
established in these studies whether the cytokine acted directly on the
adipose tissue.
Observations of leptin production in obese transgenic TNF-deficient
mice also suggest a stimulatory effect of TNF on leptin production
(20). Serum leptin is lower in transgenic mice lacking TNF compared
to wild-type obese mice of equivalent weight, suggesting that TNF
increases leptin production in wild-type mice and that in the absence
of this stimulus, leptin production is lower in the knockout mice.
However, serum insulin, which is a stimulus for leptin production (21),
was also significantly lower in the TNF-deficient mice (22).
Therefore, as in the studies mentioned above, it is not clear whether
TNF acts directly on the adipose tissue to regulate leptin
production.
In vitro, TNF has been reported to either stimulate (17)
or inhibit (23) leptin release from murine adipocytes treated under
identical conditions. In one study using 3T3-L1 adipocytes, a transient
stimulation of leptin release was evident at 5 h of treatment, but
by 24 h leptin release in the presence of TNF was significantly
less than that from untreated cells (20). A second report found
inhibition of ob gene expression in differentiated 3T3-L1
cells when analyzed after 24 h of treatment (24). A recent study
in rodent adipocytes anchored in a defined matrix of basement membrane
protein found that a 48-h exposure to TNF inhibited leptin release
and that inhibition was maintained up to 96 h in culture (25). It
was further observed that TNF increased glucose uptake into the
adipocytes by 96 h, but not the conversion of glucose to lactate.
These investigators have previously demonstrated that glucose
metabolism is an important stimulus for leptin production in rat
adipocytes (26). It was therefore concluded that TNF significantly
inhibited leptin production in rat adipocytes, but that this inhibitory
effect was independent of the effects of TNF on glucose metabolism
(25).
To date there have been no reports on the effect of TNF on leptin
production in human adipocytes. Therefore, the current studies were
undertaken to examine the direct effect of TNF on leptin production
in human SC and omental adipocytes. Leptin release was quantitated up
to 48 h to model the chronic paracrine effect of adipose
tissue-derived TNF. The interaction of TNF with dexamethasone was
examined to determine whether these two compounds regulated leptin
production through similar mechanisms. The effect of TNF on glucose
uptake was also assessed. Our data suggest that the long term effect of
TNF on human adipocytes is inhibition of leptin synthesis and
release.
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Materials and Methods |
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Adipocytes (2 mL packed cells) were suspension cultured in 10 mL
DMEM-Ham’s F-12 plus 10% FBS in 125-mL sterile polycarbonate flasks
(Corning, Inc., Corning, NY) at 37 C and 95%
O2-5% CO2. The medium was
replaced every 24 h with fresh medium. Control and treated
adipocytes from each subject were cultured in parallel over each 48-h
period. Culture medium was purchased from Sigma (St.
Louis, MO), and FBS was obtained from Life Technologies, Inc. (Grand Island, NY). In initial experiments recombinant
murine TNF (Life Technologies, Inc.) was used, and in
later experiments recombinant human TNF (R&D Systems, Minneapolis,
MN) was used. There was no difference in the extent of inhibition of
leptin release by human or mouse recombinant TNF, and the data were
pooled. Antihuman TNF antibody was purchased from R&D Systems.
Dexamethasone (D2915, water soluble) was obtained from
Sigma.
Leptin released into the medium during each 24-h period was quantitated with a commercially available RIA kit (Linco Research, Inc., St. Charles, MO). Leptin in the medium at 48 h represents the sum of that released during the first 24-h period plus that released during the second 24-h period. The within-assay variation (percent coefficient of variation) of the leptin assay is 8.3%, and the between-assay variation is 6.2% at 4.9 ng/mL. The limit of detection is 0.5 ng/mL. Samples (200 µL) were measured in duplicate and ranged between 5–10 ng on the standard curve. The use of 200 µL does not alter the sensitivity, reproducibility, or variability of the assay. The values obtained from the assay were divided by 2 to normalize for the use of twice the volume of sample called for in the assay. The culture medium containing 10% FBS contained no detectable leptin.
RT-PCR was used to measure ob mRNA expression as previously described (28). All comparisons between samples were made on the linear portion of the amplification curve between 20–35 cycles. No product was obtained in the absence of reverse transcriptase. The data are expressed as the ratio of ob complementary DNA (cDNA) to actin cDNA. There was no difference in the amount of actin cDNA among the samples studied.
Glucose and lactate in the culture medium were measured on a glucose analyzer (model 2300, YSI, Inc., Yellow Springs, OH). Glucose uptake was determined by measuring medium glucose before and after each medium change and calculating the decrease.
All data are expressed as the mean ± SEM. The percent
inhibition of leptin release was calculated as the difference between 1
and the ratio of leptin release in the presence of TNF divided by that
from untreated cultures, multiplied by 100. All statistical comparisons
were made by Student’s paired t test (P <
0.05 was taken as statistically significant) where appropriate. A
block-treatment ANOVA model was used to examine the effect on leptin
release of coincubation with dexamethasone and TNF (Fig. 2
).
Subjects were used as blocks to reduce possible error variability.
After a significant ANOVA, Tukey’s test for multiple comparisons was
used to determine which treatment pairs had significantly different
rates of leptin release. A paired comparison (control and treatment) on
adipocytes from each individual is denoted as n = 1.
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Results |
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, leptin was released into the medium during
each 24-h period, such that the cumulative concentration of leptin in
the medium was significantly greater at 48 h than at 24 h
(P < 0.05). At a concentration of 100 ng/mL, TNF
significantly inhibited leptin production at 24 and 48 h of
culture (P < 0.05).
Leptin production from SC adipocytes was inhibited by TNF in a
dose-dependent manner. At a concentration of 10 ng/mL, TNF inhibited
leptin production 21.6 ± 4.3% (n = 16; P <
0.005) At the lowest concentration tested, 1 ng/mL TNF significantly
inhibited leptin release 17.7 ± 5.2% by 48 h in culture
(n = 11; P < 0.01). Neither 10 nor 1 ng/mL TNF
significantly attenuated leptin production within the first 24 h
of treatment.
Dexamethasone is a strong stimulus for leptin production. To determine
whether TNF could inhibit both basal and stimulated leptin release,
SC adipocytes were coincubated with 0.1 µmol/L dexamethasone and 10
ng/mL TNF. As illustrated in Fig. 2, leptin release from SC adipocytes treated with dexamethasone for
48 h was double that from untreated adipocytes.
Dexamethasone-stimulated leptin release in the presence of TNF was
not different from that induced by dexamethasone alone. As a percentage
of the control value, dexamethasone increased leptin production
193 ± 29% in untreated adipocytes and by 206 ± 31% in
adipocytes treated with TNF. These observations suggest that TNF
and dexamethasone regulate leptin production through different
mechanisms.
TNF also reduced leptin production in omental adipocytes. As
observed for the SC adipocytes, leptin was released into the medium
from omental adipocytes in a time-dependent manner (Fig. 3). At a concentration of 100 ng/mL, TNF
significantly inhibited leptin production within the first 24 h of
culture (P < 0.05). By 48 h, TNF inhibited
leptin production by 40.8 ± 6.3% (Fig. 3). At 10 ng/mL, TNF
had no effect on leptin production within the first 24 h of
culture. By 48 h, 10 ng/mL TNF significantly inhibited leptin
release from omental adipocytes by 21.0 ± 9.6% (6.2 ± 1.6
vs. 5.2 ± 1.9 ng/mL; n = 7; P <
0.05). There was no significant difference in TNF inhibition of
leptin release in omental vs. SC adipocytes.
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was due to the cytokine and
not to an unknown contaminant, SC adipocytes were treated with 10 ng/mL
TNF, which had been previously incubated with 10 µg/mL anti-TNF
antibody for 30 min before addition to the culture medium. Anti-TNF
antibody completely prevented the reduction in leptin release induced
by TNF (Fig. 4).
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inhibited leptin production by reducing ob gene
expression. As shown in Fig. 5, ob
mRNA at 48 h in SC adipocytes treated with 100 ng/mL TNF was
significantly less than that in untreated cells. The ob gene
expression was also significantly reduced by the 48-h treatment with 10
ng/mL TNF (53.9 ± 9.3 vs. 38.4 ± 8.4
arbitrary units for untreated and TNF-treated adipocytes,
respectively; n = 10; P < 0.05). The extent of
inhibition of ob gene expression achieved with 100 and 10
ng/mL TNF was not different when measured after 48 h of
treatment (23.6 ± 5.9% vs. 23.1 ± 9.3%
inhibition for 100 and 10 ng/mL, respectively).
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treatment had no effect on glucose metabolism in SC or omental
adipocytes. As illustrated in Table 1,
there was no difference in glucose uptake or lactate release over the
48-h incubation in adipocytes treated with 100 ng/mL TNF compared to
untreated cells. At a concentration of 10 ng/mL, TNF also had no
effect on glucose metabolism in either SC or omental adipocytes (data
not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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on leptin production in human adipocytes. We observed that
TNF inhibited leptin release from SC and omental adipocytes from
morbidly obese subjects in a time- and dose-dependent manner. At the
highest concentration tested, TNF inhibition of leptin release was
significant within the first 24 h of treatment, and the cytokine
was equally effective in both SC and omental adipocytes. Although
TNF reduced basal leptin production, it had no effect on
dexamethasone-stimulated release, a finding that suggests that the two
compounds regulate leptin production through different mechanisms. The
attenuation of leptin release by TNF appears to be mediated at least
in part through a reduction in ob gene expression and does
not involve changes in glucose metabolism.
Previous in vitro experiments using mouse adipocytes have
been inconclusive regarding the direct effect of TNF on leptin
synthesis. In the study by Finck et al. (17) TNF
increased leptin release during a 24-h incubation of epididymal
adipocytes obtained from both endotoxin-sensitive (OuJ) and
endotoxin-insensitive (HeJ) mice. In contrast, at similar cytokine
concentrations and treatment time, Yamaguchi et al. (23)
observed TNF-induced inhibition of leptin release in parametrial
adipocytes from 12- to 14-day pregnant mice. Although it is possible
that TNF could have opposite effects on adipocytes from different
fat pads, in our hands TNF inhibited leptin release to the same
extent in both SC and omental adipocytes. Our findings are in accord
with experiments in differentiated 3T3-L1 cells (20, 24) and cultured
rat adipocytes (25) that exposure to TNF for 24 h or longer
inhibits ob gene expression and leptin release. Also in
agreement with the present findings, Yamaguchi et al. (23)
observed that TNF (100 ng/mL) inhibited leptin release in sc
adipocytes from pregnant women. Taken together, it therefore appears
that chronic exposure to TNF inhibits leptin production.
Early observations in rodents of an acute stimulation of leptin release
by TNF led to the suggestion that leptin could mediate, in whole or
in part, the reduced food intake and weight loss associated with
infection and cancer (15, 16, 17, 18). Similar findings in humans, that both
TNF (19) and interleukin-1 (29) acutely increase leptin release,
would support this hypothesis. However, in both humans and rodents the
effect of cytokines to increase serum leptin is transient, with a
return to precytokine administration levels within 24 h (16, 19, 29). In the case of interleukin-1, leptin levels returned to
baseline despite continued administration of the cytokine (29).
Although we did not study time points earlier than 24 h, the
results of the present study would suggest that the acute increase in
leptin release with cytokine administration is not due to a direct
effect of the cytokine on adipocytes, but may be a secondary response.
Furthermore, as leptin is believed to be a long term regulator of food
intake and energy balance, it is difficult to reconcile the transient
increase in leptin as the mechanism for cytokine-induced anorexia.
Indeed, lipopolysaccharide administration to leptin-deficient
ob/ob and leptin receptor-deficient db/db mice
increased TNF to the same extent in both animal models and induced
anorexia in the absence of a functional leptin signal system (30). An
alternative possibility for the acute transient increase in leptin with
TNF is that it may serve as a signal to up-regulate the immune
system (17). Leptin receptors are present on many different hemopoietic
cells (5), and leptin stimulates the proliferation of naive and memory
T cells (31).
There are several possible mechanisms through which TNF could
inhibit leptin synthesis. TNF decreases lipoprotein lipase activity
and stimulates lipolysis in adipocytes (7, 8, 9, 10, 14). These actions of
TNF to limit lipid accumulation and/or increase lipid release from
the adipocyte could reduce leptin production, although it is not clear
at this time through what mechanism the adipocyte "senses" the
amount of stored lipid and translates this into leptin release. TNF
also induces insulin resistance in adipocytes by reducing the tyrosine
kinase activity of the insulin receptor (32, 33), and prolonged
exposure of 3T3-L1 adipocytes to the cytokine (72–96 h) results in
loss of insulin receptor substrate-1 message and protein (34). As
ob gene expression is regulated by glucose metabolism (26) a
TNF-mediated reduction in glucose uptake could down-regulate leptin
production. This does not appear to be the case in our studies, as
there was no effect of TNF on basal glucose uptake or lactate
production in either the SC or omental adipocytes during the 48-h
incubation. These findings are in accord with those of Medina et
al. (25), who did not observe a significant effect of TNF on
glucose uptake in rat adipocytes within the first 48 h of
treatment. In contrast, these investigators found that a longer
exposure to TNF (96 h) actually resulted in a significant increase
in glucose uptake and decreased leptin production. Medina et
al. (25) therefore conclude, and we would concur, that TNF
significantly inhibits leptin production, but that this effect is not
mediated through the effects of TNF on glucose metabolism.
One final mechanism through which TNF may alter leptin production is
through its effects on the expression of the transcription factor
C/EBP. TNF (
85 ng/mL) has been observed to reduce C/EBP by
25% in 3T3-L1 cells exposed to the cytokine for 24 h (35). A
C/EBP-binding site is located within the proximal 60 bp of the
ob gene promoter and has been demonstrated to be necessary
for ob gene transcription (36, 37, 38). TNF could directly
attenuate ob gene expression by reducing the cellular
content of C/EBP protein. A TNF-mediated reduction in C/EBP
would also explain the reduction in basal, but not
dexamethasone-stimulated, leptin production, as dexamethasone increases
ob gene promoter activity through cis-elements
other than that for C/EBP (39). In support of this possibility we
observed a significant reduction in ob gene expression in
TNF-treated cells. This finding is in agreement with the report of
Medina et al. (25), who observed a significant reduction in
ob mRNA in TNF-treated rat adipocytes. Additional
experiments will be necessary to completely elucidate the mechanism
through which TNF reduces ob gene expression and leptin
production.
The observation that TNF inhibits leptin release from the adipose
tissue could have important physiological implications in the
regulation of adipose tissue deposition. It is possible that
TNF-mediated attenuation of leptin release could contribute to the
development of excess adipose tissue by masking the actual amount of
adipose tissue that central mechanisms regulating body weight are
sensing. In addition, other actions of leptin, such as its effects on
glucose homeostasis, could also be attenuated (5). The positive
correlation between TNF mRNA and ob mRNA in human adipose
tissue (40) as well as the positive correlation between serum leptin
and serum TNF receptor (measured as a surrogate for TNF) in
humans (41, 42) suggest that the mechanisms regulating the production
of these two cytokines by the adipose tissue are tightly linked.
However, these correlations do not rule out the possibility of a
dysregulation between TNF and leptin production with increasing
adiposity. In this regard it should be noted that our experiments were
performed on adipocytes obtained from extremely obese individuals, and
it is possible that TNF may have a different effect on leptin
production in adipocytes from leaner individuals.
In summary, TNF inhibits leptin production in both SC and omental
adipocytes from morbidly obese humans in a time- and dose-dependent
manner. The attenuation in leptin secretion appears to be mediated
through a reduction in ob gene expression and does not
involve alterations in glucose metabolism. Additional experiments will
be necessary to determine the exact mechanisms that regulate the
production of both TNF and leptin in the adipose tissue and the
roles of both cytokines in the development of excess adipose
tissue.
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Acknowledgments |
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Footnotes |
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Received August 12, 1999.
Revised October 12, 1999.
Accepted October 27, 1999.
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References |
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