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Diabetes Research Institute at the Heinrich Heine University, Dusseldorf, Germany
Address all correspondence and requests for reprints to: Hans Hauner, M.D., Diabetes Research Institute, Heinrich Heine University, Auf’m Hennekamp 65, D-40225 Duesseldorf, Germany. E-mail: hauner{at}dfi.uni-duesseldorf.de
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) inhibits fat cell differentiation and
may also mediate insulin resistance in adipocytes. Both TNF receptors
are expressed in adipose tissue, but it is unknown how both receptors
are involved in these biological functions. We therefore studied the
effect of receptor-specific TNF muteins on adipose differentiation and
insulin-stimulated glucose transport of in vitro
differentiated human adipocytes in primary culture. Adipocyte precursor
cells exposed to the 60-kDa TNF receptor (p60-TNFR)-specific
TNFR32W-S86T showed a marked decrease in the percentage of
differentiating cells in response to adipogenic factors as well as a
reduction in peroxisome proliferator-activated receptor-
2 (PPAR2)
messenger RNA (mRNA) and glycerophosphate dehydrogenase (GPDH)
activity, but increased endogenous TNF mRNA expression. When cells were
incubated with the p80-TNFR-specific TNFD143N-A145R,
adipogenesis and PPAR2 mRNA expression were stimulated, GPDH
activity was unchanged, and TNF mRNA was completely suppressed.
Insulin-stimulated 2-deoxy-D-glucose transport was
inhibited by both muteins. The p60-TNFR-mediated inhibition increased
continuously during 6 h of treatment and was associated with a
down-regulation of glucose transporter-4 (GLUT4) mRNA and GLUT4
protein, whereas the p80-TNFR-specific mutein caused a transient
increase in GLUT4 mRNA, but did not alter GLUT4 protein expression
after a 24-h incubation. We conclude that p60-TNFR mediates the
antiadipogenic effect as well as the down-regulation of GLUT4 by TNF,
thereby leading to long-term inhibition of insulin-stimulated glucose
transport. In contrast, activation of the p80-TNFR induces an
adipogenic effect and transiently up-regulates GLUT4 expression. Here,
the acute inhibition of insulin-stimulated glucose transport may be
induced by interference with the insulin signaling pathway. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF) is a
multifunctional cytokine that exerts a variety of biological effects
(for review, see Ref. 1). In addition to its immunological action, high
levels of circulating TNF seem to be responsible for the development of
cachexia in patients with cancer or infectious diseases (for review,
see Ref. 2). Based upon this observation, subsequent studies suggested
an important role of TNF for adipose tissue growth and metabolism
(3, 4, 5, 6). TNF was also found to be expressed in adipose tissue of rodents
and humans. As adipose tissue TNF messenger RNA (mRNA) amounts are
increased in obese subjects, it was assumed that this locally produced
TNF could function as an endogenous inhibitor of adipose tissue growth
and may be involved in the development of obesity-linked insulin
resistance (7, 8, 9, 10). This hypothesis is substantiated by many in vitro studies in different preadipose and adipose cell models. Under most experimental conditions TNF prevents adipose differentiation in rodent as well as human adipose tissue (3, 4) caused by a variety of mechanisms. TNF was reported to impair the uptake and storage of fatty acids by decreasing the expression and activity of lipoprotein lipase (5, 6). Moreover, TNF suppresses glucose uptake and subsequently prevents de novo lipid synthesis (11). This inhibition of lipid storage and, in addition, activation of lipolysis (5) results in lipid depletion of mature adipocytes and finally leads to the reversion of the adipocyte phenotype (3, 4).
Interestingly, TNF inhibits insulin-stimulated glucose uptake by different mechanisms. In rat Fao hepatoma cells, components of the insulin signaling pathway were reported to be down-regulated within 1 h of TNF exposure (12). Comparable results were described after short-term TNF treatment of human adipocytes (13) and also after chronic 5-day incubation of 3T3 adipocytes with TNF (14). In addition, long-term TNF treatment down-regulates mRNA expression of the insulin-responsive glucose transporter-4 (GLUT4) (11). Based upon these findings, TNF appears to inhibit insulin-stimulated glucose transport by suppressing both the production and translocation of the GLUT4 protein.
Although some TNF effects on adipose tissue metabolism are now well characterized, little is currently known about the mechanisms preceding signal transduction. TNF mediates its pleiotropic effects by activation of two different receptors, a 60-kDa TNF receptor subtype (p60-TNFR) and an 80-kDa TNF receptor subtype (p80-TNFR) (15). Both receptors are expressed in stromal preadipose and adipose cells obtained from human adipose tissue (10). Little is known about the relative contributions of both TNF receptors to the role of TNF in adipose differentiation and fat cell function. Studies in 3T3-L1 adipocytes using receptor-specific agonistic antibodies suggested that TNF exerts its inhibitory effect on insulin signaling through stimulation of the p55-TNFR (16). Therefore, it was the aim of this study to define the receptor specificity of TNF action on the differentiation and metabolism of human adipocytes in primary culture by using recently developed TNF receptor-selective TNF muteins. The specific binding of these TNF muteins to recombinant TNF receptors and their specific functional activity were extensively studied in established human cell models of TNF action (17).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell preparation and culture
The isolation of human adipocyte precursor cells was performed
as previously described (18). Stromal cells isolated from adipose
samples by collagenase digestion were inoculated at a density of
approximately 30,000 cells/cm2 in DMEM/Ham’s
F-12 medium (1:1; both from Life Technologies, Inc.,
Eggenstein, Germany) supplemented with 10% FCS. After cell adhesion
for 20 h, the adipose conversion process was induced by serum-free
DMEM/Ham’s F-12 medium (1:1) containing 0.2 nM
T3, 100 nM cortisol, and 66
nM human insulin (donated by Hoechst AG, Frankfurt,
Germany) as adipogenic factors. Human recombinant TNF (Pepro,
Frankfurt, Germany) and receptor-specific TNF muteins (TNF
W32T86 and TNF N143R145,
donated by Dr. Loetscher, Hoffmann-La Roche AG, Basel, Switzerland) was
added at different periods of time as indicated. The cultures were
harvested immediately after incubation with wild-type (wt-) TNF or the
respective TNF mutein (after 3 days for mRNA analysis) or after 16 days
[for analysis of glycerophosphate dehydrogenase (GPDH) activity and
the mRNA pattern].
Determination of GPDH activity
Cells were harvested in 50 mM Tris-HCl, 1
mM EDTA, and 1 mM ß-mercaptoethanol (pH 7.4).
GPDH activity was determined in sonicated cell extracts according to an
established procedure (19). The protein content of the extracts was
measured using a modification of the method of Lowry et al.
(20) after protein precipitation with 6% trichloroacetic acid.
mRNA analysis
Total RNA was extracted with Trizol reagent (Life Technologies, Inc.) according to the instructions of the
manufacturer. One microgram of the purified RNA was used for random
primed complementary DNA (cDNA) synthesis as previously described (21).
Four percent of the RT volume was used for one PCR reaction, which also
contained 0.5 U Taq polymerase; 40
µM deoxy (d)-CTP, dGTP, and dTTP (all from
Life Technologies, Inc.); 20 µM
[-33P]dATP (SA, 
50 mCi/20 µmol;
Amersham Pharmacia Biotech, Braunschweig, Germany); 1.5
mM MgCl2; and 10
µM of each primer sequence in 20
mM Tris-HCl and 50 mM KCl
(pH 8.4) in a total volume of 50 µl. The primer sets were: for
TNF-, 5'-AAG ACC CCT CCC AGA TAG ATG-3' and 5'-GAG TGA CAA GCC TGT
AGC CCA-3'; for peroxisome proliferator-activated receptor-2
(PPAR2), 5'-CTC CTA TTG ACC CAG AAA GCG A-3' and 5'-GTG GAG ATG CAG
GCT CCA CTT-3'; for GLUT4: 5'-GAG GAA GGA GGA AAT CAT GCC-3' and 5'-CTG
CGC GTC CAG CTC TTC TAA-3'; and for Sp1, 5'-GTT CAG AGC ATC AGA CCC
CTC-3' and 5'-GAG AGT GGC TCA CAG CCT GTC-3'. PCR running conditions
were 20-sec denaturation (94 C), 20-sec annealing (57 C), and
20-sec reaction for 30 cycles. The quantification of the PCR
products was performed by phosphorimaging after separating the
radiolabeled PCR products on a denaturing (8.3
M urea) 5% PAGE (22). A cDNA fragment of the
transcription factor Sp1 was coamplified in each assay as an internal
standard. Sp1 expression is known to be stable in human preadipocytes
and adipocytes as reported recently (21). The specificity of the PCR
products was tested by Southern hybridization or nested primer
analysis. Sequential numbers of cycles were run to ensure that
amplification of both fragments was within the exponential range of the
PCR.
Glucose transport assay
2-Deoxy-D-glucose uptake was determined as a
functional parameter of the glucose transport system as previously
described (11). Seventy-two hours before the assay, insulin and glucose
concentrations were reduced to 20 pM and 5 mM,
respectively. wt-TNF or recombinant TNF (1 nM) was added 6,
4, and 2 h before glucose uptake was started, and cells were
incubated either with or without 100 nM human insulin for
15 min before 1 µCi/dish 3H-labeled
2-deoxy-D-glucose (4.5 µM) was added. After
20 min at 37 C, glucose uptake was terminated on ice, cells were washed
with PBS, and lysis was performed for 20 min in PBS containing 0.1%
SDS. The amount of incorporated radioactivity was evaluated in a liquid
scintillation counter (Beckman Coulter, Inc., Munich,
Germany). Values were corrected for the unspecific uptake as previously
described (11).
Western blotting of GLUT4 protein
For Western blotting of GLUT4 crude membrane fractions were
prepared from in vitro differentiated human fat cells
cultured in 100-mm dishes (3–4 x 106
cells) as described recently (11). Protein samples (15–25 µg) were
subjected to SDS-PAGE and transferred to polyvinylidene fluoride
filters (Immobilon-P, Millipore Corp., Bedford, MA) in a
semidry blotting apparatus. The blots were incubated with a 1:100
dilution of a polyclonal antibody raised against GLUT4 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), washed several times,
incubated with a second antibody antirabbit IgG conjugated with
horseradish peroxidase, and detected with a chemiluminescence substrate
(Lumi Light Plus, Roche, Mannheim, Germany).
Statistics
Results are presented as a mean percentage of the control
value ± SE for five or more determinations or
as a percentage of the control value ± SD for less
than five determinations. Controls were defined as 100%. Statistically
significant differences were tested using Student’s t test
for paired data. P 
0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Replacement of 1 nM wt-TNF by 1 nM
p60-TNFR-specific TNF mutein (TNFR32W-S86T) led
to a similar degree of inhibition of adipose differentiation
(percentage of differentiated cells, 5 ± 3%). However, when
cells were treated with 1 nM p80-TNFR-specific
TNFD143N-A145R, a 1.5- to 2-fold increase in the
number of differentiated cells was observed (percentage of
differentiated cells, 58 ± 18%; P = NS
vs. controls; Fig. 1
).
Concomitant administration of both TNF muteins at concentrations of
0.01, 0.1, and 1 nM each, respectively, resulted
in a dose-dependent inhibition of adipogenesis, comparable to the
effects of the same concentrations of wt-TNF alone (data not shown),
indicating that stimulation of the p60-TNFR overrides the stimulatory
effect of the p80-TNFR mutein.
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, upper graph). When newly
differentiated fat cells were chronically exposed to either 0.1 or 1
nM wt-TNF or TNFR32W-S86T
from days 15–25, a dose-dependent depletion of cellular lipid droplets
was observed, which was accompanied by a down-regulation of GPDH
activity. After exposure of newly differentiated adipocytes to
TNFD143N-A145R, neither a loss of cellular lipids
nor a change in GPDH activity was detectable (Fig. 2, lower
graph).
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2 using a semiquantitative RT-PCR
technique. Compared with control cultures, cells treated with 1
nM TNF or TNFR32W-S86T for the
initial 3 days showed markedly decreased PPAR2 mRNA amounts when
cells were harvested after 15 days of culture. In contrast, in cultures
initially exposed to 1 nM p80-TNFR-specific mutein,
PPAR2-mRNA levels were elevated more than 2-fold on day 15 (Fig. 3A).
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).
Effect of TNF muteins on insulin-stimulated glucose transport and
GLUT4 mRNA expression in newly differentiated human adipocytes
After 18 days in the adipogenic medium, when cells have acquired
the adipocyte phenotype, glucose transport was measured. Cultures
exposed to 1 nM wt-TNF showed a significantly reduced rate
of insulin-stimulated glucose uptake after a 2-h incubation. This
inhibitory effect was slightly greater after 4- and 6-h incubation
periods, respectively. Basal glucose uptake was not significantly
altered during exposure for up to 6 h (Fig. 4, upper graph). A comparison
of TNFR-specific effects clearly showed that stimulation of either
p60-TNFR or the p80-TNFR was sufficient to significantly reduce
insulin-stimulated glucose uptake within 2 h of incubation.
Although the p60-TNFR-mediated inhibition of insulin-stimulated glucose
transport increased with exposure time, the p80-TNFR-mediated effect
was already maximal after a 2-h period, but then rapidly returned to
baseline levels within 6 h. As observed for wt-TNF, neither mutein
significantly influenced basal transport under these conditions (Fig. 4, middle and lower graphs).
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). In contrast, stimulation of p60-TNFR
by TNFRR32W-S86T resulted in a similar, if not
more pronounced, down-regulation of GLUT4 mRNA, which became diminished
when cells were exposed to TNFR32W-S86T for
24 h (Fig. 5B). Surprisingly, GLUT4 expression was slightly, but
significantly, stimulated when cultures were incubated with 1
nM TNFD143N-A145R for not longer than
4 h (Fig. 5C).
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).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 mRNA
and GPDH activity. Furthermore, the p60-TNFR-specific ligand was found
to induce a dose-dependent reversion of the fat cell phenotype in fully
developed adipocytes, indicated by an almost complete loss of
intracellular lipid droplets, as recently reported for soluble wt-TNF
(4). These findings very closely resemble the results obtained after
treatment with wt-TNF and therefore suggest that the p60-TNFR is
mediating these metabolic effects of soluble TNF in human adipose
tissue as reported for most other organ systems (1). This conclusion is
also supported by the results of a recent study in TNFR-deficient
preadipocyte cell lines established from knockout ob/ob mice
lacking p55-TNFR, p75-TNFR, or both. In this study the TNF-related
inhibition of the adipose differentiation program was predominantly
attributed to p55-TNFR, which is the rodent homolog of human p60-TNFR
(23).
Surprisingly, the p80-TNFR-directed ligand caused the opposite
effect, i.e. a stimulation of adipogenesis. This was obvious
from the morphological appearance of the cultures. The number of
differentiating cells as well as the amount of PPAR2 mRNA were
nearly doubled. In addition, the mRNA of the insulin-responsive GLUT4,
which is expressed in a differentiation-dependent fashion (24), was
slightly up-regulated after 2–4 h of stimulation with 1
nM TNFD143N-A145R. These
findings are also in agreement with the results of the above-mentioned
study in TNFR knockout mice, where a lack of the p75-TNFR was
associated with a significant decrease in body weight compared with
that of wild-type animals and mice lacking both receptors (25).
However, when both selective TNFR agonists were combined, the effect of
TNFD143N-A145R was clearly overridden by the
action of the p60-TNFR-specific TNFR32W-S86T in
our model of human adipocytes.
Although the observed changes in morphology as well as in PPAR2 mRNA
expression were substantial, GPDH activity remained at the level of the
control cells after exposure to the p80-TNFR-specific mutein. GPDH
activity, however, is a limiting factor for de novo lipid
synthesis. The observation that this key enzyme was not influenced, in
contrast to the obviously increased lipid accumulation of the cells, is
presently unexplained. However, it is noteworthy that adipocyte GPDH is
a homodimeric enzyme, which may be allosterically regulated in its
catalytic activity (26). As GPDH activity was measured in cell extracts
under distinct conditions, the results obtained may reflect only the
amount of active enzyme molecules, not their former velocity in intact
cells.
Recent studies in the 3T3-L1 preadipocyte cell-line using p55-TNFR agonistic antibodies or ceramide, a lipid messenger of p55-TNFR signaling, have demonstrated that the murine analog of the p60-TNFR is responsible for the induction of disturbances in insulin receptor signaling (16). Indeed, our results clearly show a marked and rapid reduction of insulin-stimulated glucose transport upon selective stimulation of the p60-TNFR. This effect could be due to an impairment of insulin signaling at the level of insulin receptor substrate-1 tyrosine phosphorylation and insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity as recently demonstrated by our group in isolated human adipocytes (13). However, our present experiments also suggest a rapid suppression of GLUT4 mRNA, which may contribute to the chronic suppression of insulin-stimulated glucose transport. It is noteworthy that measurement of GLUT4 protein after a 24-h exposure of adipocytes to either TNFR32W-S86T or TNFD143N-A145R showed that only stimulation of p60-TNFR induced a reduction in GLUT4 protein, whereas the stimulatory effect of the selective p80-TNFR agonist on GLUT4 mRNA expression was only temporary and did not significantly affect the amount of GLUT4 protein. Thus, it may be speculated that the inhibitory effect of the selective p80-TNFR agonist may be exerted at the level of insulin signaling and/or GLUT4 translocation. This is also in agreement with the above-mentioned study in which neutralization of the p80-TNFR ameliorated the inhibitory action of TNF on insulin-stimulated glucose transport in human adipocytes (13).
A comparison of these receptor-specific responses with the effects of wt-TNF clearly indicates that the effects of soluble wt-TNF are primarily mediated by a p60-TNFR-specific signal. This is particularly the case for the observed long-term effect on adipogenesis. However, concerning glucose transport the rapid wt-TNF effect could also involve the p80-TNFR. It may be concluded from these experiments that the p80-TNFR may represent a signal transducer of short-term effects, and the p60-TNF may be a mediator of both short- and long-term effects. This assumption would be in accordance with a clinical study of TNFR expression in adipose tissue. In this study, the p60-TNFR was stably expressed, whereas the p80-TNFR was highly regulated (10).
Another aspect addressed by our experiments is the regulation of endogenous TNF expression. Up-regulation of TNF expression by a stimulation of the p60-TNFR would extend the TNF signal in an auto-/paracrine manner. In contrast, selective activation of the p80-TNFR led to a down-regulation of TNF expression. The stimulation of endogenous TNF mRNA expression by wt TNF and the selective p60-TNFR agonist was not unexpected, as similar results were reported for other cell types (1). It is also known that the TNF promotor contains a TNF-responsive element (27). Thereby, our experiments suggest that the autostimulation of TNF expression, at least in adipocytes, is mediated by the p60-TNFR. The suppression of endogenous TNF mRNA by TNFD143N-A145R is a new finding and could at least partly explain the stimulation of adipogenesis, as other adipogenic substances, such as phosphodiesterase inhibitors, have been found to act as inhibitors of TNF expression in several cell species (1, 28), including human preadipocytes and adipocytes (29).
Our results provoke the question of how these opposite signals operate in vivo. It is known that soluble TNF primarily stimulates the p60-TNFR, whereas the membrane-bound TNF precursor is able to activate both receptors independently (30). Moreover, like TNF itself, both TNF receptors were shown to be cleaved by proteolytic activities (31, 32, 33). Such mechanisms and probably the regulation of ligand and receptor expression would be suitable to explain the transduction of a TNF signal by both or exclusively one of the two TNF receptor subtypes.
Based upon such arguments, a molecular switch at the receptor level from adipogenic to antiadipogenic TNF action and vice versa may be conceivable. To extend this speculation, a TNF signal in adipose tissue generated by fat cells would normally be antiadipogenic and regulated by a critical fat cell size to prevent further expansion. This prevention would be achieved by the induction of insulin resistance due to interference with insulin signaling and suppression of GLUT4 production. In contrast, in the case of abundant supply with triglycerides and in the presence of high insulin concentrations the TNF signal could be switched to a more adipogenic, p80-TNFR-mediated action to allow storage of excess energy. This would induce both insulin resistance in enlarged fat cells and recruitment of adipocyte precursor cells for differentiation.
In conclusion, our results indicate that TNF is not only acting as an antiadipogenic factor for fat cells and their precursors, but also seems to be able to promote fat cell differentiation under certain conditions via a specific p80-TNFR-mediated effect. This pattern of opposite signaling includes the regulation of GLUT4 expression, where p60-TNFR- mediated signals induce a long-term down-regulation, while p80-TNFR-mediated signals do not substantially affect GLUT4 expression. Both TNF receptors appear to mediate a suppression of insulin-stimulated glucose uptake and to be involved in insulin resistance. Further investigations are required to further elucidate the pathways by which both TNF receptors may specifically interfere with insulin signaling.
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Acknowledgments |
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Footnotes |
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Received October 6, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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prevents the differentiation of human adipoycte precursor
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