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Original Studies |
German Diabetes Research Institute, 40225 Dusseldorf, Germany; and Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (S.R.B., G.P.C.), Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Hans Hauner, M.D., German Diabetes Research Institute, Auf’m Hennekamp 65, 40225 Dusseldorf, 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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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Catecholamines are known as powerful lipolytic hormones in humans (9), whereas glucocorticoids increase the expression and activity of lipoprotein lipase (LPL), the key enzyme for fatty acid uptake (10, 11, 12). Regarding IL-6, a positive correlation was observed between exercise-induced peak plasma epinephrine or norepinephrine and IL-6 levels in humans (13), whereas glucocorticoids suppress IL-6 production in vitro and in vivo (13, 14, 15, 16, 17). In rodents, IL-6 levels are closely related to psychological and physiological stress, which induces catecholamine release (18, 19). Administration of epinephrine to rats in vivo resulted in a dose-dependent increase in plasma IL-6 concentrations (20). In vitro, norepinephrine and ß-adrenergic agonists stimulated IL-6 release from murine brown adipocytes (21). On the other hand, treatment with IL-6 is known to influence energy metabolism; IL-6 reduces the production and activity of LPL in adipose tissue of mice in vivo and in murine 3T3-L1 adipocytes in vitro (10, 12) and increases hepatic de novo fatty acid synthesis (20, 23). Administration of IL-6 to mice resulted in weight loss, which was prevented by pretreatment with monoclonal antibodies against IL-6 (24). As adipose tissue is innervated by postganglionic sympathetic nerves releasing norepinephrine, the regulation of adipocyte IL-6 production via ß-adrenergic receptor activation is of interest concerning the hypothesis that some of the catecholamine-induced catabolic effects could be mediated or potentiated by IL-6.
To date, the expression of IL-6, and especially its receptor system, by human white adipocytes is incompletely characterized. In humans, only preliminary data exist on the regulation of adipocyte IL-6 production by ß-adrenergic receptor activation and glucocorticoids, as well as on the local role of IL-6 in adipose tissue. Therefore, using a model of in vitro differentiating human breast adipocyte precursor cells, this study attempted to investigate 1) the expression of IL-6 and its receptor system components IL-6 receptor (IL-6R) and gp130; 2) the effects of IL-6 on markers of adipocyte functions, such as glycero-3-phosphate dehydrogenase (GPDH) activity, glycerol production, and glucose transport; and 3) the effects of both the nonselective ß-adrenergic receptor agonist isoproterenol and cortisol on adipocyte IL-6 production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human adipose tissue samples were obtained from the mammary adipose tissue of healthy 19- to 63-yr-old women (mean ± SD, 35 ± 12 yr) undergoing surgical mammary reduction. The BMI range of the donors was between 19.8 and 29.4 (mean ± SD[SCAP], 25.4 ± 2.8). All women were otherwise healthy and free of metabolic or endocrine diseases. Informed consent was obtained from the women before the surgical procedure. The study was approved by the ethical committee of the University of Dusseldorf.
Cell culture
After removal, adipose tissue samples of 100–200 g wet weight were immediately transported to the laboratory in Dulbecco’s PBS containing 20 mg/mL BSA. The isolation of adipose tissue-derived adipocyte precursor cells was performed as described with minor modifications (25). Adipose tissue was dissected from fibrous material and visible blood vessels, minced into small pieces and digested for approximately 90 min in PBS containing 20 mg/mL BSA and 250 U/mL collagenase type CLS (Biochrom KG, Berlin, Germany). The dispersed tissue was filtered through a nylon mesh (pore size, 150 µm) and centrifuged for 10 min at 200 x g. Sedimented cells were resuspended in an erythrocyte lysis buffer consisting of 0.154 mol/L NH4Cl, 10 mmol/L KHCO3, and 100 µmol/L ethylenediamine tetraacetate and incubated for 10 min, then washed with PBS, and finally resuspended in DMEM containing L-glutamine and 4.5 g/L glucose (ICN Biomedicals, Inc., Eschwege, Germany) mixed 1:1 with nutrient mixture Ham’s F-12 containing L- glutamine (Life Technologies, Inc., Karlsruhe, Germany) and supplemented with 33 µmol/L D-biotin, 17 µmol/L D-pantothenic acid, 50 µg/mL gentamicin, and 10% FCS. For isolation of ribonucleic acid (RNA), 750,000 cells/well were seeded in 6-well culture plates (Becton Dickinson and Co., Heidelberg, Germany), for immunohistochemistry 150,000 cells/well were seeded in 4-well culture slides (Becton Dickinson and Co.), for lipolysis and glucose uptake 350,000 cells/well, and for GPDH activity and all other experiments 150,000 cells/well were seeded in 12-well culture plates (ICN Biomedicals, Inc.). After overnight attachment, cells were washed twice with PBS and cultured in a chemically defined, serum-free medium to induce differentiation into adipocytes. This adipogenic medium consisted of medium as described above, with the exception of FCS, supplemented with 10 µg/mL transferrin, 100 nmol/L cortisol, 66 nmol/L insulin, and 200 pmol/L T3. To potentiate adipose differentiation, 200 µmol/L 3-isobutyl-1-methylxanthine (IBMX) and 1 µg/mL troglitazone were added to the adipogenic medium during the first 2–3 days. Medium was changed every 48–72 h. Cells were kept at 37 C in a humidified atmosphere of 5% CO2. Within 16 days of culture, up to 70% of the attached adipocyte precursor cells differentiated into adipocytes according to morphological criteria. To minimize variations in experimental results due to different densities of mature adipocytes, only cultures with a differentiation rate greater 40% (mostly those with 50–60%) were used. For evaluation of the basal IL-6 background secretion by nonadipocytes, cells were simultaneously cultured for 16 days in a medium without the adipogenic factors IBMX, troglitazone, T3, and cortisol. Chronic effects of IL-6 on GPDH activity were measured at different time points as indicated. All other experiments were performed with differentiated cells on day 16.
Isolation of human adipocytes from adipose tissue
For preparation of mature adipocytes, adipose tissue was treated as described above with the following modifications of the enzymatic digestion procedure. The digestion medium contained 40 mg/mL BSA, the digestion time was 30 min, and the dispersed tissue was filtered through a nylon mesh with a pore size of 280 µm. The cell suspension obtained was washed five times by gentle shaking with PBS containing 40 mg/mL BSA. After the washing procedure, the pure adipocyte fraction was used for RNA isolation.
RT-PCR
All RT-PCR reagents were purchased from Life Technologies, Inc., and used according to the manufacturer’s instructions
with minor modifications as listed below. Total RNA from 1.5 x
106 cells was isolated with TRIzol and tested for
genomic DNA by PCR with specific intron overspanning primers for
glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) (26). RNA
probes devoid of genomic DNA were reverse transcribed in 20-µL
reactions with a Superscript II kit in the presence of 0.5
mmol/L deoxy-NTP and 25 ng/µl
oligo(deoxythymidine)12–18 primer. PCR was
performed in 25-µL reactions including 1 µL from the generated
complementary DNA, 1 U recombinant Taq DNA polymerase, 2.5
mL 10 x buffer, 1.5 mmol/L MgCl2, 0.2
mmol/L of each deoxy-NTP, and 1 µmol/L of specific primers for IL-6
(26), IL-6R (27), and gp130
(28). Complementary DNA generated from RNA of peripheral
blood lymphocytes was used as a positive control (not shown). General
PCR conditions were 3-min initial denaturing at 94 C; one cycle of 15-s
denaturing at 94 C, 30 s at primer-specific annealing temperature,
and 45-s elongation at 72 C; and a 7-min final elongation at 72 C.
Primer sequences, primer-specific annealing temperatures, and
primer-specific numbers of cycles are listed in Table 1
. Semiquantitative multiplex PCR was
performed as described above with minor modifications. After six cycles
with IL-6 primers alone, GAPDH primers were added as housekeeping gene
control, and another 24 cycles with both primers were performed using
an annealing temperature of 66 C. Reaction products were added to a
1.5% agarose gel, stained with ethidium bromide (0.5 µg/mL), and
photographed under UV light. A 100-bp ladder was used as the standard
(the 600-bp band is 2- to 3-fold pronounced). The identity of PCR
products was confirmed by restriction mapping (not shown). Reaction
products of semiquantitative multiplex PCR were treated as described
above, and then ethidium bromide emission was measured using the
Luminescence Imager (Roche, Mannheim, Germany). Emission
of IL-6 bands was normalized to GAPDH bands and expressed as a
percentage of the control.
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Cells on culture slides were washed with PBS and directly used for immunohistochemistry or were dried for 30–60 min in the air flow of the laminar bench, wrapped in tin foil, and stored at -80 C. Before staining, cells were immediately fixed in 96%, 80%, 70%, and 50% ethanol for 5 min each step, followed by 10 min in H2O. Antigen detection was performed with the LSAB+ kit (horseradish peroxidase) (DAKO Corp., Hamburg, Germany) and the 3-amino-9-ethylcarbazole substrate system (Coulter-Diagnostics, Hamburg, Germany) according to the manufacturer’s instructions, using the following antibodies: polyclonal goat antihuman IL-6 (AF-206-NA; R & D Systems, Inc., Wiesbaden, Germany), polyclonal goat antihuman IL-6R (AF-227-NA; R & D Systems, Inc.), monoclonal mouse antihuman IL-6 (AHC0862; Biosource Technologies, Inc., Ratingen, Germany), monoclonal mouse antihuman IL-6R (AHR0861; Biosource Technologies, Inc.), monoclonal mouse antihuman gp130 (AHT3001; Biosource Technologies, Inc.), and monoclonal mouse antihuman leukocyte common antigen (CD45; DAKO Corp.).
Regulation of IL-6 release
Before the incubations, cells were washed with PBS. The time-course of ß-adrenergic regulation of IL-6 secretion by cultured adipocytes was determined at the time intervals indicated in the presence or absence of 1 µmol/L isoproterenol (Sigma-Aldrich Corp., Deisenhofen, Germany). The effect of 100 nmol/L cortisol in the adipogenic medium on IL-6 production by in vitro differentiated adipocytes was evaluated after a 24-h incubation compared to control cultures. IL-6 accumulation in the supernatants was quantified using the IL-6 EASIA kit (Biosource Technologies, Inc.).
Measurements of GPDH activity, glycerol production, and glucose uptake
The activity of GPDH was determined according to a previously described method (29). Lipolysis was assessed by measuring glycerol accumulation in the culture medium using a luminometric assay (30). Glucose transport was determined by measuring the accumulation of [3H]2-deoxy-D-glucose in the cells. Cells were washed twice with PBS and incubated for 24 h in the presence or absence of 10 nmol/L IL-6 using a modified adipogenic medium (final glucose concentration, 5 mmol/L, without insulin). To evaluate the acute effects of IL-6, cells were preincubated for 22 h with the modified medium alone before IL-6 was added for another 2 h. The stimulatory effect of insulin was assessed by adding 1 µmol/L human insulin 20 min before the assay. The assay started with the addition of 3H-labeled 2-deoxy-D-glucose (Amersham Pharmacia Biotech, Braunschweig, Germany) to a final concentration of 37 kilobecquerels/well. Hexose uptake was terminated after 15 min by placing the culture plates on ice and washing the cells twice with ice-cold PBS. Then, cells were incubated for 20 min with PBS containing 0.1% SDS. Finally, the radioactivity of the cell material was counted in a liquid scintillation counter. The IL-6 used in the experiments was recombinant human IL-6 (Promocell GmbH, Heidelberg, Germany) with a reported specific activity of 2–4 x 108 U/mL as assessed by proliferation of IL-6-dependent 7-TDI mouse hybridoma cells.
Statistical analysis
The numbers of independent experiments are given in the figure
legends. Data were expressed as the mean ± SEM.
Because of the interindividual differences in IL-6 secretion by fat
cell cultures from different donors, the data in Figs. 5 and 6 are
expressed as a percentage of the control (mean ±
SEM). The statistical significance of differences between
matched data pairs was evaluated by repeated measures ANOVA, followed
by Bonferroni’s posttest (selected pairs of columns, Figs. 3B, 5, 6A, 6B, and 7) or Dunnett’s posttest (all treated columns vs.
control column, Fig. 6C) using the means of the independent
experiments. As GPDH activities on day 21 (Fig. 3A) and lipolysis data
(Fig. 4) were taken from six and nine independent experiments,
respectively, matched data pairs were analyzed using paired
t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RT-PCR analysis detected messenger RNA (mRNA) expression of IL-6,
IL-6R, and gp130 in freshly isolated pure fractions of human adipocytes
(Fig. 1). Similar results were obtained
from in vitro differentiated human adipocytes in primary
culture (data not shown). At the protein level, immunohistochemical
staining with specific antibodies detected positive signals for IL-6,
IL-6R, and gp130 only in in vitro differentiated adipocytes,
but not in undifferentiated adipocyte precursor cells (Fig. 2, A–C). The percentages of
immunohistochemically stained adipocytes were 3.5 ± 0.63% for
IL-6, 2.2 ± 0.36% for IL-6R, and 18.5 ± 2.28% for gp130
(mean ± SD; n = 4 different cell
preparations). Apart from the adipocytes, single cells were also
positive for IL-6 and its receptor system. These round cells were CD45-
positive leukocytes (Fig. 2D).
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GPDH activity was determined as an established marker of
triglyceride synthesis (31). Chronic supplementation of
the adipogenic medium with 1 nmol/L IL-6 resulted in a reduction of
GPDH activity to 67 ± 9% of the control value on day 21 (n
= 6; P < 0.05), whereas no alteration was observed on
days 3, 7, and 14 (Fig. 3A
). Exposure of
adipocytes to 10 nmol/L IL-6 for 24 h on day 21 decreased GPDH
activity to 81 ± 5% of the control value (n = 4;
P < 0.05; Fig. 3B). The effect of IL-6 on lipolysis
was determined by measuring glycerol accumulation in the cell culture
supernatants. Incubation of cultured cells with 10 nmol/L IL-6 for
6 h had no effect on lipolysis, whereas 24-h exposure increased
basal glycerol release by 42 ± 12% (P < 0.01)
and isoproterenol-induced glycerol release by 21 ± 6%
(P < 0.05), respectively (Fig. 4). Twenty-four-hour exposure to IL-6
concentrations smaller than 10 nmol/L had no significant effect on
lipolysis (data not shown). IL-6 did not affect glucose transport.
Neither 2-h nor 24-h incubation with 10 nmol/L IL-6 altered basal or 1
µmol/L insulin-stimulated glucose transport in in vitro
differentiated human adipocytes (Fig. 5).
IL-6 secretion in response to ß-adrenergic activation
When in vitro differentiated adipocytes were incubated
with the nonselective ß-adrenergic agonist isoproterenol, a marked
time- and dose-dependent stimulation of IL-6 secretion was observed.
Figure 6 demonstrates the time course of
IL-6 secretion (Fig. 6A) and IL-6 mRNA expression (Fig. 6B) induced by
1 µmol/L isoproterenol. There was a rapid increase in IL-6 release,
which was already significant after 1.5 h (P <
0.01), reached a maximum of 6.2-fold above the basal level after 3
h (P < 0.001), and remained significantly increased
after 6 and 12 h (each P < 0.001). IL-6 mRNA
expression followed the kinetics of protein production, with a
significant maximum after 3 h of incubation (P <
0.05), but decreased to basal levels after 6 and 24 h. The
dose-response relationship of IL-6 secretion is shown in Fig. 6C. IL-6
levels were elevated after 3 h of incubation with isoproterenol in
the range from 10 µmol/L to 100 pmol/L, whereas smaller
concentrations had no effect. However, the elevation of IL-6 was
only significant in response to 1 µmol/L isoproterenol
(P < 0.01).
Effects of cortisol on IL-6 secretion by human adipocytes
The adipogenic medium contains 100 nmol/L cortisol, and
glucocorticoids are known to suppress IL-6 production in
vitro and in vivo (13, 14, 15, 16, 17). Therefore,
in vitro differentiated human adipocytes after 16 days of
culture under adipogenic conditions were incubated for 24 h in the
presence or absence of 100 nmol/L cortisol in the culture medium. Under
these conditions, cortisol induced a moderate, but significant,
reduction of IL-6 levels to 66 ± 10% of the control value
(Fig. 7). Even under maximum
adipogenic culture conditions, a substantial proportion of the
adipocyte precursor cells remained undifferentiated, and a minor
contamination of CD45-positive leukocytes (Fig. 2D) was found in most
cultures. To determine to which extent this nonfat cell fraction may
contribute to IL-6 production in primary cultures of in
vitro differentiated adipocytes, adipocyte precursor cells were
seeded and cultured in medium without the adipogenic factors IBMX,
troglitazone, T3, and cortisol.
Under nonadipogenic conditions, the cells did not differentiate into
adipocytes. In these cultures, IL-6 release on day 16 was only 13
± 4% of the IL-6 production in cultures of in vitro
differentiated adipocytes exposed for 24 h to cortisol-free
adipogenic medium (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In our experiments chronic treatment with IL-6 resulted in a significant decrease in GPDH activity and consequent reduction of triacylglycerol accumulation. This finding is in line with the IL-6-induced reduction of LPL activity in mouse tissue and 3T3-L1 adipocytes (10, 12). The negative regulation of adipocyte GPDH may therefore represent a mechanism by which chronically high endogenous IL-6 levels contribute to weight loss in cachexia.
Another interesting finding of this study is the observation that IL-6 stimulates lipolysis by human adipocytes. This effect was independent of and additive to isoproterenol- induced lipolysis. Although the molecular mechanisms remain to be elucidated, our results suggest that IL-6 augments catecholamine-induced stimulation of lipolysis through an independent mechanism, as a maximum concentration of isoproterenol was chosen. As ß-adrenergic stimulation by isoproterenol was also found to increase adipocyte IL-6 release, a dual action of catecholamines on lipolysis appears conceivable: a direct effect via ß-adrenergic receptors and an indirect additive effect via IL-6 release.
Stouthard et al. (35) reported that IL-6 modestly increases basal glucose uptake by murine 3T3-L1 adipocytes. In contrast, neither basal nor insulin-induced adipocyte glucose transport was affected by IL-6 in our human cell culture model, although these cells express the glucose transport system of human adipocytes (36).
To date, little is known about the regulation of IL-6 release by human
adipocytes. White adipose tissue is innervated by the sympathetic
nervous system, and its activation results in the local release and
action of norepinephrine (37). A recent study reported a
stimulatory effect of norepinephrine, isoprenaline, and the
ß3-selective agonist CGP-12117 on IL-6 release
from cultured murine brown fat adipocytes, whereas stimulation of
-adrenergic receptors had no effect (21). Based on this
finding, we investigated the involvement of catecholamines in the
regulation of IL-6 production by human adipocytes and found that the
nonselective ß-adrenergic agonist isoproterenol induced an acute and
sustained concentration-dependent increase in adipocyte IL-6 release.
This might be explained by the downstream signaling of G
protein-coupled ß-adrenoceptors resulting in elevation of
intracellular levels of cAMP and activation of the cAMP-responsive
element within the IL-6 promoter (38).
Our findings clearly demonstrate that within the investigated culture system, differentiated adipocytes are the main source of IL-6 production (at least 87%). This is consistent with the study by Orban et al., which demonstrated high basal levels of IL-6 in the in vivo microperfusion eluates of sc abdominal fat (5), underscoring the fact that adipose tissue is an important source of circulating IL-6. The physiological significance of the stimulatory activity of isoproterenol is unclear, as the study of Orban et al. found no significant increase in IL-6 levels by this ß-agonist during in vivo microperfusion of sc adipose tissue (5). This discrepancy may be a consequence of the use of different adipose tissue depots. It is also possible that the perfusion system is a local stress factor, which by itself induces ß-adrenergic activation, leading to nearly maximal local IL-6 secretion. As a consequence, the unstimulated IL-6 levels in the perfusion eluates might not be further stimulated by exogenous isoproterenol. However, one has to keep in mind that the regulation of lipolysis in vivo is a complex process, as many stimulatory and inhibitory factors can be involved, and that cell cultures do not fully reflect intact tissue functions (9, 37).
The observation that isoproterenol elevates IL-6 release from human adipocytes only at high concentrations may prompt the speculation that adipocyte-derived IL-6 secretion is predominantly stimulated by local sympathetic activation and only to a lesser extent by circulating catecholamines. Interestingly, both catecholamines and IL-6 decrease LPL activity (10, 12, 39, 40). Again, it is tempting to speculate that the effect of catecholamines on LPL is at least partially mediated by increased levels of locally produced IL-6.
Adipocyte-derived IL-6 may contribute to circulating IL-6 concentrations. Mohamed-Ali et al. (3) reported significantly higher levels of IL-6 in venous blood from sc adipose tissue than in arterial blood supplying this tissue. Furthermore, a positive correlation between circulating IL-6 levels and BMI was observed in obese men (8). Apart from the increased adipose tissue mass, however, the elevated systemic concentrations of IL-6 in obesity could be due to generally higher sympathetic nerve activity in obese subjects (41, 42).
Although catecholamines are positively correlated with IL-6 production, glucocorticoids were reported to suppress circulating IL-6 levels (13, 16) as well as IL-6 secretion by human fibroblasts (14, 15) and immune cells (17) in vitro. In agreement with these reports, we found that cortisol reduced the release of IL-6 from in vitro differentiated human adipocytes. However, the observed suppression was quite modest. The physiological significance of this finding is currently unknown, but one can conclude that glucocorticoids and IL-6 exert opposite effects on adipose tissue metabolism. Thus, whereas glucocorticoids increase the expression and activity of LPL, the key enzyme for fatty acid uptake (10, 11, 12), IL-6 has the opposite action. A similar opposite regulation by glucocorticoids and IL-6 may be involved in the regulation of GPDH, another key enzyme for the accumulation of triacylglycerides in adipocytes. It is, therefore, conceivable, but unproven, that some of the effects of glucocorticoids on adipocytes may also be mediated by the suppression of IL-6 production.
In conclusion, differentiated human breast adipocytes are an important source of IL-6. These cells express IL-6R and gp130, indicating that this cytokine has auto- or paracrine actions in human adipose tissue. Furthermore, our results demonstrate a stimulatory effect of IL-6 on lipolysis as well as a reduction of GPDH. The secretion of IL-6 by adipocytes was stimulated by ß-adrenergic activation in both an acute and a long-lasting manner and was reduced by glucocorticoids. Therefore, local IL-6 production by and local action of IL-6 on human adipocytes may play roles in the metabolic alterations observed during stress reactions and in certain forms of cachexia.
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Acknowledgments |
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Received February 22, 2000.
Revised November 2, 2000.
Revised January 9, 2001.
Accepted January 12, 2001.
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References |
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, in vivo. J Clin Endocrinol Metab. 82:4196–4200. and interleukin-6 expression in mouse
brown adipocytes. FEBS Lett. 411:83–86.[CrossRef][Medline]
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