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Departments of Medicine (V.M.-A., L.F., R.G.) and Cardiovascular Genetics (S.E.H.), University College London Medical School, Whittington Hospital, London N19 3UA, United Kingdom; Harvard School of Public Health (V.M.-A., J.S., G.H.), Boston, Massachusetts 02115; Pennington Biomedical Research Center (D.A.Y., J.P.), Louisiana State University, Baton Rouge, Louisiana 70808-4124; and Department of Medicine, Diabetes, and Endocrinology Research Group (J.P.), University of Liverpool, University Hospital Aintree, Liverpool L9 7AL, United Kingdom
Address all correspondence and requests for reprints to: Jonathan Pinkney, M.D., University of Liverpool, Department of Medicine, Clinical Sciences Centre, Longmoor Lane, Liverpool L9 7AL, United Kingdom. E-mail: jpinkney{at}liverpool.ac.uk
Abstract
Circulating IL-6 levels are elevated in obesity. Although IL-6 is expressed in adipose tissue, neither its regulation nor cell of origin is well characterized. Here we investigated the ß-adrenergic regulation of IL-6 release in a combination of studies on humans and animals in vivo and cultured adipocytes in vitro. Human in vivo study: Human volunteers were infused with isoproterenol, norepinephrine, or saline {4 M:4F; mean (SD) age 35.5 (5.8) yr; body mass index 24.6 (4.2) kg/m-2}. Plasma IL-6 levels increased during a 3-h infusion of isoproterenol (P = 0.01) and fell 2 h post infusion (P = 0.05). IL-6 levels did not change significantly with either norepinephrine or saline. Murine in vivo study: C57BL6/J male mice were injected ip with dobutamine (ß1 agonist), clenbuterol (ß2), CL316243 (ß3), or saline placebo. Plasma IL-6 levels at 3 h were increased by clenbuterol (P = 0.02) and CL316243 (P = 0.02) but not dobutamine (P = 0.51), compared with placebo. In vitro studies: In human peripheral blood cells, lipopolysaccharide treatment enhanced secretion of IL-6 (vs. controls; P < 0.001), whereas isoproterenol inhibited IL-6 secretion (P = 0.012) and norepinephrine had no significant effect. In contrast, isolated human adipocytes and differentiated 3T3F442A adipocytes all rapidly secreted IL-6 in response to adrenergic agonists (P < 0.01, compared with untreated cells). We conclude that ß2/ß3 adrenoceptor stimulation on adipocytes, rather than macrophages, may be responsible for the increases in plasma IL-6 concentrations observed during sympathetic activation and in obesity.
IL-6 IS A MAJOR circulating cytokine with effects on cell growth and differentiation (1), the acute phase responses (2), and both carbohydrate and lipid metabolism (3, 4, 5, 6). IL-6 has a ubiquitous tissue distribution and is highly expressed in, and released from, both macrophages and adipocytes (7, 8). Although it has been suggested that about 20% of circulating IL-6 is derived from peripheral blood cells (PBC), plasma levels of IL-6 are markedly elevated in obese subjects (9), and our previous work has suggested that up to 30% of this cytokine could be derived from adipose tissue (10). However, despite its abundance and this metabolic profile, neither the regulation nor the biological roles of IL-6 in metabolism are well understood. In the obese state, however, it is plausible that IL-6 released from an expanded adipose tissue mass could contribute to certain aspects of the associated pathophysiology, including a proinflammatory state predisposing to atherosclerosis.
The sympathetic nervous system (SNS) may be an important regulator of the production of cytokine-like molecules such as leptin (11, 12) and IL-6, in addition to its pivotal role in fuel metabolism and the response to changes in energy demand during flight or fight. In rodents SNS activation during stress was associated with elevated plasma IL-6 levels (13). Furthermore, epinephrine has been shown to induce an acute rise in plasma IL-6 (14). These observations are consistent with a possible role for catecholamines as mediators of the exercise-induced elevation of plasma IL-6 levels (15). Although the tissues responsible for the adrenergic-induced surge in plasma IL-6 levels have not been identified, it has been observed that ß-adrenergic stimulation induces the expression and release of IL-6 in murine brown adipocytes (16). This observation raised the interesting possibility that adipose tissue could also be an important contributor to the adrenergic-mediated rise in plasma IL-6 levels. Consistent with this hypothesis, isoproterenol was found recently to induce IL-6 gene expression and secretion in cultured human breast adipocytes (17).
Here we examine further the hypothesis that ß-adrenergic stimulation of human adipocytes is primarily responsible for the adrenergic-mediated IL-6 response. The hypothesis was investigated using a combination of in vivo and in vitro approaches. First, plasma concentrations of IL-6 in humans were measured in response to infusions of norepinephrine and the nonspecific ß-agonist isoproterenol. Second, the effects of treatment with dobutamine (ß1), clenbuterol (ß2) and CL316243 (ß3) on plasma levels of IL-6 in mice were investigated, comparing responses with those observed in plasma leptin. Finally, the adrenergic regulation of IL-6 expression by these agonists was investigated in vitro in human PBC and adipocyte primary cultures and in differentiated murine 3T3 F442A adipocytes. On the basis of these studies, we propose that the secretion of IL-6 from adipose tissue may represent a new auxiliary mechanism through which the SNS influences fuel metabolism and energy balance.
Subjects and Methods
Subjects
Healthy volunteers, with a spectrum of adiposity, were recruited from departmental staff and advertisements. All subjects studied were clinically well, with no recent infections. All were euthyroid, and none had diabetes or asthma or were receiving treatment with sympathetic agonists or antagonists or steroids. Subjects were excluded if there was any clinical history of cardiovascular disease, including hypertension. Permission for the study was granted by the institutional ethical committee and all subjects gave informed written consent. The studies were conducted in accordance with the guidelines of the Declaration of Helsinki. Subjects were weighed in the fasted state, their height recorded, and body fat determined by electrical bioimpedance (Bodystat, Douglas, Isle of Man, UK), and all were allocated to three groups, matched for age, sex, and adiposity (mean [SD] age 35.5 (5.8) yr; 10 males and 10 females; body mass index 24.6 (4.2) kg/m-2). Eight subjects were infused with isoproterenol, six with norepinephrine, and six were studied as controls with 0.9% saline placebo. A representative group of 12 subjects also underwent open adipose tissue biopsy in the fasted state on a separate occasion.
Infusion protocol
Subjects attended the clinical investigation unit between 0700 and 0900 h, after an overnight fast from midnight. Cannulae were inserted into both antecubital veins, one for infusion and one for blood sampling, and subjects were allowed to relax for 30 min. Heart rate was monitored continuously and blood pressure recorded with an automated monitor every 15 min. Blood was drawn into EDTA at baseline before infusion and then at 30-min intervals. All samples were spun and separated immediately and frozen at -70 C until analysis. Isoproterenol or norepinephrine was infused at a rate beginning at 0.5 µg/min-1. Thereafter, the infusion rates were increased at intervals of 15 min until steady biological responses were achieved for both agents, and then the infusions were continued to 3 h. For isoproterenol, the infusion rate was titrated upward to give target biological responses of heart rate [gt] 100 min-1 but no greater than twice the resting heart rate. Norepinephrine, being less chronotropic (dose for dose) than isoproterenol, was infused to maintain an increase in systolic blood pressure of between 10% and 20%. The infusions were continued for 3 h, with blood sampling every 30 min; following discontinuation of the infusions, further blood samples were collected at 15, 30, 60, and 120 min. Isoproterenol and norepinephrine infusions were well tolerated by all subjects. Saline infusions were performed using an identical protocol.
Murine in vivo study
C57BL6/J male mice, aged 7 wk, were obtained from The Jackson Laboratory (Bar Harbor, ME). Animals were individually housed in wire cages on a reversed light-dark cycle. Mice were fed ad libitum on regular chow and studied at age 8 wk. The animals were all maintained in conditions in accordance with those recommended in the NIH Guide for the Care and Use of Laboratory Animals. Animals were randomized to receive 0.9% saline, ß1 adrenergic agonist, ß2 agonist, or ß3 agonist (n = 8 per group). ß1 and ß2 were obtained from Sigma (Poole, Dorset, UK) and ß3 from American Cyanamid (Pearl River, NY). Drugs were administered in equal-volume doses, injected ip at 1.0 mg·kg-1 body weight, at the onset of the dark phase. After 3 h, animals were killed by decapitation and EDTA plasma was collected, separated, and frozen immediately at -70 C.
Isolation of human adipocytes
Open biopsies of sc abdominal adipose tissue were obtained under local anesthetic. Two to four grams of tissue was obtained. Biopsies were treated with collagenase for 1 h in a shaking incubator at 37 C in 10% CO2 and filtered through a 260-µm filter. Cells were spun at 4 C, 3000 rpm for 5 min. The top adipocyte layer was transferred into a 15-ml tube, and cell suspensions were prepared in DMEM (Life Technologies, Inc./BRL, Paisley, UK). Adipocyte numbers were estimated using an improved Neubaur hemacytometer (Philip Harris Scientific, Ashby-de-la-Zouche, UK), without a coverslip. The cell suspension was diluted to 1 x 106/ml-1. Then 200-µl aliquots of the cell suspension were treated with isoproterenol, norepinephrine, or lipopolysaccharide (LPS) for 5 and 10 h. At the end of the incubation, cells were centrifuged for 5 min at 2000 rpm and the supernatant collected and stored at -70 C until assay. IL-6 levels were expressed in picograms per milliliter.
Human peripheral blood cells
Peripheral blood samples were obtained from the same subjects as were undergoing adipose tissue biopsy and on the same occasion. The 0.5-ml aliquots of blood, diluted to 2 x 108 white cells·ml-1 with RPMI 1640 media, were incubated with LPS (2.5, 25, and 50 µg), norepinephrine, or isoproterenol (0.025, 0.05, and 0.1 µM), in 4.5 ml DMEM for 4 h at 37 C. After incubation, cells were spun and discarded and the supernatant aliquoted and stored at -70 C for analysis. IL-6 release was expressed as pg·ml-1 because equal numbers of cells were used for each intervention. Blood was also sent to the routine hematology laboratory for full blood count and differential white cell counts.
3T3-F442A murine adipocytes
Cells were seeded (6 x 104 cells per well) into 6-well plates (Costar, UK) and allowed to grow to about 80% confluence in DMEM/10% calf serum at 37 C/10% CO2. Differentiation into adipocytes was induced by treating cells with DMEM/10% calf serum supplemented with 0.5 mM isobutyl methyl xanthine, 1 µM dexamethasone and 1 µM insulin (1 µg·ml-1) for 3 d and then fed every 48 h with DMEM/10% calf serum and insulin. Differentiation-dependent expression and release of IL-6 was checked on these cells at 0 (undifferentiated), 2, 4, 6, 8, and 10 d after induction. Differentiated adipocytes were stimulated with norepinephrine (0.2–1 µM), isoproterenol (0.2–1 µM), salbutamol (ß2) (0.2–1 µM), dibutyryl cAMP (10 mM), or ß3 (0.2–1 µM) for 4 h at 37 C/10% CO2.
Laboratory investigations
IL-6 in adipocyte culture supernatants was quantified using Cytoscreen mouse ELISA (Biosource Technologies, Inc. Ltd., Camarillo, CA). This assay detected to <8 pg·ml-1 (2 SD + mean OD of zero standard, assayed 20 times), with inter- and intraassay coefficients of variation less than 10%. IL-6 in human plasma and human primary adipocyte cultures were assayed by high-sensitivity two-site ELISA (R & D Systems, Abingdon, Oxon, UK). Human plasma leptin was determined by an in-house RIA (10) and mouse leptin by ELISA (R & D Systems).
Statistical analyses
Data were analyzed using the SPSS, Inc. version 6.0 statistical package (Statistical Package for the Social Sciences; SPSS, Inc. UK Ltd., Chertsey, UK). Nonparametric methods were employed. Data are presented as medians and ranges or interquartile ranges in the text and as mean and SD in the figures. Comparisons were made with Mann-Whitney or Wilcoxon tests, as appropriate. Significance was defined as 2-tailed P < 0.05.
Results
Human infusion study
The median (interquartile range) infusion rate achieved by 3
h was 7.5 (4.5–8.8) µg·min-1 for
norepinephrine and 2.0 (1.8–2.5) µg·min-1
for isoproterenol. The isoproterenol infusion significantly increased
heart rate, systolic blood pressure, circulating insulin, and FFA
concentrations, and these results have been reported previously
(11). Norepinephrine also produced a significant increase
in systolic blood pressure but not heart rate. Infusion of
isoproterenol resulted in a swift rise in plasma IL-6 levels. Plasma
IL-6 levels rose from 0.51 (0.47–1.40) at baseline to 3.40
(2.34–5.17) pg·ml-1 at 60 min (Wilcoxon test,
P = 0.01), remaining high at 3 h (4.53
[2.50–5.69]; P = 0.01), followed by a fall toward
baseline, although still significantly higher, in the postinfusion
period (2.90 [1.27–3.97]) P = 0.01). In contrast,
there was no significant change in plasma IL-6 levels during infusion
of norepinephrine, and IL-6 levels were unchanged also in response to
saline placebo. Fig. 1
shows the time
courses for the changes in plasma IL-6 in response to
isoproterenol.
|
Administration of ß2 or ß3 led to increases in plasma IL-6 concentrations, compared with ß1 or saline-injected control groups, in which IL-6 concentrations did not differ from those of uninjected mice. ß2 increased plasma IL-6 concentrations at 3 h to 76.82 (55.38–93.01), compared with 10.10 (4.14–15.16) pg·ml-1 in ß1-treated animals (P = 0.002), and 0.70 (0.50 - 6.3) in saline treated animals (P = 0.002). In ß3-treated animals, IL-6 concentrations were increased to 32.0 (17.0–91.0) pg·ml-1 at 3 h, compared with saline (P = 0.009).
In contrast to the effects of adrenergic agonists on IL-6 production,
median (interquartile range) plasma leptin levels were suppressed to
2500 (1200–2900) pg·ml-1 by
ß3, compared with 5000 (4300–8600) with
ß1 (P = 0.007) and 2900
(1200–4800) pg·ml-1 with
ß2 (P = 0.007). Figure 2 shows the opposing effects of
ß3 on IL-6 and leptin release, compared with
saline placebo.
|
Levels of IL-6 in the supernatant were increased in a
dose-dependent fashion by LPS, from 2.2 (0.8–6.7)
pg·ml-1 in unstimulated cells to 309.9
(171.1–396.6) pg·ml-1 with the maximum dose
(P = 0.008) (Fig. 3). In
contrast, isoproterenol led to a significant dose-dependent fall in
supernatant IL-6 levels at the highest dose (P =
0.007), compared with untreated cells. No significant change in IL-6
concentrations was observed with norepinephrine at the highest dose
(P = 0.44).
|
In control medium (DMEM), IL-6 concentrations were 5.65 (1.61–15.3) at 5 h and 15.95 (2.34–45.59) pg·ml-1 at 10 h (P < 0.01), showing constitutive release. IL-6 secretion from isolated human adipocytes increased from 3.56 (0.68–19.74) at 5 h to 25.62 (1.68–39.86) pg·ml-1 after 10 h with isoproterenol treatment (P = 0.02). IL-6 release at 10 h was greater with isoproterenol than in control medium (P = 0.02), but there was no significant difference between control and isoproterenol at the 5-h time point (P = 0.20). Similarly, norepinephrine induced IL-6 secretion from 3.67 (1.27–27.21) at 5 h to 24.48 (1.87–32.25) pg·ml-1 at 10 h, but this was not statistically significant (P = 0.18). In contrast, LPS treatment lead to a nonsignificant decrease in IL-6 production from 13.77 (2.08–36.62) at 5 h to 9.61 (1.76–39.51) pg·ml-1 at 10 h (P = 0.63).
Although it is not possible, strictly to compare IL-6 release rates per cell in human adipocytes vs. white blood cells, because of different counting methods, cell concentrations, and experimental durations, IL-6 release rates were relatively similar in maximally LPS-stimulated white cells (0.075 pg·105 cells-1·hour-1) vs. isoproterenol-treated adipocytes (0.125 pg·105cells-1·hour-1).
Murine 3T3-F442A adipocytes
Significant increases in supernatant IL-6 concentrations were
observed in response to treatment of adipocytes with adrenergic
agonists as well as dibutyryl cAMP, compared with untreated cells
(Table 1). Furthermore, treatment of
adipocytes with LPS did not result in significant changes in release of
IL-6 or leptin (P = NS).
|
The present studies suggest that IL-6 release from adipocytes is markedly enhanced by ß2/ß3 adrenoceptor stimulation. In contrast, adrenergic agonists suppressed IL-6 release from PBC. The present investigations differ from most previous reports in that the in vitro data were complemented by in vivo studies in both animals and humans, permitting speculation on the likely physiological significance of the adrenergic-cytokine interaction observed in vitro. In view of the previous observations that circulating IL-6 concentrations are elevated in obesity and that adipose tissue releases IL-6 into the circulation (10), the present data suggest that the SNS may be an important regulator of IL-6 release from adipose tissue. This mechanism may also explain the observed surges in circulating IL-6 that followed treatment with adrenergic agonists in both animals and humans.
In a previous human in vivo study, it was observed that
isoproterenol, administered locally into abdominal adipose tissue, had
no apparent effect on IL-6 release, determined by microdialysis,
whereas a standard meal led to a significant rise in IL-6 release
(18). In that study, however, a trend was observed toward
increased IL-6 release, although this did not reach statistical
significance, perhaps because of factors such as sample size, variance
of IL-6 concentrations, and assay sensitivity. In contrast, leptin
concentrations in the microperfusate were suppressed by isoproterenol,
consistent with our present data. As a possible explanation for the
apparent lack of effect of isoproterenol on IL-6 release in this study,
the authors raised the possibility of secondary effects on IL-6 release
(e.g., by TNF
) or regional heterogeneity of adipose
tissue response to isoproterenol. Nevertheless, it was demonstrated
recently that cultured human breast adipocytes secrete IL-6 in response
to isoproterenol (17). Before the above investigations,
there were few previous data on adrenergic-IL-6 interactions in
adipocytes and adipose tissue. Burysek and Houstek (16)
observed adrenergic stimulation of IL-6 release in brown adipocytes.
Adrenergic regulation of IL-6 has been reported in several other cell
types, including hepatocytes (19), pituicytes
(20), endothelial cells (21), and astrocytes
(22, 23), although whether these tissues contribute to
circulating IL-6 concentrations is uncertain. In rats, stress is
associated with increased IL-6 levels (13, 24), and
injections of epinephrine have been shown to increase plasma levels of
IL-6 (14). Other indirect evidence that SNS activation
stimulates IL-6 release is that the peak plasma catecholamine and IL-6
levels coincide during exercise in humans (15). Also,
plasma catecholamine and IL-6 levels correlate in patients with heart
failure (25), and IL-6 levels are elevated in
phaeochromocytoma (26). Thus, in the absence of
inflammation, IL-6 from nonimmune cells may be an important metabolic
regulator, and during episodes of acute inflammation IL-6 of immune
origin, induced in response to LPS and other cytokines, IL-6 influences
metabolism through the same set of mechanisms.
The in vitro data demonstrate that norepinephrine stimulates
IL-6 release from adipocytes. In contrast, in the human study, no
significant increase in plasma IL-6 was observed during norepinephrine
infusion. The apparent discrepancy may be explained by the balance
among 2, ß2, and
ß3-adrenoceptor-mediated effects in the
adipocyte (27). The adrenoceptor-binding affinity of
norepinephrine is in the order 2 >
ß1 
ß2 >
ß3. Therefore, norepinephrine at low
concentrations suppresses adipocyte cAMP and activates
ß2 and ß3 adrenoceptors
only when higher concentrations are reached. It is likely, therefore,
that in the in vivo situation, the slow build-up of
exogenous norepinephrine resulting from the infusion protocol initially
inhibits IL-6 release from adipocytes. The local tissue concentration
of norepinephrine may be sufficient to activate
2 but not ß receptors. The ability of
norepinephrine to stimulate IL-6 release from adipocytes, however,
through ß2 and ß3 adrenoceptor activation, is confirmed by the
result of the in vitro study (Table 1
), in which we observe
a clear stimulatory effect. In the in vitro situation, the
rapid rise in the norepinephrine concentration following its addition
to the medium may be sufficient to promote immediate
ß2- and ß3-mediated
effects sufficient to overcome any 2-mediated
inhibitory effect. It can be suggested, therefore, that endogenous
norepinephrine released from sympathetic nerve varicosities in adipose
tissue reaches concentrations high enough to overcome
2-mediated inhibition and exert ß-mediated
increases of intracellular cAMP levels and IL-6 release.
IL-6 released from adipose tissue has both paracrine and endocrine
effects. It is well recognized that IL-6 has widespread effects on
peripheral carbohydrate and lipid metabolism (4, 5, 6, 28, 29, 30, 31), and additional actions of IL-6 include activation of
the hypothalamic-pituitary-adrenal axis (32, 33, 34, 35, 36),
induction of fever (37), and anorexia (38).
However, the significance of adrenergic-mediated IL-6 release in the
adipocyte may need to be seen in the light of the simultaneous
suppression of leptin secretion that was demonstrated in the in
vivo studies. Interestingly, a negative relationship between
circulating IL-6 and leptin was observed in a study of critically ill
humans (39). We have not addressed the question of a local
effect of IL-6 on leptin release, although in one report IL-6 was
observed to reduce leptin release in 3T3-L1 adipocytes
(40). The adipocyte mechanisms responsible for, and the
implications of, the divergent regulation of leptin and IL-6 remain
unclear, but there may be important consequences, both locally and
systemically, because both cytokines signal through gp130 and the
JAK-STAT system (41, 42). The present studies have not
addressed the mechanism responsible for the divergent effects of
ß-adrenoceptor stimulation in adipocytes, compared with PBC, but
different and ß adrenoceptor profiles resulting in divergent
regulation of cAMP and contrasting effects of cAMP on IL-6 release in
the two cell types are obvious possibilities to be investigated.
In conclusion, ß2/ß3-adrenergic stimulation results in increased IL-6 production both in humans and mice. ß-adrenergic induced secretion of IL-6 was demonstrated in cultured adipocytes but not in PBC, suggesting that adipocytes may be an important source of the adrenergic-mediated increase in circulating IL-6 levels and account for the elevation in plasma IL-6 levels observed in obesity. This response is accompanied by suppression of plasma leptin levels, such that IL-6 and leptin secretion change in a reciprocal manner during acute ß2/ß3-adrenoceptor stimulation. The ß-adrenergic stimulation of IL-6 release from adipose tissue provides a novel mechanism, potentially mediating a range of adrenergic effects on energy balance.
Acknowledgments
Footnotes
This work was supported by the generous assistance of the Wellcome Trust (to J.P.), British Heart Foundation (Grant PG98034), and Jules Thorn Charitable Trust (Grant 97/18A) in various aspects of this project.
Abbreviations: ß1, Dobutamine; ß2, clenbuterol; ß3, CL316243; LPS, lipopolysaccharide; PBC, peripheral blood cells; SNS, sympathetic nervous system.
Received May 21, 2001.
Accepted August 29, 2001.
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on glucose transport in 3T3–L1
cells: lack of cross-talk between tyrosine kinase receptors and
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