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Original Studies |
, in Vivo1
University College London Medical School (V.M.-A., S.G., A.R., D.R.K., J.S.Y., S.W.C.), London, United Kingdom N19 3UA; St. Luke’s Hospital (J.M.M.), Kansas City, Missouri 64111; and Washington University School of Medicine (S.K.), St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Dr. V. Mohamed-Ali, University College London Medical School, G Block Archway Wing, Whittington Hospital, London, United Kingdom N19 3UA.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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(TNF) and interleukin-6 (IL-6) across a sc
adipose tissue bed in the postabsorptive state in 39 subjects [22
women and 17 men; median age, 36 yr (interquartile range, 26–48 yr);
body mass index, 31.8 kg/m2 (range, 22.3- 38.7
kg/m2); percent body fat, 28.7% (range, 17.6–50.7%)]. A
subgroup of 8 subjects had arterio-venous differences measured across
forearm muscle. Thirty subjects were studied from late morning to early
evening; 19 ate a high carbohydrate meal around 1300 h, and 11
continued to fast. We found a greater than 2-fold increase in IL-6
concentrations across the adipose tissue bed [arterial, 2.27 pg/mL
(range, 1.42–3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36–9.62
pg/mL); P < 0.001], but not across forearm
muscle. Arterial plasma concentrations of IL-6 correlated significantly
with body mass index (Spearman’s r = 0.48; P
< 0.01) and percent body fat (Spearman’s r = 0.49;
P < 0.01). Subcutaneous adipose tissue IL-6
production increased by the early evening (1800–1900 h) in both
subjects who had extended their fasting and those who had eaten.
Neither deep forearm nor sc adipose tissue consistently released TNF
[across adipose tissue: arterial, 1.83 pg/mL (range, 1.36–2.34
pg/mL); venous, 1.85 pg/mL (range, 1.44–2.53 pg/mL);
P = NS: across forearm muscle: arterial, 1.22 pg/mL
(range, 0.74–2.76 pg/mL); venous, 0.99 pg/mL (range, 0.69–1.70
pg/mL); P = NS]. Although both IL-6 and TNF are
expressed by adipose tissue, our results show that there are important
differences in their systemic release. TNF is not released by this
sc depot. In contrast, IL-6 is released from the depot and is thereby
able to signal systemically. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Tumor necrosis factor- (TNF) and interleukin-6 (IL-6) are
cytokines with metabolic and/or weight-regulating effects. For both of
these cytokines, messenger ribonucleic acid has been demonstrated in
human adipose tissue, and both proteins are present in adipose tissue
homogenates and culture media (5, 6, 7, 8). TNF induces insulin resistance
by effects on phosphorylation of insulin receptors and the insulin
receptor substrate-1 (9, 10). TNF induces IL-6 messenger ribonucleic
acid production (6). Both TNF and IL-6 inhibit lipoprotein lipase
(LPL) activity and decrease its production in murine adipocyte cell
lines (11, 12) as well as increase lipolysis (13, 14). Such actions
will help to limit obesity (15). TNF and IL-6 cause weight loss in
mice, which is inhibited by pretreatment with either anti-TNF or
anti-IL-6 monoclonal antibodies, respectively (16). It is, however,
debatable as to whether cytokines expressed in adipose tissue can act
as endocrine signals to bring about metabolic effects (17). To date,
there are no data showing in vivo release of these molecules
by human adipose tissue. We, therefore, undertook this study to test
the hypothesis that adipose tissue releases IL-6 and TNF, which
could then act as endocrine mediators.
We used the Fick principle to determine release rates of TNF and
IL-6 from a sc adipose tissue depot, and in a subset of our subjects we
also examined local release by forearm tissue. To determine whether
cytokine release was modified acutely by food, the effects of food and
fasting were also examined.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Arterio-venous differences were measured in 39 healthy Caucasian subjects (22 women and 17 men) studied in the postabsorptive state (after fasting overnight). This group had a median age of 36 yr (interquartile range, 26–48 yr), a body mass index (BMI) of 31.8 kg/m2 (range, 22.3–38.7 kg/m2), a percent body fat of 28.7% (range, 17.63–50.7%), and a total fat mass of 27.8 kg (range, 12.3–56.5 kg). Cannulas were inserted, using local anesthesia, into a radial artery and a superficial epigastric vein draining the sc abdominal adipose tissue (18, 19). A deep antecubital vein (18, 19, 20, 21) was also cannulated in 8 of the leaner male subjects [age, 26 yr (range, 22–34 yr); BMI, 23.8 kg/m2 (range, 21.8–25.6 kg/m2)]; these subjects were chosen with the expectation that their deep forearm tissue would contain less adipose tissue (19). The oxygen saturation in the deep forearm venous samples was less than 60%, implying that deep venous blood was being sampled (20). All lines were kept patent by a slow infusion of isotonic saline. Blood samples were taken simultaneously from the different sites. Previous work has shown that venous blood from superficial epigastric veins approximates the effluent from an adipose tissue bed, and arterio-venous differences across abdominal adipose tissue yield results in good agreement with those of microdialysis studies (22). Deep antecubital vein samples, taken 2 min after inflation of a wrist cuff, approximate the venous effluent of the skeletal muscle.
Body composition was measured by electrical bioimpedance (Biostat, Douglas, UK) and dual photon absorptiometry (Lunar Instruments, Madison, WI) in those subjects in whom forearm cannulas were inserted. The waist/hip ratio was measured using a steel tape.
All subjects gave informed written consent to these studies, which had previously been approved by the local ethics committee.
Blood sampling
Postabsorptive samples were obtained (in duplicate) between 1100–1400 h, corresponding to a overnight fast of 13–15 h. Nineteen subjects [10 women and 9 men; BMI, 33.2 kg/m2 (range, 25.0–46.0 kg/m2); age, 46 yr (range, 27–52 yr)] then ate a high carbohydrate meal (energy content, 50% of estimated 24-h basal metabolic rate of the subject; 70% energy from carbohydrate, 20% from fat, and 10% from protein). Postprandial samples were taken 1, 3, and 5 h after eating. Eleven female subjects [BMI, 34.6 kg/m2 (range, 20.6–36.7 kg/m2); age, 34 yr (range, 24–40 yr)] continued their fast for a similar period. In both fed and prolonged fasted groups, final samples were taken between 1800–1900 h.
To investigate whether drawing samples from indwelling cannulas per se affected cytokine concentrations, samples were drawn by routine venepuncture as well as via a cannula. In 11 different healthy Caucasian volunteer subjects [6 women and 5 men; age, 31 yr (range, 24–36 yr); BMI, 22.4 kg/m2 (range, 21.5–24.1 kg/m2)], samples were taken by routine venepuncture and from a cannula left in the contralateral arm for at least 15 min before sampling.
Blood flow measurements and assays
Abdominal sc adipose tissue blood flow was measured using the 133Xe washout technique, based on the principle that the disappearance of 133Xe radioactivity is proportional to adipose tissue blood flow (23). Blood flow measurements were made twice during the postabsorptive baseline. At the time of each subsequent blood sample, an additional blood flow measurement was made. 133Xe washout was measured using a Mediscint system (24) (Oakfield Instruments, Witney, UK) during the period of baseline sampling and during the postprandial or prolonged fast. Adipose tissue blood flow was calculated as previously described (2, 19), using a partition coefficient of 10 mL/g for all subjects. Forearm blood flow was measured by venous occlusion plethysmography (19, 21) (Hokansen system, P.M.S. Instruments, Maidenhead, UK). Plasma flow was calculated from blood flow and hematocrit.
The plasma glucose concentration was determined with glucose oxidase
reagent (Beckman, Brea, CA). Insulin was assayed specifically using a
commercial kit (Dako Diagnostics, Ely, UK). TNF and IL-6 were
measured using enzyme-linked immunosorbent assays that are specific for
the total amounts (i.e. bound and unbound) of cytokines (R&D
Systems, Oxford, UK). The TNF assay had a limit of detection of 0.10
pg/mL, an intraassay coefficient of variation (CV) of 6.9%, and an
interassay CV of 8.4%. The IL-6 assay had a limit of detection of 0.09
pg/mL, an intraassay CV of 5.3%, and an interassay CV of 9.2%. All
samples from one individual were always run in the same batch.
Calculations and statistics
The local cytokine production by sc adipose tissue was
calculated by the Fick principle (21), i.e. the product of
the arterio-venous difference and local plasma flow. To estimate by
extrapolation the contribution of adipose tissue to systemic turnover
of IL-6, the local secretion rate was multiplied by the total body fat
mass, as reflected by body composition measurement (19, 21). These
calculations assume adipose tissue homogeneity. Although there is
evidence for adipose tissue heterogeneity in general (9), there are no
specific data relating to whether such heterogeneity applies to IL-6
and TNF, so such extrapolations should be interpreted with
caution.
All data are presented as the median (with the interquartile range in parentheses), except in the figures, where means and SEMs are used for simplicity. Comparisons between sites and of trends with time were made using Wilcoxon’s paired tests and ANOVA, respectively (on data normalized by logarithmic transformation as necessary). To determine the relationships between variables, Spearman’s correlation coefficients (rs) were used.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In 39 healthy Caucasian subjects with normal plasma concentrations
of glucose [4.9 mmol/L (range, 4.6–5.2 mmol/L)] and insulin [59.3
pmol/L (range, 30.2–81.2 pmol/L)], postabsorptive concentrations of
IL-6 were significantly higher (P < 0.001) in
abdominal venous samples [6.71 pg/mL (range, 3.36–9.62 pg/mL)] than
in arterial samples [2.27 pg/mL (range, 1.42–3.53 pg/mL); Fig. 1
]. Conversely, arterial and abdominal
venous concentrations of TNF were similar [1.83 pg/mL (range,
1.36–2.34 pg/mL) and 1.85 pg/mL (range, 1.44–2.53 pg/mL),
respectively].
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concentrations (Table 1). Although
glucose and insulin concentrations tended to be higher in the obese
subjects, these variables did not correlate significantly with IL-6
concentrations (data not shown).
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Subcutaneous abdominal adipose tissue IL-6 release in vivo was determined from net arterio-venous balance and local plasma flow and was 3.84 pg/100 g adipose tissue/min (range, 1.86–11.6 pg/100 g adipose tissue/min) for the whole group. Local adipose tissue IL-6 production was greater in subjects with a higher waist/hip ratio (correlation of postabsorptive local IL-6 production rate per 100 g sc adipose tissue with waist/hip ratio; rs = 0.56; P < 0.01).
Concentrations of IL-6 in both arterial and abdominal venous samples
taken during the afternoon and evening (until 1800–1900 h) were
consistently higher (P < 0.01, by ANOVA) than those
taken earlier in the day (1100–1400 h) regardless of whether subjects
had eaten. Blood flows were similar in both groups and did not change
significantly with time, but arterio-venous differences widened in the
afternoon and evening in both groups (see Fig. 2). The local adipose tissue IL-6
production rate increased significantly (P < 0.05 for
both groups) compared to values seen around 1100–1400 h [by 160%
(range, 120–200%) in the fed group and by 140% (range, 110–190%)
in the fasted group]. A secondary reanalysis comparing six women from
the fasted group with six age- and body composition-matched women from
the fed group similarly showed local IL-6 production increasing
significantly in both groups with time, but no significant effect of
eating.
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between the arterial and abdominal samples even after prolonged fasting
or after eating (data not shown). Although in a few subjects, venous
concentrations of TNF were higher than those in arterial blood, the
reverse was true for a similar number. There was no consistent trend to
the TNF arterio-venous difference, with obese individuals no more
likely to show net release than lean subjects. Forearm studies
No significant arterio-venous differences of either TNF or IL-6
were seen across the forearm in eight subjects [arterial TNF, 1.22
pg/mL (range, 0.74–2.76 pg/mL); forearm venous TNF, 0.99 pg/mL
(range, 0.69–1.70 pg/mL); arterial IL-6, 1.87 pg/mL (range, 1.57–2.31
pg/mL); forearm venous IL-6, 2.34 pg/mL (range, 1.28–4.09
pg/mL)].
Levels of TNF and IL-6 did not differ significantly in 11 paired
samples obtained by venepuncture and through an indwelling cannula,
showing the lack of influence of sampling through an indwelling cannula
on these concentrations (data not shown).
Extrapolations of adipose tissue IL-6 production rates
Assuming that the whole body adipose tissue mass (WBFM), as
determined by body composition measurements, released IL-6 at the same
rate as the sc depot studied here, we estimated by extrapolation the
WBFM IL-6 production rate [1.41 ng/min (range, 0.22–2.67 ng/min].
The WBFM IL-6 production rate so calculated correlated with the
circulating IL-6 concentration (rs = 0.63;
P < 0.001), waist/hip ratio (rs = 0.56;
P < 0.01), BMI (rs = 0.41;
P < 0.01), and percent body fat (rs =
0.46; P < 0.01; Fig. 3).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There was no net secretion of TNF by this adipose tissue depot,
suggesting that TNF from sc adipose tissue does not influence LPL
action (11), lipolysis (13), or insulin signaling (9, 10) through
endocrine mechanisms (6, 26). Arterio-venous difference studies cannot
exclude the possibility that TNF acts as an autocrine or paracrine
mediator of insulin resistance (9, 10). Like IL-6, TNF also has a
rapid turnover in plasma (27), and one would expect to see an
arterio-venous difference across a tissue actively releasing
significant amounts of the cytokine. Systemic levels of TNF
correlate with insulin resistance in subjects with cancer and chronic
sepsis (28). TNF antibodies reduce insulin resistance in rodents,
but in a recent study, an infusion of anti-TNF antibodies to
subjects with noninsulin-dependent diabetes mellitus did not change the
insulin sensitivity of either glucose or fat metabolism (28).
Adipose tissue heterogeneity is well recognized (4, 29) and allows the
possibility that other adipose tissue beds may secrete TNF or that
various disease states may induce such release. Our results do not
exclude the possibility that different adipose tissue depots release
different combinations of cytokines; thus, sc tissue may preferentially
release leptin (4) and IL-6, whereas visceral may mainly release
TNF.
Our results show that IL-6 is released by adipose tissue. Adipose tissue release has been shown in vivo for only a few proteins, such as LPL (30), adipsin (31), and leptin (2). IL-6 is thus only the second protein "hormone" reported to be released by human sc adipose tissue.
The release of IL-6 into the systemic circulation and the fact that
this release is greater in obese subjects support a possible novel role
for IL-6 as a systemic regulator of body weight (an adipostat) and a
regulator of lipid metabolism. Our results for IL-6 show similarities
with findings for leptin (2, 32), with a clear net release of both
molecules that increases with adiposity. To act as an adipostat, a
molecule should be released by adipose tissue and be capable of
bringing about metabolic changes so as to restore energy balance,
either via the hypothalamus or by effects on other tissues. Evidence
suggests that IL-6 satisfies these criteria. Firstly, IL-6 is expressed
by 3T3 L1 cells, pericardial fat pads, and mammary adipose tissue (6, 8, 33). We now show IL-6 release by adipose tissue, although the cell
type of origin cannot be determined by tissue arterio-venous balance
studies. Secondly, IL-6 reduces LPL activity both in vitro
and in vivo (11, 12), which may down-regulate adipose tissue
triglyceride deposition and promote futile cycling. Thirdly, IL-6
stimulates thermogenesis and satiety via the synthesis of PGs and
corticotropin-releasing factor (34), perhaps contributing to the
control of obesity. IL-6 receptors are present in the hypothalamus
(35), which also supports the proposal that this cytokine has direct
central actions. Fourthly, IL-6 modulates the action of aromatase, a
key regulatory enzyme for estrogen metabolism (8); estrogens have long
been recognized as influencing satiety and adipose tissue distribution.
Finally, there are several potential mechanisms for the interaction
between leptin and cytokine signals. TNF modulates the synthesis of
both leptin (36, 37) and IL-6 (6, 8). The leptin receptor shares
homology with the gp130 signal-transducing component of the IL-6
receptor (38). This might allow IL-6 to modulate the actions of leptin,
a molecule that is produced by adipocytes (39), binds to hypothalamic
receptors, and regulates energy balance by causing changes in food
intake, physical activity, and thermogenesis (40).
We conclude that adipose tissue releases large amounts of IL-6 in vivo. IL-6 appears able to mediate several weight-regulating processes. IL-6 adipose tissue production and systemic concentrations increase with adiposity. Adipose tissue production of IL-6 is greater in the evening than around noon regardless of whether subjects eat a high carbohydrate meal [in contrast to leptin (32)]. It is attractive to speculate that IL-6 and leptin could act synergistically to maintain adipose tissue energy equilibrium. Thus, IL-6, previously considered a proinflammatory cytokine with the ability to induce the full acute phase response, may also have a housekeeping role in lipid metabolism.
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Footnotes |
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Received May 30, 1997.
Revised August 19, 1997.
Accepted August 21, 1997.
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