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Original Studies |
Developmental Endocrinology Branch (Z.O., G.P.C.), National Institute of Child Health and Human Development (NICHD), Bethesda, Maryland 20892; Clinical Pathology Department (A.T.R., M.S.), National Institutes of Health, Bethesda, Maryland 20892; and Institute of Biomedical Engineering (Z.T.), Graz University of Technology, 8010 Graz, Austria
Address all correspondence and requests for reprints to: Zsolt Orban, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Building 10, Room 10N262, 10 Center Drive, Bethesda, Maryland 20892-1862. E-mail: orbanz{at}cc1.nichd.nih.gov
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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(TNF), or interleukin-6 (IL-6) by serially sampling sc abdominal
adipose interstitial fluid by open-flow microperfusion before and after
a standardized meal and in response to isoproterenol (1 µmol/L)
delivered locally. Post cibum IL-6 rose up to 5-fold,
whereas leptin and TNF secretion did not change; TNF, but not
IL-6, correlated positively with indices of lipolysis.
Isoproterenol-induced lipolysis was accompanied by a transient 40%
reduction in leptin and a parallel 85% elevation of TNF
concentration, whereas IL-6 levels did not change; again, TNF
correlated positively with lipolysis. These data show that secretion of
some, but not all, metabolically relevant polypeptides by adipose
tissue is modulated within a short time frame by food or stress
stimuli, suggesting a role of these peptides in local
autocrine/paracrine or distant endocrine effects on fat metabolism.
TNF’s close correlation with lipolysis suggests that this cytokine
participates in a local positive autocrine feedback loop, potentiating
lipolysis and inhibiting insulin’s antilipolytic actions. The
regulations of adipose leptin, TNF, and IL-6 secretion seem distinct
from each other and different in the fed vs. fasting
state. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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(TNF), and interleukin-6 (IL-6) are produced and
secreted by fat tissue (4, 5, 6). Leptin administration decreases food
intake and induces weight loss via activation of the
sympathetic nervous system and causes a decrease in fat cell size,
depletion of triglyceride stores, and inhibition of preadipocyte
differentiation (7). The hypothalamus coordinates most of these actions
through distinct pathways by modulating behavioral patterns, autonomic
outflows, and the metabolic rate (8). Systemic actions of leptin are
accompanied by local effects directing energy balance away from energy
storage via down-regulation of adipocyte acetyl-CoA
carboxylase and LPL activity (9) and up-regulation of hormone-sensitive
lipase (10). Adipose expression of TNF correlates with adipocyte
volume and is elevated in overweight individuals. TNF reduces GLUT4
expression (11), suppresses LPL activity (12), potentiates hepatic VLDL
synthesis (13), and induces insulin resistance (14). This latter
contributes to the impairment in glucose homeostasis that usually
accompanies obesity. Not much is known about the function of IL-6 in
adipose, but similarly to TNF and leptin, this cytokine inhibits LPL
activity (15). Moreover, several potential mechanisms may explain an
interaction between tissue leptin and these cytokines. TNF inhibits
leptin synthesis (2), whereas IL-6 may inhibit TNF and might
modulate leptin’s actions via the leptin receptor, given
the homology of this receptor with the gp130 signal-transducing
component of the IL-6 receptor (16, 17, 18).
The innervation of adipose tissue also has an impact on its metabolic
activity (19), and disturbances of the autonomic nervous system seem to
be involved in the development of obesity in experimental animals and
man (20). Catecholamines increase triglyceride hydrolysis in various
adipose compartments, activate the expression of mitochondrial
uncoupling proteins, and inhibit adipocyte proliferation (21). Negative
energy balance leads to lipolysis, along with reductions in plasma
leptin, whereas feeding leads to opposite changes. This relation
between lipolysis and adipocyte signaling, at times of insufficient or
abundant energy availability, suggests that certain factors may
simultaneously regulate lipolysis and adipocyte secretion of various
hormones. Moreover, the fact that circulating levels and tissue
expression of leptin, TNF, and IL-6 correlate with fat mass (22, 23)
raises the possibility that these or other, yet to be described,
fat-derived peptides may function as humoral signals of energy stores.
We tested the hypotheses that episodic food intake or ß-adrenergic
stimulation during fasting acutely modulate adipose secretion of
leptin, TNF, and IL-6 by measuring interstitial levels of these
peptides in abdominal sc fat in humans in response to a meal and local
administration of isoproterenol, a nonselective ß-adrenergic
agonist.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The physical characteristics and metabolic parameters of the
study participants are summarized in Table 1
. Twelve healthy normal volunteers took
part in either of the two study protocols (below). Six subjects
participated in both and were studied at separate times at least 3
weeks apart. No subjects were on medications, and all had a normal
physical examination, fasting glucose, cholesterol, and triglyceride
levels, as well as normal thyroid, liver, and kidney function. The
study was approved by the NICHD Institutional Review Board, and each
subject gave informed consent. Studies were carried out in the morning,
after an overnight fast, in the supine position. Adipose interstitial
fluid was sampled serially (see below), and blood was drawn hourly
through an indwelling iv cannula for measurements of glucose, insulin,
leptin, free fatty acid (FFA), and triglycerides.
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Subcutaneous abdominal adipose tissue interstitial fluid was sampled with open-flow microperfusion, a method that allows direct monitoring of macromolecules in the extracellular space of various tissues. The technique has been validated and recently described in detail (24). Briefly, microperfusion probes were prepared from a conventional 18-gauge Angiocath, by the creation of 120 perforations (diameter, 0.4 mm) along a 3-cm length of the cannula. This fenestration allows solutes, as well as macromolecules, in the interstitial fluid compartment adjacent to the probe, to equilibrate along a concentration gradient with the fluid inside the probe. Such a technique, therefore, makes it possible to determine changes in concentrations of various hormones and metabolites in the tissue of interest, as well as to deliver substances (drugs, metabolites, and others) locally to the tissue bed. This latter feature can be explored in situations where the goal is to determine the direct effects of a particular intervention and where such an intervention systemically would disturb various homeostatic systems. The probe was inserted into the sc adipose tissue, 8–10 cm lateral to the umbilicus, and held in place for 6 h. The inner cannula of the system was attached to a plastic reservoir containing artificial extracellular fluid (135 mmol/L NaCl, 3 mmol/L KCl, 1 mmol/L MgCl2, 1.2 mmol/L CaCl2, 0.2 mmol/L ascorbic acid, and 2 mmol/L Na-phosphate, pH 7.4). A peristaltic pump (Minipuls, Gilson Inc., Middletown, WI) was used to achieve a constant flow of approximately 2 µL/min. Before the perfusion was started, 0.5 mL of perfusion fluid was circulated through the system via negative pressure applied through the outflow tubing, to remove tissue debris that would impede free movement of fluid. Fraction collection was started after 60 min of equilibration. This period of time was chosen because several investigators found 30–60 min to be optimal for restoration of the physiologic milieu and equilibration between fluid compartments after placement of sc microdialysis probes into adipose tissue (25). Fractions were collected on ice every 30 min.
Protocol 1
To determine whether food intake results in altered dynamics of
in situ secretion of leptin, TNF, or IL-6 in the fat, we
sampled adipose interstitial fluid before and after a meal. Subjects
(n = 8) were fasting after midnight and during the first 2 h
of the study. Subsequently, a meal was consumed (Boost Plus,
Mead Johnson & Company, Evansville, IN), the calorie content of
which was calculated to be one third of the individual’s daily
requirements (10 kcal/kg BW). The liquid supplement we used is
nutritionally balanced; protein, fat, and carbohydrates provide 16%,
34%, and 50%, respectively, of the total calories. Therefore, the
physiologic responses from ingestion of the formula should be
representative of those after a typical meal. Adipose interstitial
fluid was sampled for 4 h postprandially (Fig. 1A). Leptin and total protein were
measured in each 30-min specimen. Subsequently, equal volumes of the
remainder of the samples collected during the hour preceding, and the
first and second 2-h period after, meal ingestion were pooled; and
concentrations of TNF, IL-6, glycerol, FFA, and protein were
measured (baseline, early postprandial, and late postprandial
fractions).
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To describe whether ß-adrenergic stimulation exerts acute
effects on adipose secretion of leptin, TNF, or IL-6, we measured
in situ levels of these peptides, as well as those of
glycerol, FFA, and protein, in response to local administration of
isoproterenol after an overnight fast. Microperfusion was carried out
simultaneously at two adjacent sites (5 cm apart). The perfusion
solution contained 1 µmol/L isoproterenol at one site, and perfusates
obtained from the other site were used as control (Fig. 1B
). Subjects
(n = 10) were fasting throughout the procedure. Leptin and total
protein were determined in each specimen. The remainder of the samples
collected during the first and second 2.5 h of the study were
pooled (61–210 and 211–360 min after start); and concentrations of
TNF, IL-6, glycerol, FFA, and protein were measured
(fractions 1 and 2).
Hormone and metabolic assays
Microperfusate analytes. Each sample was
spectrophotometrically screened for hemoglobin before analysis, to
exclude the possibility of blood contamination. Leptin, TNF, and
IL-6 were measured with sensitive enzyme-linked immunosorbent assays
(R&D Systems, Minneapolis, MN) that have a sensitivity of 15 pg/mL, 0.5
pg/mL, and 0.156 pg/mL, respectively. Incomplete equilibration and
slight changes in the perfusion rate are inherent to any perfusion
technique and may result in alterations of perfusate analyte
concentrations, so that they may not accurately reflect true
interstitial levels. To decrease the possibility of such variability,
microperfusate hormone levels were corrected for the protein
concentration in the same specimen and were expressed in nanograms per
milligram of protein. Microperfusion glycerol, FFA, and protein
measurements were performed on a Cobas Fara centrifugal analyzer (Roche
Diagnostics Systems, Montclair, NJ). For measurements of glycerol, an
enzyme-based assay kit for triglyceride (Boehringer Mannheim, Indianapolis, IN) was modified by deleting the lipase
reagent and increasing the sample vol to 85 µL. FFAs were determined
with an enzymatic method (Wako Chemicals, Richmond, VA). Total
protein was measured by the bicinchoninic method (Pierce Chemical Co., Rockford, IL), and microperfusion glycerol and FFA
concentrations were also corrected for protein. A few individual
specimens, with a protein concentration more than double or less than
half of that of neighboring samples, were excluded. Determination of
glycerol, FFA, and protein in all pooled specimens derived from the two
protocols were performed in one batch and separately.
Plasma analytes. Serum glucose and triglycerides were determined enzymatically on a Hitachi 917 chemistry analyzer (Boehringer Mannheim). Serum insulin was measured using a microparticle enzyme immunoassay (Abbott Laboratories, Abbott Park, IL). Unesterified fatty acids were analyzed by an enzyme-based kit (Wako Chemicals). Serum leptin was determined with the Human Leptin Quantikine kit (R&D Systems).
Statistical analysis
Data are shown as the mean ± SE.
Microperfusate concentrations of analytes measured in the first
protocol, pre- and postprandially and in response to isoproterenol
vs. control in the second protocol, were compared with
ANOVA. Single linear correlation was used to detect the relationship
between perfusate glycerol, FFA, and TNF levels. Systemic variables
(plasma glucose, insulin, triglycerides, FFA, and leptin) at the
various time-points were compared with baseline values, with ANOVA.
Significance was assumed at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Administration of a meal resulted in expected elevations in plasma
glucose and insulin, whereas FFA levels declined, and leptin and
triglycerides did not change (Fig. 2A).
Microperfusate glycerol, FFA, leptin, and TNF did not change during
the 4 h postprandial period (Fig. 2B and Table 2). In contrast, IL-6 levels were
878 ± 289 ng/mg and 1240 ± 471 ng/mg in the early and late
postprandial fractions, which represent a 3.6- and 5.1-fold elevation,
compared with the preprandial baseline (245 ± 119 ng/mg,
P < 0.01). Microperfusate glycerol and FFA levels
correlated positively to each other (Fig. 2C). We also observed a
significant correlation between these two indices of lipolysis and
TNF (Fig. 2C). Microperfusate IL-6 did not correlate with either of
these measures (data not shown).
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Plasma levels of glucose, FFA, triglycerides, and leptin (measured
hourly during the study) were unchanged, compared with baseline;
whereas those of insulin did show some decline (Fig. 3A). Microperfusate
glycerol and FFA levels in fractions 1 and 2 were 70.4 ± 10 and
78.7 ± 15 mmol/L·mg, and 65 ± 3 and 70 ± 11
mmol/L·mg, respectively (Fig. 3B and Table 3). Local administration
of isoproterenol resulted in increases in glycerol (201 ± 44 and
187 ± 35 mmol/L·mg in fractions 1 and 2, P =
0.02 for both). Similar, albeit proportionately smaller, increases were
observed with FFA [91 ± 7 mmol/L·mg in fraction 1
(P = 0.01) and 99 ± 8 mmol/L·mg in fraction 2
(P = 0.045)]. Glycerol and FFA levels, measured in the
same specimen, correlated well in the control samples, less in the
samples containing isoproterenol (data not shown). Isoproterenol
resulted in a 41% reduction in leptin during the first 90 min
(0.46 ± 0.07 ng/mg vs 0.78 ± 0.1 ng/mg,
P < 0.05), but this suppression gradually diminished;
so that after 150 min, leptin levels were identical at the two sites
(0.57 ± 0.09 ng/mg vs 0.6 ± 0.13 ng/mg,
respectively). TNF levels were 4.3 ± 0.4 and 6.0 ± 0.8
ng/mg in fractions 1 and 2 (Fig. 3B). Isoproterenol resulted in an 85%
increase in TNF in fraction 1 (7.9 ± 1.3 ng/mg,
P < 0.05), and this increase was blunted to 50% in
fraction 2 (9 ± 1.2 ng/mg, P = 0.07). IL-6 in
fraction 1 was 258 ± 81 ng/mg and increased to 599 ± 103
ng/mg in fraction 2 (P = 0.02). Isoproterenol did not
produce changes in the levels of this cytokine [378 ± 108 and
695 ± 123 ng/mg, respectively, in fractions 1 and 2;
P = not significant (NS)]. The induction of lipolysis
by isoproterenol did not abolish the positive correlation among
glycerol, FFA, and TNF (Fig. 3C).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Experimental evidence also suggests that leptin secretion may serve as
a short-term physiologic regulator of certain metabolic processes, at
least in rodents (27). Calorie availability results in a transient
increase of carbon flux through the nutrient-sensing hexosamine
biosynthetic pathway, leading to accumulation of uridine
5'-diphosphate-N-acetylglucosamine in muscle and fat. This,
in turn, elicits marked increases in leptin messenger RNA and protein
expression in these tissues within a short time frame (28). We did not
observe increases in either in situ or plasma leptin in the
immediate postprandial period in our volunteers. Concordant with our
findings are observations by others that failed to detect food-mediated
up-regulation of leptin expression or secretion in the short-term
(within hours) in man (29, 30). In contrast, definite long-term
elevations in systemic leptin, TNF, and IL-6 levels are seen in
obesity and insulin-resistant states. Such increases are postulated to
serve as a behavioral or metabolic brake; they curb subsequent calorie
intake and prevent further storage of energy in the form of
triglycerides. Thus, the picture that emerges from these and other
human studies is that, although increased leptin is an important
homeostatic response to overall energy surplus, the augmented synthesis
of this adipocyte product takes several days to occur; therefore, it is
unlikely that acute leptin secretion participates to an appreciable
extent in the acute feedback regulation of energy homeostasis in man.
Given the permissive effects of leptin on the
hypothalamic-pituitary-gonadal axis and the sympathetic system, and the
fact that ingestion of an average meal is not coupled to immediate
suppression of leptin, may, in fact, allow better adaptation of the
individual to his or her environment and, thus, represent a survival
benefit. Thus, fasting-induced hypoleptinemia requires prolonged
positive energy balance to be reversed, allowing maintenance of
sustained arousal and food-seeking behavior to secure nutrient
stores.
Our findings that food-induced alterations in the
hormo-nal-metabolic environment do not lead to acute increases in
TNF secretion are also concordant with those of Santos et
al., who observed no changes in systemic TNF levels after
several days of feeding (31).
Circulating FFAs may have a central role in the induction of insulin
resistance, whereas insulin resistance leads to elevation of
circulating FFA levels (32). TNF itself induces tissue resistance to
insulin’s actions, and a polymorphism of the TNF gene leading to
increased tissue expression of this cytokine has been associated with
obesity (33). It is possible that part of the resistance to insulin’s
actions, in conditions such as obesity or type 2 diabetes, can be
attributed to inappropriately increased rates of local TNF secretion
and/or lipolysis. Our observation that TNF secretion in
situ correlated with indices of local lipolysis in both the fed
and fasting states, and even when the latter was stimulated by a ß-
adrenergic agonist, suggests that these two functions of adipose
tissue are tightly linked to each other and have the same ultimate
physiologic purpose, i.e. provision of FFAs to the systemic
circulation and, hence, increased FFA uptake and use by peripheral
tissues.
The metabolic effects of IL-6 are complex and have not been extensively
studied. IL-6 in the adipose tissue is produced, in part, by fat cells
and, in part, by the stromal-vascular cells, fibroblasts, and
endothelial cells contained in the tissue bed (6). Regardless of the
cellular source, there is evidence, from arterio-venous difference
studies, that sc adipose tissue releases IL-6 (34). Indeed, the
gradient between venous effluent and arterial IL-6 concentration far
exceeds that for TNF-. IL-6 induces physiologic changes reminiscent
of the catabolic state, which include increased resting energy
expenditure, increases in plasma FFA and fat oxidation, and increased
metabolic clearance of glucose (35). Detection of a clear relation
between IL-6 and prandial status has been hampered by the fact that
circulating IL-6 levels are very low, sometimes below the limit of
detection [(36) and unpublished observations]. Surprisingly, we found
that adipose microperfusate IL-6 levels are orders of magnitude higher
than those in plasma (data not shown), and these concentrations are
within a range expected to have biological sequelae. Furthermore, the
fact that in situ IL-6 rose 5-fold post cibum
also indicates that this cytokine may have a paracrine role in the
modulation of physiologic responses at the tissue level, and supports a
possible novel role for IL-6 in lipid metabolism and as a regulator of
body weight. The absence of significant changes in glycerol and FFA
levels precludes postprandial suppression of lipolysis being
responsible for such an increase. IL-6 might also have a suppressive
effect in situ on leptin and TNF secretion (37, 38);
thus, the absence of postprandial increases of these peptides may, at
least partly, be related to the rise in IL-6.
White adipose tissue is innervated by a chain of functionally connected autonomic neurons, and this innervation affects its metabolic activity (39, 40, 41). Fat cells possess adrenergic receptors, which stimulate lipolysis and adipocyte differentiation, activate the expression of mitochondrial uncoupling proteins, and inhibit adipocyte proliferation (19). Disturbance of the autonomic nervous system seems to be essential for the development of obesity in both animals and humans (42), because it results in impaired net release of FFA and glycerol from the adipose tissue. Lipolysis takes place in metabolic conditions that are associated with increases in sympathetic outflow, including stress, exercise, acute fasting, and uncontrolled diabetes. It is commonly held that supraphysiologic fat accumulation is primarily the result of impaired lipolysis. In rodents, obesity is associated with decreases in the expression of the ß3- and ß1-adrenoreceptors (43), and treatment with selective adrenergic agonists reverses diet-induced obesity (via increased lipolysis) and normalizes leptin gene expression (44, 45).
We found that ß-adrenergic stimulation suppressed adipose leptin
secretion, albeit transiently. Our observations are in line with those
of Pinkney et al., who described decreases in systemic
leptin levels as a response of iv isoproterenol administration (46). We
observed eventual disappearance of leptin suppression within hours. Our
findings, as well as those of others, suggest that the sc adipose
tissue develops tolerance to continuous adrenergic stimulation (47, 48). Isoproterenol did not result in significant changes in IL-6 in the
adipose tissue, which we would have expected in the light of earlier
work that demonstrated increases in IL-6 levels as a result of
sympathetic activation (49). Several factors may have contributed to
this apparent discrepancy. First, the isoproterenol-induced short-term
modulation of leptin, TNF, glycerol, or FFA may have abrogated the
effect of ß-adrenergic stimulation itself on IL-6 secretion. Second,
it is possible that ß-adrenergic stimulation of adipose IL-6 is
confined to severe stress, and IL-6 may not participate in the
regulation of adipose functions as a result of short-term physiologic
changes in the local catecholaminergic tone. Third, regional
heterogeneity may exist, with regard to the responsiveness of IL-6
secretion to ß-adrenergic stimulation.
Isoproterenol induced a marked increase in TNF secretion. Whether
lipolysis, along with such decreases in leptin and increases in TNF
secretion, occurs to a similar extent as a result of increases in
regional adrenergic regulation in situations such as starvation or
stress, is not known. We suggest that these changes represent a
physiologic adaptive mechanism to these metabolic challenges at the
tissue level, the autocrine consequences of which include decreased LPL
activity, insulin resistance, and increased lipolysis. These, in turn,
result in enhanced mobilization of stored triglycerides, as would be
expected at times of need for readily available energy substrates. Our
observation that adrenergic-receptor-mediated lipolysis is coupled to
TNF secretion, underscores the role of the autonomic sympathetic
nervous system in the regulation of adipose sensitivity to insulin and
lipid metabolism (50).
Received February 17, 1999.
Accepted March 1, 1999.
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V. Mohamed-Ali, L. Flower, J. Sethi, G. Hotamisligil, R. Gray, S. E. Humphries, D. A. York, and J. Pinkney {beta}-Adrenergic Regulation of IL-6 Release from Adipose Tissue: In Vivo and in Vitro Studies J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5864 - 5869. [Abstract] [Full Text] [PDF]
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