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Tumor Necrosis Factor- Modulates Human in Vivo Lipolysis

The Centre of Inflammation and Metabolism at Department of Infectious Diseases Rigshospitalet (P.P., C.P.F., T.I., B.K.P, G.v.H.), Faculty of Health Sciences, and Department of Biomedical Sciences (G.v.H.), University of Copenhagen, 2100 Copenhagen, Denmark; and Copenhagen Muscle Research Centre (P.P., C.P.F., T.I., G.v.H.), Rigshospitalet, 2400 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Peter Plomgaard, Centre of Inflammation and Metabolism, Department of Infectious Diseases, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. E-mail: plomgaard{at}dadlnet.dk.

	Abstract

Top Abstract Introduction Subjects and Materials Results Discussion References

 
Context: Low-grade systemic inflammation is a feature of most lifestyle-related chronic diseases. Enhanced TNF- concentrations have been implicated in the development of hyperlipidemia.

Objective: We hypothesized that an acute elevation of TNF- in plasma would cause an increase in lipolysis, increasing circulatory free fatty acid (FFA) levels.

Subjects and Methods: Using a randomized controlled, crossover design, healthy young male individuals (n = 10) received recombinant human (rh) TNF- (700 ng/m^–2·h^–1) for 4 h, and energy metabolism was evaluated using a combination of tracer dilution methodology and arterial-venous differences over the leg.

Results: Plasma TNF- levels increased from 0.7 ± 0.04 to 16.7 ± 1.8 pg/ml, and plasma IL-6 increased from 1.0 ± 0.2 to 9.2 ± 1.0 pg/ml (P < 0.05) after 4-h rhTNF- infusion. Here, we demonstrate that 4-h rhTNF- infusion increases whole body lipolysis by 40% (P < 0.05) with a concomitant increase in FFA clearance, with no changes in skeletal muscle FFA uptake, release, or oxidation. Of note, systemic glucose turnover and lactate and catecholamine levels were unaffected by rhTNF- infusion.

Conclusion: This study demonstrates that a relatively low dose of rhTNF- induces systemic lipolysis and that the skeletal muscle fat metabolism is unaffected.

	Introduction

Top Abstract Introduction Subjects and Materials Results Discussion References

 
Accumulating data in the literature suggest that cytokines may have profound metabolic effects, with regard to both glucose and lipid metabolism. Most studies have focused on the effects of TNF- and IL-6. Elevated circulating levels of these cytokines accompany a number of chronic disorders, including type 2 diabetes (1) and ischemic heart disease (2). High levels of IL-6 and TNF- in patients with the metabolic syndrome are associated with truncal fat mass (3), and both TNF- and IL-6 are produced in adipose tissue (4, 5), however, these studies are of epidemiological nature and cannot establish causality.

A number of studies have demonstrated that IL-6 enhances lipolysis (6, 7). In addition, it has been shown that IL-6 enhances lipid oxidation in vitro (7), ex vivo (8), and in vivo (7, 9), furthermore, that the IL-6-mediated phosphorylation of acetyl-coenzyme A carboxylase and subsequent palmitate oxidation is AMP-activated protein kinase dependent (10). In accordance, Wallenius et al. (11) demonstrated that IL-6-deficient mice developed mature-onset obesity and insulin resistance. In addition, when the mice were treated with IL-6, there was a significant decrease in body fat mass in the IL-6 knockout but not in the wild-type mice. To determine further whether IL-6 affected lipid metabolism, physiological concentrations of recombinant human (rh) IL-6 have been administered to healthy young and elderly humans, as well as patients with type 2 diabetes (7, 9). These studies identified IL-6 as a modulator of fat metabolism in humans, increasing lipolysis and fat oxidation without causing hypertriacylglycerolemia.

TNF- increases lipolysis in human (12, 13), rat (14, 15, 16), and mouse (3T3-L1) (17, 18) adipocytes. Moreover, isolated rat soleus muscle incubated with TNF- did not change fatty acid oxidation, but it increased fatty acid incorporation into diacylglycerol, which may be involved in the development of TNF- -induced insulin resistance in skeletal muscle (8). Extrapolation from the results of animal studies to humans is especially difficult in inflammation research because humans are far more sensitive to endotoxins than rodents (19). In addition, many cell culture studies of supraphysiological concentrations of cytokines may generate results, which is of little importance in human physiology. A recent clinical trial demonstrated that anti-TNF- treatment increased high-density lipoprotein without influencing low-density lipoprotein, which suggests that TNF- is involved in the development of a risk lipid profile (20). In contrast, IL-6 blocker treatment induces increased levels of both high-density and low-density lipoprotein (21). Interestingly, direct evidence exists that TNF- induces peripheral insulin resistance in humans in vivo (22), whereas IL-6 does not (10, 23). However, in humans information is lacking of the effect of moderately elevated TNF- levels on systemic and skeletal muscle in vivo lipid metabolism. Therefore, the aim of the present study was to investigate the role of low-dose rhTNF- infusion, mimicking TNF- concentrations of relevance for chronic diseases and acute infections, on systemic and skeletal muscle lipid metabolism in healthy individuals.

We hypothesized that TNF- would increase the release of fatty acids into the circulation, whereas TNF- would have little effect on muscle lipid metabolism.

	Subjects and Materials

Top Abstract Introduction Subjects and Materials Results Discussion References

 
Subjects

There were 10 male Caucasian subjects who participated in the study. Volunteers were aged 26 ± 1.3 yr (mean ± SE), weighed 73.9 ± 2.2 kg, and had a body mass index of 22.6 ± 0.6 kg/m². They underwent a medical examination and a standard set of blood analysis, which all were normal. The subjects were normally physically active without participating in any competitive sports. They were informed about the risks and discomfort associated with the experimental protocol both orally and in writing. The protocol was approved by the Municipal Ethical Committee for Copenhagen and Frederiksberg (KF: 01–215/04), and was in accordance with the Declaration of Helsinki.

Protocol

The subjects came to the laboratory on 2 d separated by at least 1 wk, where they either received the rhTNF- (Beromun) 700 ng/m^–2·h^–1 (Boeringer-Ingelheim, Biberach an der Riss, Germany) or albumin 20%, which was the vehicle for rhTNF- infusion. The subjects reported to the laboratory at 0700 h after an overnight fast. A catheter was inserted into the femoral vein and artery under local anesthetics; furthermore, a catheter was inserted into the antebrachial vein for infusion of stable isotope-labeled tracers. A deuterium-labeled glucose tracer [6,6-²H₂]glucose (Cambridge Isotopes, Andover, MA) and [U-¹³C₁₆]palmitate (Cambridge Isotopes) tracers were infused. The tracer infusion rates were 0.4 µmol/kg·min (prime 17.6 µmol/kg) for [6,6-²H₂]glucose and 0.015 µmol/kg·min for [U-¹³C₁₆]palmitate, and to determine palmitate oxidation rate, a prime of 1.5 µmol/kg NaH¹³CO₃ was administered. The tracer infusion was commenced 2 h before the infusion of rhTNF-. After 2-h infusion of tracers, three basal samples were obtained with intervals of 10 min. rhTNF- was infused for 4 h, and blood was drawn from the arterial and venous catheter every 30 min. Two hundred microliters of blood were analyzed immediately for hematocrit, hemoglobin, pH, oxygen saturation and O₂, and CO₂ tension on an ABL 700 (Radiometer, Copenhagen, Denmark). Leg blood flow was measured using Doppler ultrasonography (model CFM 800; Vingmed Sound, Horten, Norway) as previously described (24).

Plasma analysis

Plasma concentrations were determined for palmitate, free fatty acids (FFAs), lactate, and glucose as previously described (25). Furthermore, plasma concentrations of TNF- and IL-6 were assessed by ELISA (R&D Systems, Inc., Minneapolis, MN). Samples were run in duplicates, and the intraassay coefficient of variation (CV) was 8.8 and 6.9% for TNF- and IL-6, respectively. Insulin was measured using ELISA (Dako, Glostrup, Denmark), and samples were run in duplicates with CV at 7.5%. Epinephrine and norepinephrine were measured using 2 CAT EIA (Labor Diagnostika Nord GmbH & Co. KG, Nordhorn, Germany), CV at 13.9 and 4.0%, respectively.

Tracer analyses

Palmitate Plasma [U-¹³C₁₆]palmitate was analyzed as described previously (26). The methylated palmitate concentration was measured by gas chromatography (Autosystem XL; PerkinElmer, Waltham, MA), and plasma [¹³C₁₆]palmitate enrichment was measured by gas chromatograph-combustion isotope ratio mass spectrometry (GC-C-IRMS; Hewlett Packard 5890 Finnigan GC combustion III, Finnigan ^plus; Finnigan MAT, Bremen, Germany).

Blood CO₂ For the determination of blood CO₂ enrichment, 0.5 ml of 2.5 M phosphoric acid was added to 0.5 ml blood in a 10-ml Vacutainer (BD, Franklin Lakes, NJ) to release CO₂. The tubes were brought to pressure with pure helium. The ¹³C to ¹²C ratio was determined by split injection (ratio 1:10) of 20 µl of the headspace on the GC-IRMS Finnigan ^plus (26).

Glucose The plasma glucose enrichment was measured as previously described (22). The tracer to tracee ratio of the benzoylated glucose derivative was measured using a liquid chromatograph mass spectrometer (aQa-Finnigan, Manchester, UK) equipped with a C-18 column (Phenomenex, Luna 3µ C18 100Å, 50 x 1.0 mm; Allerod, Denmark), and the benzoylated glucose was introduced into the mass spectrometer via electrospray ionization. Enrichment was calculated by measuring the area under the curve for the M and M+2 peak.

Calculations

Whole body palmitate and glucose turnover was calculated using a nonsteady-state method as described by Steele (27):

and

Where R_a is the rate of appearance, R_d is the rate of disappearance, F is the infusion rate of tracer, pV is the volume of distribution of the tracee, C is the concentration of tracee, E is the enrichment of tracer, and t designates time in minutes.

Leg net uptake was calculated as: net uptake = (C_a – C_v) x plasma/blood flow. Where C_a and C_v are the concentration in the artery and vein, respectively. To calculate the net leg uptake of palmitate and glucose, the plasma and blood flows have been used, respectively. The leg palmitate uptake was calculated as: uptake = fractional extraction x C_a x plasma flow. Where fractional extraction is:

The leg palmitate release was calculated as: release = uptake – net balance. Palmitate oxidation was calculated as:

% palmitate uptake oxidized =

where C_v,CO2 and C_a,CO2 are the venous and arterial concentration of CO₂, respectively, and E_v,_CO2 and E_a,CO2 are the enrichment of venous and arterial CO₂, respectively. C_a and C_v are the concentration of palmitate in the artery and vein, respectively, and E_a and E_v the arterial and venous palmitate enrichments. Finally, a_c is the acetate correction factor during rest, as determined by van Hall et al. (28).

Statistics

Data are generally presented as mean ± SE. If data were not normally distributed, a log transformation was performed and geometric ± SE presented. Age, weight, body mass index, net uptake of glucose and palmitate were normally distributed. To evaluate the effect of time and treatment, a mixed model was applied using the SAS software version 9.1, (SAS Institute, Cary, NC). If a significant effect of time was detected, the effect of time was assessed for each group separately using the proc mixed procedure. As a post hoc test, the false discovery rate was calculated (29) to estimate where the significant differences were located; P < 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Materials Results Discussion References

 
Plasma cytokines and hormones

During rhTNF- infusion, the level of TNF- was elevated from 0.7 ± 0.04 pg/ml to a level of approximately 16.7 ± 1.8 pg/ml (P < 0.05). TNF- level was unchanged in the control study (Fig. 1A). The plasma IL-6 concentration reached a level of 9.2 ± 1.0 pg/ml (P < 0.05) after 4-h rhTNF- infusion (Fig. 1B). The plasma insulin concentration slightly decreased during rhTNF- infusion, albeit only different from the control trial at time point 1 h. Epinephrine and norepinephrine did not change (Table 1) in both trials.

View larger version (11K): [in this window] [in a new window]   FIG. 1. Plasma cytokine concentrations presented as geometric means ± SEM. Open bars represent the control trial and closed bars the rhTNF- trial. The TNF- infusion was commenced after obtaining the "0" sample and continued during 4 h. A, TNF- plasma concentration. B, Plasma concentration of IL-6. $, Difference (P < 0.05) between trials. *, Difference (P < 0.05) from time point zero.

View this table: [in this window] [in a new window]   TABLE 1. Metabolites during the TNF- infusion compared with the placebo

The plasma palmitate concentration was increased during the last hour of rhTNF- infusion compared with pre-infusion. However, no difference was observed between the control and rhTNF- trial (Fig. 2A). Systemic palmitate turnover was increased by infusion of rhTNF-. The R_a increased after 3-h rhTNF- infusion (P < 0.05) concomitantly with an increase in palmitate uptake, R_d (data not presented; Fig. 2B).

View larger version (14K): [in this window] [in a new window]   FIG. 2. Systemic palmitate concentration (A) and rate of appearance of palmitate (B). During the TNF- trial, the infusion of rhTNF- was infusion commenced after obtaining the "0" sample and continued during 4 h. Data are presented as geometric means ± SEM. Open bars represent the control trial and closed bars the rhTNF- trial. $, Difference (P < 0.05) between trials. *, Difference (P < 0.05) from time point zero.

View larger version (17K): [in this window] [in a new window]   FIG. 3. Leg palmitate kinetics. Data are presented as means ± SEM. Open bars designate control trial and closed bars the rhTNF- trial, in which rhTNF- was infusion commenced after obtaining the "0" sample and continued 4 h. The net palmitate uptake (A), the unidirectional leg palmitate uptake (B) and releases (C), and the percent palmitate uptake oxidized (D).

Neither the arterial glucose nor the lactate concentrations were changed by rhTNF- (Table 1). Glucose turnover decreased during the experiment (P < 0.05), similarly in the control and rhTNF- (Fig. 4A). Skeletal muscle glucose utilization, as the leg net glucose uptake, was unaffected by rhTNF- and time (Fig. 4B).

View larger version (13K): [in this window] [in a new window]   FIG. 4. Whole body glucose turnover (A) and the leg net glucose uptake (B) are presented during the two trials in which rhTNF- was administered from 0–4 h. Data are presented as means ± SEM. Open bars designate the control trial and closed bars the rhTNF- infusion.*, Difference (P < 0.05) from time point zero.

	Discussion

Top Abstract Introduction Subjects and Materials Results Discussion References

In vitro studies have demonstrated that TNF- increases lipolysis in adipocytes (15, 16) presumably via a nuclear factor-B dependent mechanism (31). It has been reported that administration of high doses of rhTNF- to human subjects causes increased plasma concentrations of FFA, indicating a catabolic/lipolytic effect of TNF- (32). In addition, a transient increase in stress hormones has been observed, leaving the possibility that the increased lipolysis is a secondary effect to TNF- administration. In rats, TNF- also increases plasma FFA and triacylglycerols, suggesting increased lipolysis. The increase in FFA has also been observed in adrenalectomized rats, suggesting an epinephrine-independent effect of TNF- on lipolysis (33). The latter finding is in agreement with the present data, demonstrating an effect on lipolysis without a concomitant increase in catecholamines. An in vivo study in dogs with TNF- infusion reported a decrease in lipolysis and an increase in glucose turnover (34). These results are rather different from this human study in which we demonstrate that rhTNF- increases lipid turnover without affecting basal glucose turnover and lactate levels.

TNF- impairs the insulin-mediated skeletal muscle glucose uptake, and the reduction in insulin sensitivity is accompanied by several changes in the insulin-signaling cascade (22). An increased phosphorylation was observed of the serine residue of the insulin receptor substrate 1 and of AS160. Furthermore, TNF- increased phosphorylation of ERK1/2, JNK, and p70S6K in human subjects (22). Moreover, rat soleus muscle strips incubated with TNF- did not change fatty acid oxidation but increased fatty acid incorporation into diacylglycerol (8). However, it appears that although TNF- clearly inhibits insulin signaling, it has no effect on non-insulin dependent glucose uptake. Few studies have investigated the effect of TNF- on FFA metabolism in muscle. TNF- has influenced the mitochondrial oxidative capacity via inhibition of complex I in mouse fibrosarcoma (35). In contrast, when isolated rat soleus muscle was incubated with TNF-, this had no direct effect on FFA uptake, oxidation, or esterification into TAG (8). The latter findings are in accordance with the present study.

In clinical or epidemiological studies, both TNF- and IL-6 are associated with decreased insulin sensitivity (36) and dyslipidemia (37). However, these cytokines seem to differ with respect to their relative importance as modulators of energy metabolism. We have previously shown that in humans, IL-6 profoundly increases lipolysis and lipid oxidation after 2-h infusion at a plasma IL-6 concentration of approximately 150 pg/ml (9). The changes in the present study with rhTNF- infusion are more modest and seem to occur at a later stage upon infusion. This might suggest that TNF- compared with IL-6 is a less important modulator of fat metabolism. However, the level of TNF- in the present study is relatively low (16 pg/ml), which might explain the more modest effect on fat metabolism compared with infusion of rhIL-6 in human subjects (43). On the other hand, as rhTNF- increases, the plasma IL-6 concentration also increases, reaching a plateau of approximately 9 pg/ml after 3-h rhTNF- infusion. Therefore, it cannot be excluded that IL-6 contributes or even causes the modest and delayed increase in FFA turnover in the present study, as seen with rhIL-6 infusion (43). A small, but significant, reduction was observed in plasma insulin concentration after 1-h rhTNF- infusion, which remained similar for the remainder of the study. Moreover, only at one time point was a difference in insulin concentration observed between the control and rhTNF- infusion. Therefore, it is unlikely that the small reduction in insulin with rhTNF- infusion contributed to the increase FFA turnover.

The present study demonstrates that acutely elevated TNF- levels increase systemic FFA appearance to, and clearance from, the circulation without a change in skeletal muscle FFA release or uptake, respectively. This implies that other tissues have increased in FFA uptake and/or release. Under postabsorptive conditions, as in the present study, adipose tissue is quantitatively the most important tissue for FFA release into the circulation (28). Therefore, adipose tissue is the most likely tissue to have enhanced FFA release into the circulation, i.e. lipolysis, causing the increase in systemic FFA appearance with rhTNF- infusion. Under postabsorptive conditions, the quantitative most important tissues for FFA clearance are skeletal muscle and the liver with total skeletal muscle FFA uptake (26) and the splanchnic area (28), accounting for about 25 and 50% of systemic FFA clearance, respectively. Thus, most likely the liver has increased FFA uptake with rhTNF- infusion causing the increased systemic FFA clearance. Using a stable isotope-labeled tracer technique, it has been demonstrated that patients with type 2 diabetes have a reduced capacity to oxidize FFA in skeletal muscle (38). This reduction is associated with an impairment in the oxidative phosphorylation, and a hereditary component has been suggested (39). This seeming contradiction might suggest that the increased levels of TNF- seen in type 2 diabetes do not play a role in their impaired skeletal muscle lipid metabolism. However, some caution is warranted because chronic exposure to TNF- like in type 2 diabetes might cause a down-regulation of the quantity and/or activity of enzymes involved in skeletal muscle lipid metabolism, which effects will not be picked up in the present study.

In conclusion, systemic inflammation, insulin resistance, and dyslipidemia accompany a cluster of lifestyle-related chronic diseases (40). Elevated TNF- concentrations negatively regulate insulin signaling and whole body glucose uptake in humans (22). In addition, the present study demonstrates that TNF- causes increased lipolysis without enhancing skeletal muscle fat metabolism. These data suggest that in several chronic conditions accompanied by low-grade inflammation, TNF- may play a mechanistic role in mediating dyslipidemia.

	Acknowledgments

 
We thank Hanne Villumsen, Nina Pluszek, Flemming Jessen, and Ruth Rousing for their excellent technical assistance.

	Footnotes

 
This study was funded by a grant from Astra Zenica, the Commission of the European Communities (contract no. LSHM-CT-2004–005272 EXGENESIS), the Novo Nordic Foundation, and the Danish Diabetes Association. The Centre of Inflammation and Metabolism is supported by the Danish National Research Foundation Grant DG 02–512–555. The Copenhagen Muscle Research Centre is supported by grants from The University of Copenhagen, the Faculties of Science and of Health Sciences at this university, and The Copenhagen Hospital Corporation. The study also received support from the Danish Medical Research Council and the Danish Natural Research Council.

Disclosure Statement: The authors have nothing to disclose.

First Published Online November 20, 2007

Abbreviations: CV, Coefficient of variation; FFA, free fatty acid; rh, recombinant human.

Received August 7, 2007.

Accepted November 8, 2007.

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