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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 4080-4082
Copyright © 1997 by The Endocrine Society

Original Studies

Tumor Necrosis Factor Increases Serum Leptin Levels in Humans

Martina Susanne Zumbach, Michael Wolfgang Josef Boehme, Peter Wahl, Wolfgang Stremmel, Reinhard Ziegler and Peter Paul Nawroth1

Department of Medicine, University of Heidelberg, 69115 Heidelberg, Germany

Address correspondence and requests for reprints to: Dr. P. Nawroth, Medizinische Klinik, Bergheimer Strasse 58, 69115 Heidelberg, Germany.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Leptin is a pleiotropic hormone believed to regulate body weight. Its function in wasting during inflammatory disease in humans is unknown.

We studied the effect of repeated tumor necrosis factor (TNF) infusion on serum leptin levels in six patients with solid tumors.

TNF infusion on day 1 resulted in an increase in serum leptin levels from 3.1 (SEM ± 0.28) ng/mL to 5.2 (SEM ± 0.6) ng/mL after 12 h (P < 0.001). The serum levels returned to baseline within 24 h. Similar results were obtained when TNF was infused on subsequent days. The study shows that leptin serum levels are under control of TNF.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WEIGHT LOSS in diseases with chronically activated host response has been the focus of previous studies, including the isolation of cachectin, later characterized as tumor necrosis factor (TNF) (1). Loss of appetite and weight is a hallmark of chronic inflammatory disease. Leptin is presumed to play a role in controlling not only food intake but also weight, by additional, as yet unknown, mechanisms (2, 3). Leptin has been studied primarily with respect to obesity (3), but not with respect to loss of appetite and wasting in cytokine-mediated chronic disease. Recently it has been shown in hamsters that cytokines affect leptin serum levels (4). This study was designed to evaluate whether leptin in humans is under the control of cytokines.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Table 1Go shows the successive serum samples of six patients, who received altogether a total of 16 courses of iv recombinant human TNF-{alpha} therapy (Knoll AG, Ludwigshafen, Germany) (120 µg/m2 body surface) (5). At each time point we obtained 16 serum samples. The leptin value presented is the mean of 16 leptin determinations. TNF was infused over 2 h daily, over 5 days. The infusions were always given in the late morning. All patients had breakfast before. If applicable, this course was repeated after 21 days. In addition, all patients received an sc therapy with interferon {alpha}-2 (5 x 106U sc on each consecutive day without interruption). The clinincal efficiency of the therapy was poor, as reported previously (5). All patients were treated according to protocols of phase II clinical trials, approved by The Ethics Committee of the University of Heidelberg. The body mass index and the baseline serum leptin levels were within the normal range (6).


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  		Table 1. Clinical characteristics of the patients

 
Serum leptin concentration

Serum leptin was measured in serum stored at -80 C. A commercially available leptin was used. The limit of sensitivity of the assay is 0.5 ng/mL, the intraassay variation under 9%, and the intraassay variation under 7%.

TNF-{alpha} was determined by ELISA as described previously (5).

Soluble TNF-receptors II were determined, as a biological marker of the TNF activity, with a commerically available kit (R & D Systems, Weisbaden, Germany) as published previously (5).

The means and SEM were calculated using the Winstat statistical program package (Kalmia Corp., Cambridge, MA). We performed the Friedman test to assess the significance between the data before administration of the first dose of TNF and the values obtained thereafter. A P-value of less than 0.01 was considered significant. The Pearson ranks correlation test was used to describe the correlation of leptin serum levels with TNF receptor serum levels.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
We evaluated serum leptin levels in six patients with solid tumors before and after treatment with TNF-{alpha}, with (days 1, 3, and 5) or without interferon alpha-2 (5). Infusion of TNF (with or without interferon alpha-2) resulted in a significant increase in plasma leptin levels (P < 0.001) when baseline was compared with that found 12 h after TNF infusion (Fig. 1Go). Serum leptin levels rose from baseline 3.1 (SEM ± 0.28) ng/mL to 5.2 (SEM ± 0.6) after 12 h (P < 0.001). The increase was identical on days with or without simultaneous interferon therapy and was evident within 6 h after TNF infusion. TNF (with or without interferon alpha-2) administration was performed each day at the same time after breakfast. Furthermore, leptin was measured at similar time points in a healthy control group not receiving TNF. We did not observe a significant rise in leptin in these probands. In the control group of six healthy persons, there was only an insignificant 15% rise of 3 ng/mL up to 3.5 ng/mL (between 0800 in the morning and 0800 in the evening). Therefore the normal leptin variations during the day were excluded as a confounding factor.



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  		Figure 1. Serum leptin levels increase after infusion of TNF. TNF was given over 120 min at 0, 24, 48, 72, and 96 h. Shown is the mean ± SEM (Friedman-test) of all patients and all cycles studied. The dash (-) marks the duration of the TNF infusion on the five seperate days. TNF therapy (iv) was combined with the sc interferon {alpha}-2 therapy on days 1, 3, and 5.

 
The leptin increase lasted a short time, and leptin serum levels returned to baseline within 24 h. Hence there was no difference between the start of a new cycle and repeated cycles after 21 days. A repeated cycle of TNF, given every 24 h for 5 days, resulted in a leptin increase each time in all patients studied.

As described previously (5), the serum levels of TNF receptors type II (TNF-R-II measured as markers of the TNF action) rose after TNF infusion. TNF receptor type II (at all timepoints and cycles measured) correlated with serum leptin (Table 2Go).


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  		Table 2. TNF R-II levels before the TNF-infusions and after 12 h

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The data presented suggest that leptin serum levels are controlled by mediators of the host response in humans as well as in hamsters (4). Activation of the host response, associated with weight loss, is explained only in part by reduced appetite and, as shown here, by an increase in serum leptin, known to participate in control of body weight (2, 3). In view of the still confusing issue of the real function of leptin, we want to add the speculation that cytokine-induced leptin may participate in loss of appetite and wasting in chronic inflammatory disease. It remains unknown whether leptin plays a role in malignancy-associated anorexia and cachexia, as none of the patients studied was cachectic or complained about severe loss of appetite. This also explains why, in the six patients studied, pre-TNF leptin levels were not elevated relative to the body mass index. The TNF levels reached under TNF therapy were higher than in most patients with inflammatory disease. However, TNF concentrations sufficient to cause maximal stimulation of their cellular receptors may be reached locally, i.e. in the adipocytes themselves or in the microcirculation. It is conceivable that TNF synthesized by adipocytes acts in an autocrine or paracrine manner in regulating local leptin production. It is intriguing to speculate that elevated TNF production of adipose tissue in patients with adiposity not only adds to disturbance in insulin, signaling important in insulin resistance, but also adds to the elevated levels of leptin observed in these patients. In this model TNF alone would be sufficient to induce leptin synthesis, as suggested previously (4). Recently, however, it has been shown that, in immunocompromised not overweight (BMI (kg/m2) 22.2 ± 0.52) AIDS patients, serum leptin levels are not elevated despite high TNF levels (7). This discrepancy to our study might be explained by 1) the difference in the immune status of the tumor patients and AIDS patients; 2) difference in the ability of adipocytes to synthesize TNF in tumor patients and AIDS patients; or by 3) inhibitors of the TNF action in AIDS patients. The patients presented in our study all had a normal or even increased BMI ranging from 22–30, excluding cachexia as a confounding factor. Furthermore TNF was biologically active at each admission in each patient, as evidenced by the increase in TNF-receptors. The persistent increase in soluble TNF-receptors aand in leptin on each consecutive day argues strongly in favor of a sufficient biological action of TNF, despite the presence of soluble TNF-receptors (5).

Another potentially confounding issue is the daily variation in plasma leptin. It was shown (8) that there is a diurnal pattern of the 24 h leptin plasma level, with an approximate 50% rise from nadir (0900 in the morning) to peak (0100 in the early morning). In our study the highest plasma leptin levels were reached 12 h after TNF in the early evening. In addition, we did not observe a similar rise in serum leptin in healthy volunteers.

This pilot study showes that cytokines such as TNF {alpha} can control leptin levels in humans; however, further studies are needed to clarify the biological significance of the increase in leptin levels, as well as the mechanism of the cytokine-induced increase in serum leptin.


   Footnotes
 
1 P. P. Nawroth was supported by a grant from DFG and Schilling Stiftung Back

Received February 25, 1997.

Revised August 14, 1997.

Accepted August 22, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Beutler B, Cerami A. 1986 Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature. 7:79–128.
  2. Pelleymounter MA, Cullen MJ, Baker MB, et al. 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 69:540–543.
  3. Levin N, Nelson C, Gurney A, Vandlen R, Suavage F. 1996 Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci USA. 93:1726–1730.[Abstract/Free Full Text]
  4. Grunfeld C, Zhao C, Fuller J, et al. 1996 Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest. 97:2152–2157.[Medline]
  5. Boehme MWJ, Waldherr R, Kist A, et al. 1996 Kinetics of soluble TNF-receptors and soluble adhesion molecules ICAM-1, E-selectin, and VCAM-1 under systemic rh-TNF therapy. Eur J Clin Invest. 26:404–410.[CrossRef][Medline]
  6. Considine R, Sinha M, Heiman M, et al. 1996 Serum immunoreactive-leptin concentrations in normal weight and obese humans. N Engl J Med. 334:292–295.[Abstract/Free Full Text]
  7. Grunfeld C, Pang M, Shigenaga JK, et al. 1996 Serum leptin levels in the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 81:4342–4346.[Abstract]
  8. Laughlin GA, Yen SSC. 1997 Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab. 82:318–321.[Abstract/Free Full Text]



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