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Endocrinology Vol. 142, No. 7 3027-3032
Copyright © 2001 by The Endocrine Society

ARTICLES

Leptin and Tumor Necrosis Factor-{alpha} Induce the Tyrosine Phosphorylation of Signal Transducer and Activator of Transcription Proteins in the Hypothalamus of Normal Rats In Vivo1

Nasser M. Rizk2, Daniela Stammsen, Gerald Preibisch and Jürgen Eckel

Molecular Cardiology, German Diabetes Research Institute, D-40225 Duesseldorf; and Aventis Pharma Deutschland GmbH (G.P.), Frankfurt 65926, Germany

Address all correspondence and requests for reprints to: Prof. Dr. Jürgen Eckel, Diabetes Research Institute, Auf’m Hennekamp 65, D-40225 Dusseldorf, Germany. E-mail: eckel{at}uni-duesseldorf.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Tumor necrosis factor-{alpha} (TNF{alpha}) reduces food intake and participates in the regulation of energy homeostasis. However, TNF{alpha} signaling in the brain and the potential interaction with leptin have not been investigated to date. Here we studied the tyrosine phosphorylation of STAT (signal transducer and activator of transcription) proteins in the hypothalamus of normal rats after iv injection of recombinant murine leptin or TNF{alpha} or coinjection of both cytokines. Immunoblot analysis of hypothalamic lysates with a phospho-specific STAT3 antibody showed a 6- to 7-fold stimulation of STAT3 tyrosine phosphorylation in response to both leptin and TNF{alpha}. Importantly, when coinjecting both cytokines, a remarkable synergistic activation (24-fold increase in STAT3 phosphorylation) could be detected. No other STAT proteins (STAT1, STAT5) were activated by leptin, whereas TNF{alpha} injection resulted in a dose-dependent phosphorylation of hypothalamic STAT5. In contrast to its action in the brain, leptin was unable to produce STAT3 phosphorylation in the liver, either alone or in combination with TNF{alpha}. These data show that TNF{alpha}, independently of leptin, activates hypothalamic STAT signaling pathways and enhances leptin action at the level of STAT3. We therefore suggest that TNF{alpha} may represent a modulator of leptin action in the hypothalamus.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IT IS NOW well recognized that adipose tissue plays an active role in energy homeostasis by releasing cytokine signals such as leptin, tumor necrosis factor-{alpha} (TNF{alpha}), and interleukin-6 (IL-6) (1). Leptin inhibits food intake and stimulates energy expenditure by binding to the long form (Ob-RL) of its receptor predominantly located in the paraventricular, arcuate, and ventromedial nuclei of the hypothalamus (2). Ob-RL is a member of the class I cytokine receptor family that is known to signal by activation of the Janus kinase/STAT (signal transducer and activator of transcription) pathway (3). Activated STATs finally dimerize and translocate to the nucleus, where they affect the expression of specific genes (4). In cultured cells leptin was found to activate STAT1, STAT3, STAT5, and STAT6 (3), whereas only STAT3 was activated in vivo (5, 6).

In addition to leptin, adipose tissue produces significant amounts of TNF{alpha}, with an elevated expression in obesity (7). This cytokine induces anorexia and reduced food intake (8, 9, 10), and transport across the blood/brain barrier has been reported (11). TNF{alpha} signaling is initiated by type 1 and type 2 TNF receptors, and the involvement of a wide panel of downstream signaling events finally leads to the pleiotropic biological effects (12). Recently, Guo et al. (13) reported activation of Janus kinase tyrosine kinases by type 1 TNF receptors with the concomitant phosphorylation of STAT1, STAT3, STAT5, and STAT6. Further, the type 1 TNF receptor has been shown to play a major role in the central actions of TNF{alpha} (14, 15). This raises the possibility of a potential cross-talk between leptin and TNF{alpha} signaling in the hypothalamus. In the present study this cross-talk was analyzed at the level of hypothalamic STAT phosphorylation in normal rats under in vivo conditions.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chemicals
Recombinant murine leptin was expressed and purified as recently described (16). Recombinant murine TNF{alpha} (endotoxin, <0.1 ng/µg) was obtained from Sigma (Munich, Germany). The STAT1, STAT3, and STAT5A/B antibodies and the phospho-specific antibodies for STAT1, STAT3, and STAT5A/B were obtained from Upstate Biotechnology, Inc. (Biomol, Hamburg, Germany). Nitrocellulose membrane (BA85, 0.2 µm) was purchased from Schleicher & Schuell, Inc. (Kassel, Germany). Supersignal substrate was obtained from Pierce Chemical Co. (KMF Laboratories, St. Augustin, Germany).

In vivo treatment
Male Wistar rats, weight matched between 260–300 g, were purchased from Harlan Co. (Borchen, Germany). All animals were submitted to a 12-h light, 12-h dark cycle and supplied with standard chow food (4.5% fat and 21% protein) and water ad libitum for 1 week before the experiment. All animals were injected following previously published protocols (5, 17). After anesthesia (Nembutal, 75 mg/kg), rats were given a single iv (via the tail vein) bolus injection of the following compounds: 1) leptin at 3.0 mg/kg BW [this dose of leptin has been shown to be effective in decreasing food intake (18) and in stimulating the DNA-binding activity of hypothalamic STAT3 in mice (17)], 2) TNF{alpha} at 12 µg/kg BW, and 3) coinjection of both cytokines (3.0 mg/kg BW leptin plus 12 µg/kg BW TNF{alpha}) or PBS as vehicle control. We also injected a low dose of TNF{alpha} (1.2 µg/kg BW) and a low dose of leptin (0.3 mg/kg) to compare the effect of such low doses with that of the high doses. After 30 min, the animals were killed by decapitation, and hypothalamus and liver were dissected and frozen immediately in liquid nitrogen. Trunk blood was collected for subsequent determination of glucose, insulin, leptin, and IL-6.

Dissection of the hypothalamus
After decapitation, the brain of the animal was rapidly excised and frozen on a cooling plate before dissection of the hypothalamus. In particular, the whole ventral region of the hypothalamus was removed as follows: a 2-mm section of tissue extending from the posterior edge of the optic chiasma to the mammillary bodies was cut, then the region extending 2 mm bilaterally from the midline and 2 mm dorsoventrally above the base of the brain was separated en bloc as previously reported (19).

Glucose, insulin, and leptin determinations
Serum samples were kept at -20 C for subsequent determination of glucose, insulin, leptin, and IL-6. Serum glucose levels were measured as previously described (20). Serum insulin and leptin levels were determined using RIA kits (Linco Research, Inc., St. Charles, MO). IL-6 was determined by Prof. Heinrich (Aachen, Germany) using a bioassay method (21).

Western blotting
Tissues were lysed in a buffer consisting of 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.1% Triton X-100, 0.5% deoxycholate, 0.1% SDS, 1 mM phenylmethylsulfonylfluoride, 1 mM sodium orthovanadate, 10 mM NaF, 1 mM EDTA, 10 µg/ml leupeptin, 10 µg/ml aprotinin, and 10 µg/ml pepstatin. The tissues were homogenized in 2 ml lysis buffer (10%, wt/vol) using an Ultra-Turrax tissue homogenizer (Jahnke & Kunkel, Staufen, Germany). Lysates were cleared by centrifugation at 10,000 rpm for 20 min at 4 C. Protein determination of the supernatant was performed by the Bradford method using a protein assay (Bio-Rad Laboratories, Inc., Hercules, CA). Twenty micrograms of the protein samples were resolved by SDS-PAGE using horizontal gradient (8–18%) gels and transferred to nitrocellulose membranes in a semidry apparatus. Thereafter, membranes were blocked with 10% nonfat dried milk in TST buffer [20 mM Tris-HCl (pH 7.4), 150 mM NaCl, and 0.05% Tween 20] for 2 h at room temperature and then incubated with the appropriate antibodies in 5% milk overnight at 4 C. After four washes in TST buffer, membranes were incubated with horseradish peroxidase-conjugated antirabbit Ig in 3% milk for 1.5 h at room temperature and washed five times in TST buffer. Proteins were detected by enhanced chemiluminescence using SuperSignal substrate (Pierce Chemical Co., Rockford, IL), and visualized and evaluated on a LUMI Imager (Roche Molecular Biochemicals, Mannheim, Germany). Stripping of membranes was performed by soaking membranes in 2% SDS, 62.5 mM Tris-HCl (pH 6.8), and 100 mM ß-mercaptoethanol for 30 min at 55 C.

Statistical analysis
Data analysis was performed using Prism (GraphPad Software, Inc., San Diego, CA) and t-ease (ISI) statistical software. The significance of reported differences was evaluated using the null hypothesis and t statistics for unpaired data.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Serum leptin concentrations after injection of cytokines
Control serum leptin concentrations were within the normal range of leptin in fasting animals (Table 1Go). There was a dramatic increase in serum leptin after injection of leptin alone or after coinjection with TNF{alpha} compared with vehicle. This peak of leptin concentration observed was far above the physiological range required to induce weight loss. Injection of TNF{alpha} did not modify serum leptin concentrations. No significant change was observed in serum glucose and insulin after cytokine injection. The bioassay of IL-6 showed the absence of any detectable release of IL-6 under all conditions (not shown in Table 1Go).


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  		Table 1. Serum leptin-glucose and insulin after cytokine injection in normal rats

 
Tyrosine phosphorylation of STAT proteins in the hypothalamus in response to leptin and TNF{alpha}
In vivo leptin signaling involves the tyrosine phosphorylation of STAT3 in the hypothalamus (5, 6, 17). We therefore investigated whether this response could also be detected after peripheral application of TNF{alpha}. As shown in Fig. 1Go (upper panel), the low dose of TNF{alpha} (1.2 µg/kg BW) was not able to induce STAT3 phosphorylation to a significant level. However, at high concentrations of this cytokine (12 µg/kg) a prominent phosphorylation of STAT3 was observed. Additional experiments using TNF{alpha} concentrations between 1–5 µg/kg showed a marginal response, indicating that high concentrations of this cytokine are required to induce STAT3 phosphorylation. Under these conditions the effect of TNF{alpha} was comparable to that obtained with leptin (Fig. 1Go). Most importantly, the coinjection of both cytokines markedly enhanced the tyrosine phosphorylation of STAT3 in a synergistic fashion (Fig. 1Go, upper panel). However, this synergism was not observed at low TNF{alpha} concentrations (not shown in Fig. 1Go). Stripping and reprobing the membranes with a STAT3 antibody confirmed that the phosphorylated band represents STAT3 and that equal amounts of protein were loaded in each lane. Quantification of phosphorylated STAT3 bands indicated a 6.1 ± 0.6-fold increase after leptin injection, a 6.8 ± 0.5-fold increase after high dose TNF{alpha}, and a 24.3 ± 0.9-fold increase after coinjection of both cytokines (Fig. 1Go, lower panel). To assess the synergistic activation of STAT3 by leptin and TNF{alpha} at more physiological leptin concentrations, we injected leptin at 0.3 mg/kg, either alone or in combination with low and high TNF{alpha} (Fig. 2Go). However, at this dose of leptin only the coinjection of a high concentration of TNF{alpha} was able to induce significant phosphorylation of STAT3. Quantification of the phosphorylated STAT3 bands showed a 7.2 ± 1.8-fold increase (Fig. 2Go). This effect was essentially the same as that observed when injecting high TNF{alpha} alone (see Fig. 1Go).



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  		Figure 1. Tyrosine phosphorylation of STAT3 in the hypothalamus of normal rats. Upper panel, Animals were treated with PBS as a control or with leptin (3 mg/kg), TNF{alpha} (1.2 or 12 µg/kg), or leptin plus TNF{alpha} (12 µg/kg), as outlined in Materials and Methods. Hypothalamic lysates were resolved by SDS-PAGE and immunoblotted with phospho-specific STAT3 antibody and STAT3 antibody as described in Materials and Methods. Representative blots of four separate experiments are shown. Lower panel, Intensities of bands corresponding to phospho-specific STAT3 were quantified by LUMI imager analysis software, corrected for STAT3 protein expression, and are expressed relative to PBS control. Data are the mean ± SEM of four separate experiments. *, P < 0.05 vs. control.

 


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  		Figure 2. Effect of low concentrations of leptin on the tyrosine phosphorylation of hypothalamic STAT3. Upper panel, Animals were treated with PBS as a control or with leptin (0.3 mg/kg) or leptin plus TNF{alpha} (1.2 or 12 µg/kg) as described in Fig. 1Go. Hypothalamic lysates were resolved by SDS-PAGE and immunoblotted with phospho-specific STAT3 antibody and STAT3 antibody. A representative immunoblot of three separate experiments is shown. Lower panel, Quantification of immunoblots was performed as described in Fig. 1Go. Data represent the mean ± SEM of three separate experiments. *, P < 0.01 vs. control.

 
Following the same protocol as that outlined above, we then evaluated the tyrosine phosphorylation of STAT5. As presented in Fig. 3Go, leptin had no effect on STAT5 phosphorylation in vivo compared with the control group, whereas TNF{alpha} showed a dose-dependent activation of STAT5 phosphorylation. Quantification of phosphorylated STAT5 bands indicated that the high dose of TNF{alpha} caused a significant increase (5.33 ± 0.8) over the control level, with the low dose still producing a significant (3.52 ± 1.12) stimulation of STAT5 activation (Fig. 3Go, lower panel). Coinjection of both cytokines produced no additional effect on STAT5 activation (5.14 ± 1.4-fold above the control) compared with the high dose of TNF{alpha}. Stripping of the immunoblots and reprobing with STAT5 antibody confirmed the presence of equal amounts of STAT5 in each lane (Fig. 3Go).



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  		Figure 3. Tyrosine phosphorylation of STAT5 in the hypothalamus of normal rats. Upper panel, Animals were treated with the indicated cytokines as outlined in Fig. 1Go. Hypothalamic lysates were resolved by SDS-PAGE and immunoblotted with phospho-specific STAT5 antibody and STAT5 antibody. A representative immunoblot of four separate experiments is shown. Lower panel, Quantification of immunoblots was performed as described in Fig. 1Go. Data represent the mean ± SEM of four separate experiments. *, P < 0.05 vs. control.

 
In contrast to the results described for STAT3 and STAT5, TNF{alpha} was unable to induce the tyrosine phosphorylation of STAT1, although this protein could be readily detected in our hypothalamus preparation (data not presented). Further, neither leptin nor the combination of leptin and TNF{alpha} resulted in detectable phosphorylation of STAT1.

Phosphorylation of STAT proteins in the liver in response to leptin and TNF{alpha}
To compare the central actions of leptin and TNF{alpha} to their peripheral effects, we assessed the tyrosine phosphorylation of STAT3 and STAT5 in the liver. Liver tissue was removed from animals used for dissection of the hypothalamus immediately after decapitation. As depicted in Fig. 4Go, application of TNF{alpha} induced a prominent phosphorylation of both STAT3 and STAT5 in the livers of these animals. However, leptin was essentially uneffective under these conditions. In contrast to the hypothalamus, the coinjection of leptin and TNF{alpha} did not induce any additional response of STAT phosphorylation in the liver compared with the effect of TNF{alpha} alone (Fig. 4Go). Quantification of data even showed a slight reduction of STAT3 and STAT5 phosphorylation after coinjection; however, this did not reach statistical significance.



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  		Figure 4. Tyrosine phosphorylation of STAT3 and STAT5 in the liver of normal rats. Animals were treated with leptin and TNF{alpha} as outlined in Fig. 1Go. Liver tissue was removed, and lysates were resolved by electrophoresis and immunoblotted for phospho-specific STAT3 and phospho-specific STAT5 as well as STAT3 and STAT5.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrates the existence of a positive cross-talk between TNF{alpha} and leptin at the hypothalamic level under in vivo conditions. A key finding of this work consists in the observation that TNF{alpha} independently activates the tyrosine phosphorylation of both STAT3 and STAT5 in the hypothalamus. In addition, TNF{alpha} is able to enhance the effect of leptin on STAT3 phosphorylation.

Administration of leptin (3 mg/kg BW) to normal rats induced the tyrosine phosphorylation of hypothalamic STAT3, whereas signals for STAT5 and/or STAT1 phosphorylation could not be detected. Our findings extend the initial observations by Vaisse et al. (17) and McCowen et al. (5) that leptin activates STAT3 phosphorylation in mouse and rat hypothalamus maximally after 30 min. In the latter study a bolus injection of 1 mg/kg leptin was used. We were unable to detect STAT3 phosphorylation in response to 0.3 mg leptin/kg BW, most likely reflecting the prominent inactivation of leptin in the circulation (5). Application of a high dose of TNF{alpha} also induced phosphorylation of hypothalamic STAT3. This observation corresponds to the recent report by Bjorbaek et al. (22) describing activation of STAT3 by TNF{alpha} in CHO cells expressing Ob-RL. The inability to detect STAT3 phosphorylation with the low dose of TNF{alpha} might indicate that TNF{alpha} is effective in vivo only under pathophysiological conditions.

In earlier studies Yang et al. (23) and Van der Meer et al. (24) showed that the simultaneous application of IL-1 and TNF{alpha} in rats had a synergistic effect on anorexia and increased the sensitivity of the host to respond to cytokines. Very recently, Han et al. (25) reported that TNF{alpha} treatment augments the interferon-{gamma}-induced STAT1 and Janus kinase 2 activation within minutes of application of these cytokines. These data support the view that TNF{alpha} and other cytokines may synergistically target the satiety center via common signaling pathways. For the first time we now show that this may also be the case for TNF{alpha} and leptin at the level of hypothalamic STAT3. However, our data suggest that synergistic effects may be limited to high concentrations of both leptin and TNF{alpha}. The dual actions of TNF{alpha} to release leptin from adipocytes (26) and to enhance the effect of leptin on STAT3 phosphorylation may explain the strong anorectic effect in conditions associated with largely elevated circulating TNF{alpha}, such as infection with endotoxemia (27), cancer (28), and human immunodeficiency virus disease (29). It is worth noting that the synergistic interaction between TNF{alpha} and leptin appears to be specific for the hypothalamus, as leptin was completely uneffective in the liver under our experimental conditions.

Interestingly, STAT5 knockout mice developed obesity associated with dwarfism and low plasma insulin-like growth factor I (30). We show here that TNF{alpha} induces the dose-dependent phosphorylation of hypothalamic STAT5 without any effect of leptin. As STAT5 is claimed to be a candidate for leptin signaling at least in vitro (3), this novel finding would raise the possibility that TNF{alpha} may elicit antiobesity effects in the hypothalamus under both physiological and pathophysiological conditions using this pathway. We were unable to detect any significant tyrosine phosphorylation of STAT1 after injection of both cytokines in contrast to cell culture studies for leptin (3, 31) and TNF{alpha} signaling (13). This conflict of in vivo studies with in vitro studies most likely reflects the tissue specificity in the assembly of receptors or associated proteins that leads to differential STAT activation relative to that in cultured cells.

Distribution of TNF{alpha} in the brain indicates localization in the periventricular and arcuate nucleus of the hypothalamus and in the solitary nucleus of the brainstem, areas that are well known to be involved in the control of food intake (32). Previous observations by Fantino et al. (33) and Plata-Salaman and co-workers (34) indicated that TNF{alpha} can induce anorexia in normal as well as obese Zucker rats by a direct action on the hypothalamus. It is well established that NPY increases food intake and that leptin decreases the hypothalamic level of NPY (35). A study by Aguilera et al. (36) demonstrated that high TNF{alpha} and low NPY serum levels are associated with anorexia and poor nutritional status among dialysis patients with renal failure. Based on our data it may be speculated that TNF{alpha} acts in a leptin-like fashion and induces the down-regulation of hypothalamic NPY. Further work will be needed to prove this hypothesis and to identify the downstream targets of TNF{alpha} signaling in the hypothalamus.

In summary, we show here that TNF{alpha} may function as an antiobesity agent by activating hypothalamic STAT5 phosphorylation. Further, it is suggested that TNF{alpha} represents a positive modulator of leptin action by inducing the synergistic activation of STAT3 phosphorylation in the hypothalamus.


   Acknowledgments
 
The excellent technical assistance of Heidi Müller and the secretarial assistance of Birgit Hurow are gratefully acknowledged.


   Footnotes
 
1 This work was supported by the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Bundesministerium für Gesundheit, the Jühling Foundation, and the Deutscher Akademischer Austauschdienst. Back

2 Present address: Physiology Department, Mansoura Faculty of Medicine, Mansoura University, Egypt. Back

Received November 27, 2000.


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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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