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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

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.




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