gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor

doi:10.1073/pnas.0600425103

gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor

*Institute for Genetics and Center for Molecular Medicine Cologne, Department of Mouse Genetics and Metabolism, University of Cologne, D-50674 Cologne, Germany;
^†Klinik II und Poliklinik für Innere Medizin, University of Cologne, D-50931 Cologne, Germany;
^‡Division of Metabolism, Endocrinology, and Diabetes, Departments of Internal Medicine and Molecular Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0638;
^‖German Research Centre for Biotechnology, D-38124 Braunschweig, Germany; and Departments of
^§Obstetrics, Gynecology, and Reproductive Sciences and
^¶Neurobiology and
**Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06519

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 31, 2006 (received for review January 17, 2006)

Abstract

Ciliary neurotrophic factor (CNTF) exerts anorectic effects by overcoming leptin resistance via activation of hypothalamic neurons. However, the exact site of CNTF action in the hypothalamus has not yet been identified. Using Cre-loxP-mediated recombination in vivo, we have selectively ablated the common cytokine signaling chain gp130, which is required for functional CNTF signaling, in proopiomelanocortin (POMC)-expressing neurons. POMC-specific gp130 knockout mice exhibit unaltered numbers of POMC cells and normal energy homeostasis under standard and high fat diet. Endotoxin (LPS) and stress-induced anorexia and adrenocorticotropin regulation were unaffected in these animals. Strikingly, the anorectic effect of centrally administered CNTF was abolished in POMC-specific gp130 knockout mice. Correspondingly, in these animals, CNTF failed to activate STAT3 phosphorylation in POMC neurons and to induce c-Fos expression in the paraventricular nucleus. These data reveal POMC neurons as a critical site of CNTF action in mediating its anorectic effect.

CNS
obesity

Footnotes

^††To whom correspondence should be addressed at:
Institute for Genetics, Department of Mouse Genetics and Metabolism, University of Cologne, Zülpicher Strasse 47, D-50674 Cologne, Germany.
E-mail: jens.bruening{at}uni-koeln.de
Author contributions: J.C.B. designed research; R.J., L.P., L.K., H.M., S.D., and M.S. performed research; W.M. contributed new reagents/analytic tools; R.J., L.P., H.M., M.S., and T.L.H. analyzed data; and R.J., T.L.H., and J.C.B. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

CNTF,

ciliary neurotrophic factor;

i.c.v.,

intracerebroventricular(ly);

POMC,

proopiomelanocortin;

PVN,

paraventricular nucleus.