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This version published online on December 16, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0353
A more recent version of this article appeared on April 1, 2005
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Submitted on September 7, 2004
Accepted on December 8, 2004

Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and SOCS3

Sarah L. Dunn, Marie Björnholm, Sarah H. Bates, Zhibin Chen, Matthew Seifert, and Martin G. Myers Jr*

Division of Metabolism, Endocrinology and Diabetes, Department of Medicine, University of Michigan Medical School, Ann Arbor, MI and Research Division, Joslin Diabetes Center, Boston, MA

* To whom correspondence should be addressed. E-mail: mgmyers{at}umich.edu.

Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera (ELR), we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits STAT3) alleviated this feedback inhibition, suggesting that STAT3 mediates the induction of a feedback inhibitor, such as SOCS3, during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase SHP-2 by overexpression of wild-type and dominant negative isoforms or RNAi-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, while RNAi-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.




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