Insufficiency of Janus Kinase 2-Autonomous Leptin Receptor Signals for Most Physiologic Leptin Actions

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Insufficiency of Janus Kinase 2-Autonomous Leptin Receptor Signals for Most Physiologic Leptin Actions

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Title: Insufficiency of Janus Kinase 2-Autonomous Leptin Receptor Signals for Most Physiologic Leptin Actions
Author: Robertson, Scott; Ishida-Takahashi, Ryoko; Tawara, Isao; Hu, Jiang; Patterson, Christa M.; Jones, Justin C.; Myers, Martin G.; Kulkarni, Rohit Narayan

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Citation: Robertson, Scott, Ryoko Ishida-Takahashi, Isao Tawara, Jiang Hu, Christa M. Patterson, Justin C. Jones, Rohit N. Kulkarni, and Martin G. Myers. 2010. Insufficiency of Janus kinase 2-autonomous leptin receptor signals for most physiologic leptin actions. Diabetes 59(4): 782-790.
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Abstract: OBJECTIVE: Leptin acts via its receptor (LepRb) to signal the status of body energy stores. Leptin binding to LepRb initiates signaling by activating the associated Janus kinase 2 (Jak2) tyrosine kinase, which promotes the phosphorylation of tyrosine residues on the intracellular tail of LepRb. Two previously examined LepRb phosphorylation sites mediate several, but not all, aspects of leptin action, leading us to hypothesize that Jak2 signaling might contribute to leptin action independently of LepRb phosphorylation sites. We therefore determined the potential role in leptin action for signals that are activated by Jak2 independently of LepRb phosphorylation (Jak2-autonomous signals). RESEARCH DESIGN AND METHODS: We inserted sequences encoding a truncated LepRb mutant (LepRb\(^{\Delta65c}\), which activates Jak2 normally, but is devoid of other LepRb intracellular sequences) into the mouse Lepr locus. We examined the leptin-regulated physiology of the resulting \(\Delta/\Delta\) mice relative to LepRb-deficient \(db/db\) animals. RESULTS: The \(\Delta/\Delta\) animals were similar to \(db/db\) animals in terms of energy homeostasis, neuroendocrine and immune function, and regulation of the hypothalamic arcuate nucleus, but demonstrated modest improvements in glucose homeostasis. CONCLUSIONS: The ability of Jak2-autonomous LepRb signals to modulate glucose homeostasis in \(\Delta/\Delta\) animals suggests a role for these signals in leptin action. Because Jak2-autonomous LepRb signals fail to mediate most leptin action, however, signals from other LepRb intracellular sequences predominate.
Published Version: doi://10.2337/db09-1556
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2844825/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:5978699
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