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Insufficiency of Janus kinase 2-autonomous leptin receptor signals for most physiologic leptin actions.

Diabetes | Apr 30, 2010

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.

Pubmed ID: 20068132 RIS Download

Mesh terms: Animals | DNA, Complementary | Estrus | Female | Genetic Vectors | Hypothalamus | Janus Kinase 2 | Leptin | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Mutagenesis, Site-Directed | Phosphorylation | Plasmids | Polymerase Chain Reaction | RNA | Receptors, Leptin | Spleen | T-Lymphocytes

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK-67536
  • Agency: NCI NIH HHS, Id: P30 CA046592
  • Agency: NIDDK NIH HHS, Id: R37 DK056731
  • Agency: NIDDK NIH HHS, Id: P60 DK020572
  • Agency: NIDDK NIH HHS, Id: R56 DK067536
  • Agency: NIDDK NIH HHS, Id: R01 DK067536
  • Agency: NIDDK NIH HHS, Id: DK-57631
  • Agency: NIDDK NIH HHS, Id: P30 DK020572
  • Agency: NIDDK NIH HHS, Id: DK-20572
  • Agency: NCI NIH HHS, Id: CA-46592

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