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

  1. Martin G. Myers Jr1,2,3
  1. 1Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan;
  2. 2Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
  3. 3Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts.
  1. Corresponding author: Martin G. Myers Jr., mgmyers{at}
  1. S.R. and R.I.-T. contributed equally to this study.


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 (LepRbΔ65c, 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 Δ/Δ mice relative to LepRb-deficient db/db animals.

RESULTS The Δ/Δ 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 Δ/Δ 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.


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    • Received October 21, 2009.
    • Accepted December 21, 2009.

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