 | Figure 1
Nature Neuroscience
8, 566 - 570 (2005)
Published online: 26 April 2005; | doi:10.1038/nn1454
Molecular and anatomical determinants of central leptin resistanceHeike Münzberg
& Martin G Myers Jr | | | | Figure 1. LRb signaling and proposed role for SOCS3 in LRb signal attenuation.
Leptin binding to LRb activates the LRb-associated Jak2 tyrosine kinase, leading to the autophosphorylation of tyrosine residues on Jak2 and the phosphorylation of Tyr985 and Tyr1138 on the intracellular tail of LRb. Although signaling by phosphorylation sites on Jak2 remains to be fully explored, Jak2 seems to activate the IRS-PI3K signaling pathway. Phosphorylation of Tyr1138 mediates the activation of the transcription factor STAT3. Among other targets, STAT3 induces the transcription (symbolized by the dashed arrows) of SOCS3 during LRb signaling. Tyr985 plays a dual role in LRb signaling, binding SHP-2 and also providing an important site of interaction for SOCS3 (SOCS3 also binds directly, albeit with lower affinity, to Jak2). SOCS3 binding to the LRb-Jak2 complex attenuates LRb-mediated signaling. We posit that the inhibitory feedback action of this LRb-SOCS3 pathway in vivo could explain the diminishing effectiveness of increasing leptin concentrations in obesity: at low concentrations of leptin, where baseline STAT3 activation is modest, induction of SOCS3 would also be modest, and incremental changes in leptin would be almost fully translated into changes in LRb signaling. At high levels of circulating leptin (as in obesity), the increased baseline STAT3 activation would result in increased expression of SOCS3, which would mitigate most of the expected increase in LRb signaling.
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