20 YEARS OF LEPTIN: Connecting leptin signaling to biological function

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   Figure 1

   Leptin signaling and biological function. Leptin binds to LepRb, activating the associated JAK2 tyrosine kinase. Activated JAK2 phosphorylates the intracellular tail of LepRb on three tyrosine residues. Phosphorylated Tyr₉₈₅ recruits SHP2, which participates in ERK signaling; Tyr₉₈₅ also serves as a binding site for the negative feedback regulator, SOCS3. Phosphorylated Tyr₁₀₇₇ partially mediates leptin's control of reproduction; while STAT5 binds this site, STAT5 does not appear to participate in this effect of leptin. Phosphorylated Tyr₁₁₃₈ engages the STAT3 transcription factor. LepRb→STAT3 signaling represents the primary mechanism by which leptin regulates energy balance, although the target genes of STAT3 in LepRb neurons remain undiscovered. Leptin also recruits the IRS2→PI3K and SH2B1 pathways, although the mechanism of their recruitment to LepRb remains unclear. Some glucoregulatory and reproductive actions of LepRb appear to be mediated by unknown signals that function independently of LepRb tyrosine phosphorylation sites.
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   Figure 2

   Hypothalamic leptin action. Leptin acts on its receptor (LepRb) on neurons in a series of interconnected hypothalamic nuclei to regulate satiety, neuroendocrine function, and autonomic tone. In the arcuate nucleus, leptin controls the melanocortin system through its opposing actions on POMC and AgRP neurons. ARC, arcuate nucleus; VMH, ventromedial hypothalamic nucleus; DMH, dorsomedial hypothalamic nucleus; LHA, lateral hypothalamic area; PVH, paraventricular hypothalamic nucleus; MC4R, melanocortin 4 receptor; POMC, pro-opiomelanocortin; AgRP, agouti-related peptide.

• © 2014 Society for Endocrinology