Fig. 2.

A model of leptin signaling and leptin resistance. Leptin binds to the long form of the leptin receptor (LEPRb) and activates LEPRb-associated JAK2. JAK2 phosphorylates LEPRb on Tyr^{985/1077/1138}. SH2-containing protein tyrosine phosphatase 2 (SHP2) binds to phospho-Tyr⁹⁸⁵ and mediates the activation of the MAPK pathway. Suppressor of cytokine signaling-3 (SOCS3) also binds to phospho-Tyr⁹⁸⁵ and inhibits leptin signaling in a negative feedback manner. STAT5 and STAT3 bind to phospho-Tyr¹⁰⁷⁷ and phospho-Tyr¹¹³⁸, respectively, and are subsequently phosphorylated and activated by JAK2. STAT3 and STAT5 activate their target genes, which mediate leptin's anorexigenic effect. JAK2 autophosphorylates on Tyr⁸¹³, which binds to SH2B1. SH2B1 simultaneously binds to insulin receptor substrate (IRS)-1 and IRS-2 and recruits IRS proteins to the LEPRb/JAK2 complex, which results in JAK2-mediated tyrosine phosphorylation of IRS-1 and IRS-2 and subsequent activation of the phosphoinositide 3-kinase (PI3K) pathway. Leptin also stimulates a JAK2-independent pathway involving the Src tyrosine kinase family members. The JAK2-dependent and -independent pathways act coordinately and synergistically to promote STAT3 activation. Leptin also regulates the CaMKK2/AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and the mammalian target of rapamycin (mTOR)/ribosomal S6 kinase (S6K) pathways; however, the molecular steps from the LEPRb to these 2 pathways are not clear. These diverse pathways act coordinately as a network to fully mediate leptin responses. LEPRb signaling is negatively regulated by SOCS3, protein tyrosine phosphatase 1B (PTP1B), and endoplasmic reticulum (ER) stress but positively regulated by SH2B1.