Fig. 1

Leptin signaling pathways. Leptin binding to LepRb activates JAK2, thus leading to phosphorylation of LepRb on Tyr985, Tyr1077 and Tyr1138. Phospho-Tyr985, -Tyr1077 and-Tyr1138 bind to downstream molecules and activate the JAK2/STAT3, JAK2/STAT5, PI3K/IRS/AKT, and SHP2/MAPK pathways. Phosphorylated STAT3 dimers translocate to the nucleus and induce the transcription of target genes (POMC, SOCS3). SOCS3 inhibits the JAK2/STAT3 pathway by interacting with phospho-Y985 or JAK2 and acting as a feedback inhibitor of leptin signaling. PTP1B also inhibits leptin signaling through dephosphorylation of JAK2. After JAK2 activation, SHP2 binds to phosphor -Y985 in the LepRb and recruits the adaptor protein Grb2, causing activation of the ERK signaling cascade. Leptin also regulates PI3K signaling through IRS phosphorylation. Leptin has also been shown to stimulate the POMC neurons, while inhibit NPY/AGRP. FoxO1 is an important downstream target of PI3K in the leptin signaling pathway. These pathways act coordinately to regulate food intake, energy balance and body weight