Description
The leptin system plays an essential role in energy homeostasis - the balance between energy intake and expenditure. Leptin acts on two classes of neurons: those expressing the appetite decreasing peptides POMC and CART and those expressing the appetite stimulating peptides NPY and AgRP, promoting the upregulation of the former and downregulation of the latter. The products of the Pomc and Agrp genes act on melanocortin receptors as agonists and antagonists, respectively and the leptin melanocortin axis exerts a central role in the control of body weight. Leptin signaling occurs primarily via Jak2-Stat3 pathway. Leptin binding to its receptor – a single membrane spanning protein with structural similarity to the class I cytokine receptor family – leads to receptor oligomerization, binding to and activation of Jak2. Jak2 activation involves autophosphorylation and phosphorylation of tyrosine residues on the cytoplasmic domain of leptin receptor. P-Y1138 can then recruit Stat3 to the Lepr-Jak3 complex followed by Stat3 phosphorylation. P-Stat3 dimerizes and translocates to the nucleus where it activates the transcription of target genes, including Socs3. Socs3 binding to P-Y985 on leptin receptor and other sites within the Lepr-Jak2 complex provides a negative regulatory feedback loop. Inhibitory effects are also imparted by Ptpn1. In vitro, Ptpn1 dephophorylates both Jak2 and Stat3. Other pathways activated by leptin include PI3K via Jak2 activation of Irs and ERK1/2 of the MAPK family via Ptpn11 which acts upstream of the pathway. It is worth mentioning that Stat and Socs proteins as well as Ptpn11 contain SH2 - src homology 2 - domains that bind to phosphotyrosines containing targets.
