Leptin signaling (WP2034)

Leptin is a peptide hormone mainly synthesised and secreted from adipocytes. It is also expressed in other tissues including placenta, stomach and skeletal muscle. Leptin mediates its effects by binding to its receptor, leptin receptor (LEPR). LEPR belongs to gp130 family of cytokine receptor. LEPR is expressed in many tissues such as brain, adipose tissue, heart, placenta, lung and liver. Alternative splicing of LEPR results in six different isoforms, LEPRa, LEPRb, LEPRc, LEPRd, LEPRe and LEPRf. LEPRb is the longest isoform and possess signaling capacity. The role of other isoforms in leptin signaling is not clear. Leptin plays a major role in the regulation of energy homeostasis and regulate food intake and energy expenditure. Leptin is found to be transported to various regions of the brain across blood brain barrier. Impairment in leptin signaling across the blood brain barrier induces leptin resistance and thus obesity. Leptin is known to regulate reproduction, bone homeostasis and immune signaling. Leptin is also implicated in various physiological processers such as angiogenesis and hematopoiesis. LEPRb forms a homodimer and binds to leptin in 1:1 stoichiometry. This tetrameric receptor/ ligand complex appears to be essential for signaling. Leptin receptor lacks intrinsic kinase activity. It mediates multiple signaling pathways by binding to cytoplasmic kinases such as Janus Kinase 2 (JAK2). Activation of JAK2 by leptin promotes the tyrosine phosphorylation of LEPRb at Tyr-986, Try-1078 and Tyr-1141, thus activating LEPRb. Activation of leptin receptor with leptin activates signaling modules such as JAK/STAT, RAS/RAF/MAPK, IRS1/PI-3K, PLCγ and AMPK/ACC modules. Tyrosine phosphorylation of LEPRb induces binding of STATs to LEPRb. Binding of STATs to the phosphorylated residues of LEPR leads to the JAK2 mediated tyrosine phosphorylation and activation of STATs. Activated STATs translocate to the nucleus and induces expression of genes such as suppressor of cytokine signaling 3 (SOCS3) and TIMP metallopeptidase inhibitor 1 (TIMP1). SOCS3 mediates feedback inhibition of leptin pathway by binding to Tyr-986 residue of LEPR. Cytosolic PTP1B also negatively regulates leptin pathway by dephosphorylating JAK2 and STAT3. Binding of leptin to its receptor results in the phosphorylation of PTPN1. Phosphorylated PTPN11 provides a docking site for GRB2, resulting in the activation of ERK module through RAS-RAF-MEK signaling. Leptin induces the activation of PI-3K by promoting the interaction and formation of SH2B/JAK2/IRS complex. Activation PI-3K mediates the activation of activation of protein kinases such as protein kinase B (AKT1) and downstream signaling cascades such as mammalian target of rapamycin (MTOR), nitric oxide synthase 3 (NOS3) and phosphodiesterase 3A, cGMP-inhibited (PDE3A). Activated AKT also regulates glycogen synthase kinase 3 alpha/beta (GSK3A/B) proteins. IkappaB kinases (IKKs) are activated in response to AKT activation. Activated IKKs induce nuclear translocation of NF-kappaB. Leptin also regulates 5'-AMP-activated protein kinase (AMPK) signaling. AMPK function as energy sensor and is activated in response to rise in AMP to ATP ratio. Activated AMPK regulate fatty acid biosymthesis by regulating the activity the enzyme, fatty acid biosynthesis-acetyl-CoA carboxylase (ACC). PLC gamma is activated in response to leptin signaling. Activated PLC gamma regulate intracellular calcium levels and also protein kinase C activation by hydrolysing phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Please access this pathway at [http://www.netpath.org/netslim/Leptin_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Nanjappa, V., Raju, R., Muthusamy, B., Sharma, J., Thomas, J. K., Nidhina, P. A. H., Harsha, H. C., Pandey, A., Anilkumar G. and Prasad, T. S. K. (2011). A comprehensive curated reaction map of leptin signaling pathway. Journal of Proteomics and Bioinformatics. 4, 184-189. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2034 CPTAC Assay Portal]

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