Leptin signaling pathway (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, PLCĪ³ 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]
last edited


Khanspers, MartijnVanIersel, Jyoti, NetPath, MaintBot, Zari, Mkutmon, Egonw, and Eweitz

Cited In


Homo sapiens



Pathway Ontology: leptin system pathway


Label Type Compact Identifier
LEPR Protein ncbigene:3953
STAT1 Protein ncbigene:6772
STAT1 Protein ncbigene:6772
PLCG2 Protein ncbigene:5336
SHC1 Protein ncbigene:6464
JAK2 Protein ncbigene:3717
PLCG1 Protein ncbigene:5335
RAF1 Protein ncbigene:5894
TIMP1 Rna None
GRB2 Protein ncbigene:2885
NCOA1 Protein ncbigene:8648
LEP Protein ncbigene:3952
LEPR Protein ncbigene:3953
PIK3R2 Protein ncbigene:5296
PIK3R1 Protein ncbigene:5295
STAT3 Protein ncbigene:6774
STAT3 Protein ncbigene:6774
SH2B1 Protein ncbigene:25970
LEP Protein ncbigene:3952
SP1 Protein ncbigene:6667
KHDRBS1 Protein ncbigene:10657
SOCS7 Protein ncbigene:30837
PTPN11 Protein ncbigene:5781
SOCS3 Protein ncbigene:9021
ERBB2 Protein ncbigene:2064
IGF1R Protein ncbigene:3840
ESR1 Protein ncbigene:2099
FYN Protein ncbigene:2534
SRC Protein ncbigene:6714
FOXO1 Protein ncbigene:2308
MTOR Protein ncbigene:2475
AKT1 Protein ncbigene:207
RELA Protein ncbigene:5970
CISH Protein ncbigene:1154
SOCS2 Protein ncbigene:8835
IKBKG Protein ncbigene:8517
CHUK Protein ncbigene:1147
IKBKB Protein ncbigene:3551
ACACB Protein ncbigene:32
MAPK8 Protein ncbigene:5599
EIF4E Protein ncbigene:1977
EIF4EBP1 Protein ncbigene:1978
STAT5B Protein ncbigene:6777
GSK3B Protein ncbigene:2932
PTEN Protein ncbigene:5728
MAP2K2 Protein ncbigene:5605
MAP2K1 Protein ncbigene:5604
MAPK14 Protein ncbigene:1432
ACACA Protein ncbigene:31
GSK3A Protein ncbigene:2931
BAX Rna ncbigene:581
NOS3 Protein ncbigene:4846
PTK2 Protein ncbigene:5747
CFL2 Protein ncbigene:1073
RPS6 Protein ncbigene:6194
CREB1 Protein ncbigene:1385
PRKAA2 Protein ncbigene:5563
BAD Protein ncbigene:572
RPS6KA1 Protein ncbigene:6195
IRS2 Protein ncbigene:3667
IRS1 Protein ncbigene:3667
SOS1 Protein ncbigene:6654
HRAS Protein ncbigene:3265
MAPK1 Protein ncbigene:5594
MAPK3 Protein ncbigene:5595
STAT3 Protein ncbigene:6774
STAT3 Protein ncbigene:6774
PTPN1 Protein ncbigene:5770
STAT3 Protein ncbigene:6774
STAT1 Protein ncbigene:6772
STAT3 Protein ncbigene:6774
STAT1 Protein ncbigene:6772
STAT1 Protein ncbigene:6772
STAT1 Protein ncbigene:6772
ESR1 Protein ncbigene:2099
ESR1 Protein ncbigene:2099
ESR1 Protein ncbigene:2099
PDE3B Protein ncbigene:5140
RELA Protein ncbigene:5970
NFKB1 Protein ncbigene:4790
REL Protein ncbigene:5966
REL Protein ncbigene:5966
BCL2L1 Rna ncbigene:598
ELK1 Protein ncbigene:2002
EGFR Protein ncbigene:3840
RPS6KB1 Protein ncbigene:6198
IL1RN Rna ncbigene:3557
IL1B Rna ncbigene:3553
PRKAA1 Protein ncbigene:5562
CREB1 Protein ncbigene:1385
CCND1 Rna ncbigene:595
JAK1 Protein ncbigene:3716
RHOA Protein ncbigene:387
ROCK1 Protein ncbigene:6093
CDC42 Protein ncbigene:998
RAC1 Protein ncbigene:5879
NFKB1 Protein ncbigene:4790
ROCK2 Protein ncbigene:9475


  1. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. NetPath: a public resource of curated signal transduction pathways. Genome Biol. 2010 Jan 12;11(1):R3. PubMed Europe PMC Scholia