Leptin signaling pathway (Homo sapiens)

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LEPRSTAT1STAT11IP3PIP3PIP2ProteinDAGLeptin Signaling PathwaycAMPReceptorProteinProteinfood intakemRNASmall moleculeLigandRegulation ofPLCG2SHC1PJAK2PPLCG1RAF1PTIMP1GRB2NCOA1 LEPLEPRPPIK3R2PPIK3R1PSTAT3STAT3PSH2B1 LEPSP1KHDRBS1PSOCS7PTPN11PSOCS3ERBB2PIGF1RESR1FYNPSRCPFOXO1PMTORPAKT1PRELAPCISHSOCS2IKBKGPCHUKPIKBKBPACACBPMAPK8PEIF4EPEIF4EBP1PSTAT5BPGSK3BPPTENPMAP2K2PMAP2K1PMAPK14PACACAPGSK3APBAXNOS3PPTK2PCFL2PRPS6PCREB1PPRKAA2PBADPRPS6KA1 PIRS2PIRS1PSOS1HRASGTPMAPK1PMAPK3PSTAT3STAT3PPTPN1STAT3STAT1PSTAT3STAT1PSTAT1PSTAT1PESR1ESR1ESR1PDE3BRELAPNFKB1RELRELBCL2L1ELK1PAMPEGFRPRPS6KB1PIL1RNIL1BPRKAA1PCREB1PCCND1JAK1PRHOAROCK1CDC42RAC1NFKB1CYNUCYNUCYNUROCK2CYNUCYNUCa2+ signalingPKC pathwayActin cytoskeletalreorganizationCYNUInduced activationEnzyme complexInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageMolecule


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 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 CPTAC Assay Portal

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Ontology Terms



  1. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GS, Venugopal AK, Telikicherla D, Navarro JD, Mathivanan S, Pecquet C, Gollapudi SK, Tattikota SG, Mohan S, Padhukasahasram H, Subbannayya Y, Goel R, Jacob HK, Zhong J, Sekhar R, Nanjappa V, Balakrishnan L, Subbaiah R, Ramachandra YL, Rahiman BA, Prasad TS, Lin JX, Houtman JC, Desiderio S, Renauld JC, Constantinescu SN, Ohara O, Hirano T, Kubo M, Singh S, Khatri P, Draghici S, Bader GD, Sander C, Leonard WJ, Pandey A; ''NetPath: a public resource of curated signal transduction pathways.''; Genome Biol, 2010 PubMed Europe PMC Scholia


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115926view08:01, 21 March 2021EgonwCopied the NetPath paper into the literature list
115924view07:58, 21 March 2021EgonwModified description
106629view20:54, 12 September 2019KhanspersModified description
105635view05:05, 10 August 2019KhanspersModified description
89856view12:24, 6 October 2016MkutmonModified description
80016view16:05, 30 April 2015Zariannotated ACACB ,EIF4E ,EIF4EBP1,GSK3B, PTEN ,GSK3A,NOS3,PTK2, PRKAA2, BAD ,RPS6KA1 ,PRKAA1 , ROCK1,,ROCK2
79545view15:37, 24 March 2015Zariadded I for PLCG2 gene
78575view14:50, 7 January 2015MaintBotadded missing graphIds
71413view19:01, 17 October 2013MaintBotRemoved source from datanodes with empty id
70095view18:37, 12 July 2013MaintBotupdating to 2013 schema
48444view14:55, 24 May 2012NetPathModified description
48443view14:54, 24 May 2012NetPathModified description
45589view09:55, 18 October 2011JyotiModified description
45588view09:54, 18 October 2011JyotiModified description
45587view09:54, 18 October 2011JyotiModified description
45586view09:53, 18 October 2011JyotiModified description
45585view09:52, 18 October 2011JyotiModified description
44885view10:11, 6 October 2011MartijnVanIerselOntology Term : 'leptin system pathway' added !
44631view18:17, 22 September 2011KhanspersNew pathway

External references


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NameTypeDatabase referenceComment
LEPProtein3952 (Entrez Gene)
ACACAProtein31 (Entrez Gene)
ACACBProtein32 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
BADProtein572 (Entrez Gene)
BAXRna581 (Entrez Gene)
BCL2L1Rna598 (Entrez Gene)
CCND1Rna595 (Entrez Gene)
CDC42Protein998 (Entrez Gene)
CFL2Protein1073 (Entrez Gene)
CHUKProtein1147 (Entrez Gene)
CISHProtein1154 (Entrez Gene)
CREB1Protein1385 (Entrez Gene)
EGFRProtein3840 (Entrez Gene)
EIF4EProtein1977 (Entrez Gene)
EIF4EBP1Protein1978 (Entrez Gene)
ELK1Protein2002 (Entrez Gene)
ERBB2Protein2064 (Entrez Gene)
ESR1Protein2099 (Entrez Gene)
FOXO1Protein2308 (Entrez Gene)
FYNProtein2534 (Entrez Gene)
GRB2Protein2885 (Entrez Gene)
GSK3AProtein2931 (Entrez Gene)
GSK3BProtein2932 (Entrez Gene)
HRASProtein3265 (Entrez Gene)
IGF1RProtein3840 (Entrez Gene)
IKBKBProtein3551 (Entrez Gene)
IKBKGProtein8517 (Entrez Gene)
IL1BRna3553 (Entrez Gene)
IL1RNRna3557 (Entrez Gene)
IRS1Protein3667 (Entrez Gene)
IRS2Protein3667 (Entrez Gene)
JAK1Protein3716 (Entrez Gene)
JAK2Protein3717 (Entrez Gene)
KHDRBS1Protein10657 (Entrez Gene)
LEPRProtein3953 (Entrez Gene)
MAP2K1Protein5604 (Entrez Gene)
MAP2K2Protein5605 (Entrez Gene)
MAPK14Protein1432 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
MAPK3Protein5595 (Entrez Gene)
MAPK8Protein5599 (Entrez Gene)
MTORProtein2475 (Entrez Gene)
NCOA1Protein8648 (Entrez Gene)
NFKB1Protein4790 (Entrez Gene)
NOS3Protein4846 (Entrez Gene)
PDE3BProtein5140 (Entrez Gene)
PIK3R1Protein5295 (Entrez Gene)
PIK3R2Protein5296 (Entrez Gene)
PLCG1Protein5335 (Entrez Gene)
PLCG2Protein5336 (Entrez Gene)
PRKAA1Protein5562 (Entrez Gene)
PRKAA2Protein5563 (Entrez Gene)
PTENProtein5728 (Entrez Gene)
PTK2Protein5747 (Entrez Gene)
PTPN11Protein5781 (Entrez Gene)
PTPN1Protein5770 (Entrez Gene)
RAC1Protein5879 (Entrez Gene)
RAF1Protein5894 (Entrez Gene)
RELProtein5966 (Entrez Gene)
RELAProtein5970 (Entrez Gene)
RHOAProtein387 (Entrez Gene)
ROCK1Protein6093 (Entrez Gene)
ROCK2Protein9475 (Entrez Gene)
RPS6Protein6194 (Entrez Gene)
RPS6KA1 Protein6195 (Entrez Gene)
RPS6KB1Protein6198 (Entrez Gene)
SH2B1Protein25970 (Entrez Gene)
SHC1Protein6464 (Entrez Gene)
SOCS2Protein8835 (Entrez Gene)
SOCS3Protein9021 (Entrez Gene)
SOCS7Protein30837 (Entrez Gene)
SOS1Protein6654 (Entrez Gene)
SP1Protein6667 (Entrez Gene)
SRCProtein6714 (Entrez Gene)
STAT1Protein6772 (Entrez Gene)
STAT3Protein6774 (Entrez Gene)
STAT5BProtein6777 (Entrez Gene)

Annotated Interactions

No annotated interactions

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