id: PW:0000363
rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000363
title: leptin system pathway
description_xrefs:
- GO:0033210
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 the
  Jak-Stat signaling pathway employing the Jak2-Stat3 combination. 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 the leptin receptor. P-Y1138 can
  then recruit Stat3 to the Lepr-Jak2 complex followed by Stat3 phosphorylation. P-Stat3 dimerizes and
  translocates to the nucleus where it regulates the transcription of target genes, including Socs3. Socs3
  binding to P-Y985 on the 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 phosphatidylinositol 3-kinase-Akt signaling
  via Jak2 activation of Irs (insulin receptor substrates) and the Raf/Mek/Erk module of MAPK cascades
  via Ptpn11 acting upstream of the two pathways, respectively. It has been shown that Sh2bpsm1 - a protein
  containing both PH and SH2 ( plekstrin and src homology 2 domains) - can recruit Irs1 and Irs2 in response
  to leptin, form a ternary complex with Irs1 or Irs2 and activate Jak2 to promote tyrosine phopshorylation
  of Irs proteins by Jak2. It is worth mentioning that Stat and Socs proteins as well as Ptpn11 contain
  SH2 - src homology 2 - domains that bind to phosphotyrosine-containing targets. Ptpn11, acting upstream
  of the ERK1/2 pathway, can interact with either phosphorylated leptin receptor or Jak2.'
diagram_image: https://rgd.mcw.edu/pathway/PW0000363/leptin%20system%20pathway/pwmap.png
pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000363/leptin%20system%20pathway/leptin%20system%20pathway.gpp
diagram_pathway_links:
- id: PW:0000102
  label: the extracellular signal-regulated Raf/Mek/Erk signaling pathway
- id: PW:0000209
  label: Jak-Stat signaling pathway
- id: PW:0000232
  label: phosphatidylinositol 3-kinase-Akt signaling pathway
diagram_gene_links:
- id: RGD:2922
  label: Irs1
- id: RGD:69316
  label: Irs2
- id: RGD:2939
  label: Jak2
- id: RGD:3000
  label: Lep
- id: RGD:3001
  label: Lepr
- id: RGD:61965
  label: Ptpn1
- id: RGD:3447
  label: Ptpn11
- id: RGD:620132
  label: Sh2bpsm1
- id: RGD:621087
  label: Socs3
- id: RGD:3772
  label: Stat3
diagram_chemicals: []
diagram_edges:
- source: Irs1
  relation: associated_with
  target: Sh2bpsm1
- source: Irs2
  relation: associated_with
  target: Sh2bpsm1
- source: Jak2
  relation: associated_with
  target: Lepr
- source: Jak2
  relation: associated_with
  target: Ptpn11
- source: Jak2
  relation: associated_with
  target: Sh2bpsm1
- source: Lep
  relation: associated_with
  target: Lepr
- source: Lepr
  relation: associated_with
  target: Ptpn11
- source: Lepr
  relation: associated_with
  target: Stat3
- source: Ptpn1
  relation: negatively_affects
  target: Jak2
- source: Ptpn1
  relation: negatively_affects
  target: Stat3
- source: Socs3
  relation: negatively_affects
  target: Jak2
- source: Socs3
  relation: negatively_affects
  target: Lepr
- source: Stat3
  relation: positively_affects
  target: leptin activated Stat3 gene targets
- source: leptin activated Stat3 gene targets
  relation: positively_affects
  target: Socs3
diagram_labels:
- Jak2 --+> Irs1
- Jak2 --+> Irs2
- Jak2 --+> Lepr
- Jak2 --+> Stat3
- Jak2 --+> the extracellular signal-regulated Raf/Mek/Erk signaling pathway
- Lepr --+> Jak2
- Lepr --+> phosphatidylinositol 3-kinase-Akt signaling pathway
- Lepr --+> the extracellular signal-regulated Raf/Mek/Erk signaling pathway
- PY1138
- PY985
diagram_other_links:
- href: /wg/home/pathway2/molecular-pathways2/leptin-activated-stat3-targets
  label: leptin activated Stat3 gene targets
references:
- id: RGD:1357909
  citation: Jequier E Ann N Y Acad Sci 2002 Jun;967:379-88.
- id: RGD:1625125
  citation: Howard JK and Flier JS, Trends Endocrinol Metab. 2006 Nov;17(9):365-71. Epub 2006 Sep 28.
- id: RGD:1625227
  citation: Kitamura T, etal., Nat Med. 2006 May;12(5):534-40. Epub 2006 Apr 9.
- id: RGD:2289366
  citation: Lund IK, etal., J Mol Endocrinol. 2005 Apr;34(2):339-51.
- id: RGD:2289807
  citation: Yang R and Barouch LA, Circ Res. 2007 Sep 14;101(6):545-59.
- id: RGD:2290292
  citation: Oswal A and Yeo GS, Obes Rev. 2007 Jul;8(4):293-306.
- id: RGD:2290293
  citation: Murakami T, etal., Biochem Biophys Res Commun. 1997 Feb 3;231(1):26-9.
- id: RGD:2290294
  citation: Yamashita T, etal., Biochem Biophys Res Commun. 1998 May 29;246(3):752-9.
- id: RGD:2302071
  citation: Duan C, etal., J Biol Chem. 2004 Oct 15;279(42):43684-91. Epub 2004 Aug 16.
- id: RGD:5129722
  citation: Waelput W, etal., Biochem J. 2000 May 15;348 Pt 1:55-61.
- id: RGD:5129836
  citation: Fruhbeck G Biochem J. 2006 Jan 1;393(Pt 1):7-20.