Biology:Leptin receptor

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Short description: Type I cytokine receptor


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor,[1] a protein that in humans is encoded by the LEPR gene.[2][3] LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 (cluster of differentiation 295). Its location is the cell membrane, and it has extracellular, trans-membrane and intracellular sections (protein regions).

History

The Leptin Receptor was discovered in 1995 by Louis Tartaglia and his colleagues at Millennium Pharmaceuticals.[4] This same team demonstrated the leptin receptor was expressed by the mouse db gene.[5] Furthermore, in 1996, after co-discovering the Leptin gene with Jeffrey Friedman et al. in 1994, (which involved a reverse genetic/positional cloning strategy to clone ob and db), Rudolph Leibel, working with collaborators also at Millennium Pharmaceuticals and colleague Streamson Chua, confirmed cloning of the leptin receptor by demonstrating that an apparent leptin receptor cloned from a choroid plexus library using leptin as ligand, mapped to a physical map that included db and fa.[6][7]

Structure

Like other cytokine receptors, Leptin receptor protein has three different regions: i) extracellular, ii) trans-membrane, and iii) intracellular. The extracellular part has 5 functional domains:[8] i) membrane distal 1st cytokine receptor homology (CRH1), ii) Immunoglobulin like (Ig), iii) 2nd cytokine receptor homology (CRH2) and iv) two membrane proximal fibronectine type-III (FNIII) domains. CRH1 domains is not essential for Leptin binding, but may have regulatory roles.[8] Ig domain interacts with Leptin and is essential for conformational change in the receptor upon ligand binding.[8] CRH2 is essential for leptin binding, deletion of this domain abolishes the leptin binding.[8] FNIII domains are essential for receptor activation upon leptin binding.[8] The structure of the quaternary complex of the complete extracellular part in complex with the cognate ligand Leptin (i.e. 2 receptor and 2 ligand) has been solved by both electron microscopy[9] and SAXS.[10]

Function

The leptin hormone regulates adipose-tissue mass through hypothalamus effects on hunger and energy use. It acts through the leptin receptor (LEP-R), a single-transmembrane-domain receptor of the cytokine receptor family.[11] In hypothalamic neurons, adequate leptin receptor function and subsequent regulation of energy metabolism and body weight depends on interactions of the receptor with gangliosides in the cell membrane.[12]

Clinical significance

Variations in the leptin receptor have been associated with obesity[13][14] and with increased susceptibility to Entamoeba histolytica infections.[15]

Animals models

The db/db mouse is a model of obesity, diabetes, and dyslipidemia wherein leptin receptor activity is deficient because the mice are homozygous for a point mutation in the gene for the leptin receptor.[16] In db/db mice, induced swimming helped to overcome obesity by upregulating uncoupling proteins.[17]

Leptin receptor and pregnancy

The leptin hormone and its receptor, also known as maternal plasma leptin, play developmental roles during pregnancy.[18] Leptin receptors have been identified in the placenta of pregnant women and also in fetal tissues.[19] Those leptin receptors are secreted by the placenta; they increase leptin levels during pregnancy thereby aiding the fetal development.[19]

References

  1. ↑ "Leptin signaling in breast cancer: an overview". Journal of Cellular Biochemistry 105 (4): 956–64. November 2008. doi:10.1002/jcb.21911. PMID 18821585. 
  2. ↑ "Identification and expression cloning of a leptin receptor, OB-R". Cell 83 (7): 1263–71. December 1995. doi:10.1016/0092-8674(95)90151-5. PMID 8548812. 
  3. ↑ "Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1". Genomics 36 (1): 221–2. August 1996. doi:10.1006/geno.1996.0455. PMID 8812446. 
  4. ↑ "Identification and expression cloning of a leptin receptor, OB-R". Cell 83 (7): 1263–71. December 1995. doi:10.1016/0092-8674(95)90151-5. PMID 8548812. 
  5. ↑ "Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice". Cell 84 (3): 491–5. February 1996. doi:10.1016/S0092-8674(00)81294-5. PMID 8608603. 
  6. ↑ "Mapping of the OB receptor to 1p in a region of nonconserved gene order from mouse and rat to human". Genome Research 6 (5): 431–8. May 1996. doi:10.1101/gr.6.5.431. PMID 8743992. 
  7. ↑ "Molecular physiology of weight regulation in mice and humans". International Journal of Obesity 32 Suppl 7 (S7): S98-108. December 2008. doi:10.1038/ijo.2008.245. PMID 19136999. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "The Leptin Receptor Complex: Heavier Than Expected?" (in en). Frontiers in Endocrinology 8: 30. 2017. doi:10.3389/fendo.2017.00030. PMID 28270795. 
  9. ↑ "Ligand-induced architecture of the leptin receptor signaling complex" (in en). Molecular Cell 48 (4): 655–61. November 2012. doi:10.1016/j.molcel.2012.09.003. PMID 23063524. 
  10. ↑ "Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins". Structure 22 (6): 866–77. June 2014. doi:10.1016/j.str.2014.04.012. PMID 24882746. 
  11. ↑ "Entrez Gene: LEPR leptin receptor". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3953. 
  12. ↑ "Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis". PLOS Biology 11 (3): e1001506. March 12, 2013. doi:10.1371/journal.pbio.1001506. PMID 23554574. 
  13. ↑ "Mutation screening and identification of a sequence variation in the human ob gene coding region". Biochemical and Biophysical Research Communications 220 (3): 735–9. March 1996. doi:10.1006/bbrc.1996.0473. PMID 8607834. 
  14. ↑ "Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population". Hypertension Research 31 (6): 1093–100. June 2008. doi:10.1291/hypres.31.1093. PMID 18716356. 
  15. ↑ "A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children". The Journal of Clinical Investigation 121 (3): 1191–8. March 2011. doi:10.1172/JCI45294. PMID 21393862. 
  16. ↑ "Diabetic kidney disease in the db/db mouse". American Journal of Physiology. Renal Physiology 284 (6): F1138–44. June 2003. doi:10.1152/ajprenal.00315.2002. PMID 12736165. 
  17. ↑ "Swim training improves leptin receptor deficiency-induced obesity and lipid disorder by activating uncoupling proteins". Experimental & Molecular Medicine 39 (3): 385–94. June 2007. doi:10.1038/emm.2007.43. PMID 17603293. 
  18. ↑ "Leptin in pregnancy and development: a contributor to adulthood disease?". American Journal of Physiology. Endocrinology and Metabolism 308 (5): E335-50. March 2015. doi:10.1152/ajpendo.00312.2014. PMID 25516549. 
  19. ↑ 19.0 19.1 "Possible role of placental leptin in pregnancy: a review". Endocrine 19 (1): 65–71. October 2002. doi:10.1385/ENDO:19:1:65. PMID 12583603. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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