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Leptin receptor

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LEPR
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLEPR, CD295, LEP-R, LEPRD, OB-R, OBR, leptin receptor
External IDsOMIM: 601007; MGI: 104993; HomoloGene: 1731; GeneCards: LEPR; OMA:LEPR - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3953

16847

Ensembl

ENSG00000116678

ENSMUSG00000057722

UniProt

P48357

P48356

RefSeq (mRNA)

NM_001122899
NM_010704
NM_146146

RefSeq (protein)

NP_001116371
NP_034834
NP_666258

Location (UCSC)Chr 1: 65.42 – 65.64 MbChr 4: 101.57 – 101.67 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor,[5] a protein that in humans is encoded by the LEPR gene.[6][7] 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

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The Leptin Receptor was discovered in 1995 by Louis Tartaglia and his colleagues at Millennium Pharmaceuticals.[8] This same team demonstrated the leptin receptor was expressed by the mouse db gene.[9] 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.[10][11]

Structure

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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:[12] 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.[12] Ig domain interacts with Leptin and is essential for conformational change in the receptor upon ligand binding.[12] CRH2 is essential for leptin binding, deletion of this domain abolishes the leptin binding.[12] FNIII domains are essential for receptor activation upon leptin binding.[12] 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[13] and SAXS.[14]

Function

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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.[15] 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.[16]

Clinical significance

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Variations in the leptin receptor have been associated with obesity[17][18] and with increased susceptibility to Entamoeba histolytica infections.[19]

Animal models

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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.[20] In db/db mice, induced swimming helped to overcome obesity by upregulating uncoupling proteins.[21]

Leptin receptor and pregnancy

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The leptin hormone and its receptor, also known as maternal plasma leptin, play developmental roles during pregnancy.[22] Leptin receptors have been identified in the placenta of pregnant women and also in fetal tissues.[23] Those leptin receptors are secreted by the placenta; they increase leptin levels during pregnancy thereby aiding the fetal development.[23]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000116678 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000057722 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N (November 2008). "Leptin signaling in breast cancer: an overview". Journal of Cellular Biochemistry. 105 (4): 956–64. doi:10.1002/jcb.21911. PMID 18821585. S2CID 25572220.
  6. ^ Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. (December 1995). "Identification and expression cloning of a leptin receptor, OB-R". Cell. 83 (7): 1263–71. doi:10.1016/0092-8674(95)90151-5. PMID 8548812.
  7. ^ Winick JD, Stoffel M, Friedman JM (August 1996). "Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1". Genomics. 36 (1): 221–2. doi:10.1006/geno.1996.0455. PMID 8812446.
  8. ^ Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. (December 1995). "Identification and expression cloning of a leptin receptor, OB-R". Cell. 83 (7): 1263–71. doi:10.1016/0092-8674(95)90151-5. PMID 8548812.
  9. ^ Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. (February 1996). "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. doi:10.1016/S0092-8674(00)81294-5. PMID 8608603. S2CID 13885070.
  10. ^ Chung WK, Power-Kehoe L, Chua M, Leibel RL (May 1996). "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. doi:10.1101/gr.6.5.431. PMID 8743992.
  11. ^ Leibel RL (December 2008). "Molecular physiology of weight regulation in mice and humans". International Journal of Obesity. 32 Suppl 7 (S7): S98-108. doi:10.1038/ijo.2008.245. PMC 2682360. PMID 19136999.
  12. ^ a b c d e Wauman J, Zabeau L, Tavernier J (2017). "The Leptin Receptor Complex: Heavier Than Expected?". Frontiers in Endocrinology. 8: 30. doi:10.3389/fendo.2017.00030. PMC 5318964. PMID 28270795.
  13. ^ Mancour LV, Daghestani HN, Dutta S, Westfield GH, Schilling J, Oleskie AN, et al. (November 2012). "Ligand-induced architecture of the leptin receptor signaling complex". Molecular Cell. 48 (4): 655–61. doi:10.1016/j.molcel.2012.09.003. PMC 3513567. PMID 23063524.
  14. ^ Moharana K, Zabeau L, Peelman F, Ringler P, Stahlberg H, Tavernier J, et al. (June 2014). "Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins". Structure. 22 (6): 866–77. doi:10.1016/j.str.2014.04.012. PMID 24882746.
  15. ^ "Entrez Gene: LEPR leptin receptor".
  16. ^ Nordström V, Willershäuser M, Herzer S, Rozman J, von Bohlen Und Halbach O, Meldner S, et al. (March 12, 2013). "Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis". PLOS Biology. 11 (3): e1001506. doi:10.1371/journal.pbio.1001506. PMC 3595213. PMID 23554574.
  17. ^ Considine RV, Considine EL, Williams CJ, Nyce MR, Zhang P, Opentanova I, et al. (March 1996). "Mutation screening and identification of a sequence variation in the human ob gene coding region". Biochemical and Biophysical Research Communications. 220 (3): 735–9. doi:10.1006/bbrc.1996.0473. PMID 8607834.
  18. ^ Masuo K, Straznicky NE, Lambert GW, Katsuya T, Sugimoto K, Rakugi H, et al. (June 2008). "Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population". Hypertension Research. 31 (6): 1093–100. doi:10.1291/hypres.31.1093. PMID 18716356.
  19. ^ Duggal P, Guo X, Haque R, Peterson KM, Ricklefs S, Mondal D, et al. (March 2011). "A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children". The Journal of Clinical Investigation. 121 (3): 1191–8. doi:10.1172/JCI45294. PMC 3049405. PMID 21393862.
  20. ^ Sharma K, McCue P, Dunn SR (June 2003). "Diabetic kidney disease in the db/db mouse". American Journal of Physiology. Renal Physiology. 284 (6): F1138–44. doi:10.1152/ajprenal.00315.2002. PMID 12736165.
  21. ^ Oh KS, Kim EY, Yoon M, Lee CM (June 2007). "Swim training improves leptin receptor deficiency-induced obesity and lipid disorder by activating uncoupling proteins". Experimental & Molecular Medicine. 39 (3): 385–94. doi:10.1038/emm.2007.43. PMID 17603293.
  22. ^ Briffa JF, McAinch AJ, Romano T, Wlodek ME, Hryciw DH (March 2015). "Leptin in pregnancy and development: a contributor to adulthood disease?". American Journal of Physiology. Endocrinology and Metabolism. 308 (5): E335-50. doi:10.1152/ajpendo.00312.2014. PMID 25516549.
  23. ^ a b Sagawa N, Yura S, Itoh H, Kakui K, Takemura M, Nuamah MA, et al. (October 2002). "Possible role of placental leptin in pregnancy: a review". Endocrine. 19 (1): 65–71. doi:10.1385/ENDO:19:1:65. PMID 12583603. S2CID 46986648.

Further reading

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

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