Leptin receptor

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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

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 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.[4]

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[5]: 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[5]. Ig domain interacts with Leptin and is essential for conformational change in the receptor upon ligand binding[5]. CRH2 is essential for leptin binding, deletion of this domain abolishes the leptin binding[5]. FNIII domains are essential for receptor activation upon leptin binding[5].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[6] and SAXS[7].

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.[8] 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.[9]

Clinical significance

Variations in the leptin receptor have been associated with obesity[10][11] and with increased susceptibility to Entamoeba histolytica infections.[12]

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.[13] In db/db mice, induced swimming helped to overcome obesity by upregulating uncoupling proteins.[14]

References

  1. ↑ 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.
  2. ↑ Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI (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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 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.
  6. ↑ Mancour LV, Daghestani HN, Dutta S, Westfield GH, Schilling J, Oleskie AN, Herbstman JF, Chou SZ, Skiniotis G (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.
  7. ↑ Moharana K, Zabeau L, Peelman F, Ringler P, Stahlberg H, Tavernier J, Savvides SN (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.
  8. ↑ "Entrez Gene: LEPR leptin receptor".
  9. ↑ Nordström V, Willershäuser M, Herzer S, Rozman J, von Bohlen Und Halbach O, Meldner S, Rothermel U, Kaden S, Roth FC, Waldeck C, Gretz N, de Angelis MH, Draguhn A, Klingenspor M, Gröne HJ, Jennemann R (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.
  10. ↑ Considine RV, Considine EL, Williams CJ, Nyce MR, Zhang P, Opentanova I, Ohannesian JP, Kolaczynski JW, Bauer TL, Moore JH, Caro JF (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.
  11. ↑ Masuo K, Straznicky NE, Lambert GW, Katsuya T, Sugimoto K, Rakugi H, Socratous F, Hastings J, Lambert EA, Ogihara T, Esler MD (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.
  12. ↑ Duggal P, Guo X, Haque R, Peterson KM, Ricklefs S, Mondal D, Alam F, Noor Z, Verkerke HP, Marie C, Leduc CA, Chua SC, Myers MG, Leibel RL, Houpt E, Gilchrist CA, Sher A, Porcella SF, Petri WA (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.
  13. ↑ 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.
  14. ↑ 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.

Further reading

  • Heshka JT, Jones PJ (July 2001). "A role for dietary fat in leptin receptor, OB-Rb, function". Life Sciences. 69 (9): 987–1003. doi:10.1016/S0024-3205(01)01201-2. PMID 11508653.
  • Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP (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.
  • Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, Snodgrass HR (May 1996). "Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction". Nature Medicine. 2 (5): 585–9. doi:10.1038/nm0596-585. PMID 8616721.
  • Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF (July 1996). "The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations". Diabetes. 45 (7): 992–4. doi:10.2337/diabetes.45.7.992. PMID 8666155.
  • 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.
  • Bennett BD, Solar GP, Yuan JQ, Mathias J, Thomas GR, Matthews W (September 1996). "A role for leptin and its cognate receptor in hematopoiesis". Current Biology. 6 (9): 1170–80. doi:10.1016/S0960-9822(02)70684-2. PMID 8805376.
  • Luoh SM, Di Marco F, Levin N, Armanini M, Xie MH, Nelson C, Bennett GL, Williams M, Spencer SA, Gurney A, de Sauvage FJ (February 1997). "Cloning and characterization of a human leptin receptor using a biologically active leptin immunoadhesin". Journal of Molecular Endocrinology. 18 (1): 77–85. doi:10.1677/jme.0.0180077. PMID 9061609.
  • Echwald SM, Sørensen TD, Sørensen TI, Tybjaerg-Hansen A, Andersen T, Chung WK, Leibel RL, Pedersen O (April 1997). "Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity". Biochemical and Biophysical Research Communications. 233 (1): 248–52. doi:10.1006/bbrc.1997.6430. PMID 9144432.
  • Thompson DB, Ravussin E, Bennett PH, Bogardus C (May 1997). "Structure and sequence variation at the human leptin receptor gene in lean and obese Pima Indians". Human Molecular Genetics. 6 (5): 675–9. doi:10.1093/hmg/6.5.675. PMID 9158141.
  • Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, McKeigue PM, Scott J, Aitman TJ (June 1997). "Leptin receptor gene variation and obesity: lack of association in a white British male population". Human Molecular Genetics. 6 (6): 869–76. doi:10.1093/hmg/6.6.869. PMID 9175732.
  • Bailleul B, Akerblom I, Strosberg AD (July 1997). "The leptin receptor promoter controls expression of a second distinct protein". Nucleic Acids Research. 25 (14): 2752–8. doi:10.1093/nar/25.14.2752. PMC 146799. PMID 9207021.
  • Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma Z, Sothern M, Udall JN, Kahle B, Leibel RL (September 1997). "Exonic and intronic sequence variation in the human leptin receptor gene (LEPR)". Diabetes. 46 (9): 1509–11. doi:10.2337/diab.46.9.1509. PMID 9287054.
  • Bjørbaek C, Uotani S, da Silva B, Flier JS (December 1997). "Divergent signaling capacities of the long and short isoforms of the leptin receptor". The Journal of Biological Chemistry. 272 (51): 32686–95. doi:10.1074/jbc.272.51.32686. PMID 9405487.
  • Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougnères P, Lebouc Y, Froguel P, Guy-Grand B (March 1998). "A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction". Nature. 392 (6674): 398–401. doi:10.1038/32911. PMID 9537324.
  • Carpenter LR, Farruggella TJ, Symes A, Karow ML, Yancopoulos GD, Stahl N (May 1998). "Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor". Proceedings of the National Academy of Sciences of the United States of America. 95 (11): 6061–6. doi:10.1073/pnas.95.11.6061. PMC 27585. PMID 9600917.
  • Kielar D, Clark JS, Ciechanowicz A, Kurzawski G, Sulikowski T, Naruszewicz M (July 1998). "Leptin receptor isoforms expressed in human adipose tissue". Metabolism. 47 (7): 844–7. doi:10.1016/S0026-0495(98)90124-X. PMID 9667233.
  • Haniu M, Arakawa T, Bures EJ, Young Y, Hui JO, Rohde MF, Welcher AA, Horan T (October 1998). "Human leptin receptor. Determination of disulfide structure and N-glycosylation sites of the extracellular domain". The Journal of Biological Chemistry. 273 (44): 28691–9. doi:10.1074/jbc.273.44.28691. PMID 9786864.
  • Haft CR, de la Luz Sierra M, Barr VA, Haft DH, Taylor SI (December 1998). "Identification of a family of sorting nexin molecules and characterization of their association with receptors". Molecular and Cellular Biology. 18 (12): 7278–87. doi:10.1128/mcb.18.12.7278. PMC 109309. PMID 9819414.

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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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