Leptin receptor explained

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

Animal 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.

Further reading

• Heshka JT, Jones PJ . A role for dietary fat in leptin receptor, OB-Rb, function . Life Sciences . 69 . 9 . 987–1003 . July 2001 . 11508653 . 10.1016/S0024-3205(01)01201-2 .
• 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 . 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 . 491–495 . February 1996 . 8608603 . 10.1016/S0092-8674(00)81294-5 . 13885070 . free .
• Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, Snodgrass HR . Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction . Nature Medicine . 2 . 5 . 585–589 . May 1996 . 8616721 . 10.1038/nm0596-585 . 34023921 .
• Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF . 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 . 992–994 . July 1996 . 8666155 . 10.2337/diabetes.45.7.992 .
• Chung WK, Power-Kehoe L, Chua M, Leibel RL . Mapping of the OB receptor to 1p in a region of nonconserved gene order from mouse and rat to human . Genome Research . 6 . 5 . 431–438 . May 1996 . 8743992 . 10.1101/gr.6.5.431 . free .
• Bennett BD, Solar GP, Yuan JQ, Mathias J, Thomas GR, Matthews W . A role for leptin and its cognate receptor in hematopoiesis . Current Biology . 6 . 9 . 1170–1180 . September 1996 . 8805376 . 10.1016/S0960-9822(02)70684-2 . 18149439 . free . 1996CBio....6.1170B .
• Luoh SM, Di Marco F, Levin N, Armanini M, Xie MH, Nelson C, Bennett GL, Williams M, Spencer SA, Gurney A, de Sauvage FJ . Cloning and characterization of a human leptin receptor using a biologically active leptin immunoadhesin . Journal of Molecular Endocrinology . 18 . 1 . 77–85 . February 1997 . 9061609 . 10.1677/jme.0.0180077 .
• Echwald SM, Sørensen TD, Sørensen TI, Tybjaerg-Hansen A, Andersen T, Chung WK, Leibel RL, Pedersen O . Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity . Biochemical and Biophysical Research Communications . 233 . 1 . 248–252 . April 1997 . 9144432 . 10.1006/bbrc.1997.6430 .
• Thompson DB, Ravussin E, Bennett PH, Bogardus C . Structure and sequence variation at the human leptin receptor gene in lean and obese Pima Indians . Human Molecular Genetics . 6 . 5 . 675–679 . May 1997 . 9158141 . 10.1093/hmg/6.5.675 . free .
• Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, McKeigue PM, Scott J, Aitman TJ . Leptin receptor gene variation and obesity: lack of association in a white British male population . Human Molecular Genetics . 6 . 6 . 869–876 . June 1997 . 9175732 . 10.1093/hmg/6.6.869 . free .
• Bailleul B, Akerblom I, Strosberg AD . The leptin receptor promoter controls expression of a second distinct protein . Nucleic Acids Research . 25 . 14 . 2752–2758 . July 1997 . 9207021 . 146799 . 10.1093/nar/25.14.2752 .
• Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma Z, Sothern M, Udall JN, Kahle B, Leibel RL . Exonic and intronic sequence variation in the human leptin receptor gene (LEPR) . Diabetes . 46 . 9 . 1509–1511 . September 1997 . 9287054 . 10.2337/diab.46.9.1509 . free .
• Bjørbaek C, Uotani S, da Silva B, Flier JS . Divergent signaling capacities of the long and short isoforms of the leptin receptor . The Journal of Biological Chemistry . 272 . 51 . 32686–32895 . December 1997 . 9405487 . 10.1074/jbc.272.51.32686 . free .
• 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 . A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction . Nature . 392 . 6674 . 398–401 . March 1998 . 9537324 . 10.1038/32911 . 1998Natur.392..398C . 4400661 .
• Carpenter LR, Farruggella TJ, Symes A, Karow ML, Yancopoulos GD, Stahl N . 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 . 6061–6066 . May 1998 . 9600917 . 27585 . 10.1073/pnas.95.11.6061 . 1998PNAS...95.6061R . free .
• Kielar D, Clark JS, Ciechanowicz A, Kurzawski G, Sulikowski T, Naruszewicz M . Leptin receptor isoforms expressed in human adipose tissue . Metabolism . 47 . 7 . 844–847 . July 1998 . 9667233 . 10.1016/S0026-0495(98)90124-X .
• Haniu M, Arakawa T, Bures EJ, Young Y, Hui JO, Rohde MF, Welcher AA, Horan T . Human leptin receptor. Determination of disulfide structure and N-glycosylation sites of the extracellular domain . The Journal of Biological Chemistry . 273 . 44 . 28691–28699 . October 1998 . 9786864 . 10.1074/jbc.273.44.28691 . free.
• Haft CR, de la Luz Sierra M, Barr VA, Haft DH, Taylor SI . Identification of a family of sorting nexin molecules and characterization of their association with receptors . Molecular and Cellular Biology . 18 . 12 . 7278–7387 . December 1998 . 9819414 . 109309 . 10.1128/mcb.18.12.7278 .

Notes and References

1. Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N . Leptin signaling in breast cancer: an overview . Journal of Cellular Biochemistry . 105 . 4 . 956–64 . November 2008 . 18821585 . 10.1002/jcb.21911 . 25572220 .
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 . Identification and expression cloning of a leptin receptor, OB-R . Cell . 83 . 7 . 1263–71 . December 1995 . 8548812 . 10.1016/0092-8674(95)90151-5 . free .
3. Winick JD, Stoffel M, Friedman JM . Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1 . Genomics . 36 . 1 . 221–2 . August 1996 . 8812446 . 10.1006/geno.1996.0455 .
4. 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 . Identification and expression cloning of a leptin receptor, OB-R . Cell . 83 . 7 . 1263–71 . December 1995 . 8548812 . 10.1016/0092-8674(95)90151-5 . free .
5. 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 . 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 . 8608603 . 10.1016/S0092-8674(00)81294-5 . 13885070 . free .
6. Chung WK, Power-Kehoe L, Chua M, Leibel RL . 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 . 8743992 . 10.1101/gr.6.5.431 . free .
7. Leibel RL . Molecular physiology of weight regulation in mice and humans . International Journal of Obesity . 32 Suppl 7 . S7 . S98-108 . December 2008 . 19136999 . 2682360 . 10.1038/ijo.2008.245 .
8. Wauman J, Zabeau L, Tavernier J . The Leptin Receptor Complex: Heavier Than Expected? . en . Frontiers in Endocrinology . 8 . 30 . 2017 . 28270795 . 10.3389/fendo.2017.00030 . 5318964. free .
9. Mancour LV, Daghestani HN, Dutta S, Westfield GH, Schilling J, Oleskie AN, Herbstman JF, Chou SZ, Skiniotis G . Ligand-induced architecture of the leptin receptor signaling complex . en . Molecular Cell . 48 . 4 . 655–61 . November 2012 . 23063524 . 10.1016/j.molcel.2012.09.003 . 3513567.
10. Moharana K, Zabeau L, Peelman F, Ringler P, Stahlberg H, Tavernier J, Savvides SN . Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins . Structure . 22 . 6 . 866–77 . June 2014 . 24882746 . 10.1016/j.str.2014.04.012 . free .
11. Web site: Entrez Gene: LEPR leptin receptor.
12. 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 . Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis . PLOS Biology . 11 . 3 . e1001506 . March 12, 2013 . 23554574 . 3595213 . 10.1371/journal.pbio.1001506 . free .
13. Considine RV, Considine EL, Williams CJ, Nyce MR, Zhang P, Opentanova I, Ohannesian JP, Kolaczynski JW, Bauer TL, Moore JH, Caro JF . 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 . 8607834 . 10.1006/bbrc.1996.0473 .
14. Masuo K, Straznicky NE, Lambert GW, Katsuya T, Sugimoto K, Rakugi H, Socratous F, Hastings J, Lambert EA, Ogihara T, Esler MD . 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 . 18716356 . 10.1291/hypres.31.1093 . free .
15. 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 . 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 . 21393862 . 3049405 . 10.1172/JCI45294 .
16. Sharma K, McCue P, Dunn SR . Diabetic kidney disease in the db/db mouse . American Journal of Physiology. Renal Physiology . 284 . 6 . F1138–44 . June 2003 . 12736165 . 10.1152/ajprenal.00315.2002 .
17. Oh KS, Kim EY, Yoon M, Lee CM . Swim training improves leptin receptor deficiency-induced obesity and lipid disorder by activating uncoupling proteins . Experimental & Molecular Medicine . 39 . 3 . 385–94 . June 2007 . 17603293 . 10.1038/emm.2007.43 . free .
18. Briffa JF, McAinch AJ, Romano T, Wlodek ME, Hryciw DH . Leptin in pregnancy and development: a contributor to adulthood disease? . American Journal of Physiology. Endocrinology and Metabolism . 308 . 5 . E335-50 . March 2015 . 25516549 . 10.1152/ajpendo.00312.2014 .
19. Sagawa N, Yura S, Itoh H, Kakui K, Takemura M, Nuamah MA, Ogawa Y, Masuzaki H, Nakao K, Fujii S . Possible role of placental leptin in pregnancy: a review . Endocrine . 19 . 1 . 65–71 . October 2002 . 12583603 . 10.1385/ENDO:19:1:65 . 46986648 .