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 LEPRgene.[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
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
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
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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. PMID18821585. S2CID25572220.
^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. PMID8812446.
^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. PMID8607834.
^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. PMID12736165.
^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. PMID25516549.
^ abSagawa 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. PMID12583603. S2CID46986648.
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. PMID11508653.
Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, et al. (May 1996). "Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction". Nature Medicine. 2 (5): 585–589. doi:10.1038/nm0596-585. PMID8616721. S2CID34023921.
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): 992–994. doi:10.2337/diabetes.45.7.992. PMID8666155.
Luoh SM, Di Marco F, Levin N, Armanini M, Xie MH, Nelson C, et al. (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. PMID9061609.
Echwald SM, Sørensen TD, Sørensen TI, Tybjaerg-Hansen A, Andersen T, Chung WK, et al. (April 1997). "Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity". Biochemical and Biophysical Research Communications. 233 (1): 248–252. doi:10.1006/bbrc.1997.6430. PMID9144432.
