“Leptin receptor”的意思、由来-开放百科全书

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. ^{{cite journal | vauthors = Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N | title = Leptin signaling in breast cancer: an overview | journal = Journal of Cellular Biochemistry | volume = 105 | issue = 4 | pages = 956–64 | date = November 2008 | pmid = 18821585 | doi = 10.1002/jcb.21911 }}
2. ^{{cite journal | vauthors = 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 | title = Identification and expression cloning of a leptin receptor, OB-R | journal = Cell | volume = 83 | issue = 7 | pages = 1263–71 | date = December 1995 | pmid = 8548812 | pmc = | doi = 10.1016/0092-8674(95)90151-5 }}
3. ^{{cite journal | vauthors = Winick JD, Stoffel M, Friedman JM | title = Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1 | journal = Genomics | volume = 36 | issue = 1 | pages = 221–2 | date = August 1996 | pmid = 8812446 | pmc = | doi = 10.1006/geno.1996.0455 }}
4. ^{{cite journal | vauthors = Leibel RL | title = Molecular physiology of weight regulation in mice and humans | journal = International Journal of Obesity | volume = 32 Suppl 7 | issue = S7 | pages = S98–108 | date = December 2008 | pmid = 19136999 | pmc = 2682360 | doi = 10.1038/ijo.2008.245 }}
5. ^¹²³⁴{{cite journal | vauthors = Wauman J, Zabeau L, Tavernier J | title = The Leptin Receptor Complex: Heavier Than Expected? | language = English | journal = Frontiers in Endocrinology | volume = 8 | pages = 30 | date = 2017 | pmid = 28270795 | doi = 10.3389/fendo.2017.00030 | pmc=5318964}}
6. ^{{cite journal | vauthors = Mancour LV, Daghestani HN, Dutta S, Westfield GH, Schilling J, Oleskie AN, Herbstman JF, Chou SZ, Skiniotis G | title = Ligand-induced architecture of the leptin receptor signaling complex | language = English | journal = Molecular Cell | volume = 48 | issue = 4 | pages = 655–61 | date = November 2012 | pmid = 23063524 | doi = 10.1016/j.molcel.2012.09.003 | url = http://www.cell.com/molecular-cell/abstract/S1097-2765(12)00779-4 | pmc=3513567}}
7. ^{{cite journal | vauthors = Moharana K, Zabeau L, Peelman F, Ringler P, Stahlberg H, Tavernier J, Savvides SN | title = Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins | journal = Structure | volume = 22 | issue = 6 | pages = 866–77 | date = June 2014 | pmid = 24882746 | doi = 10.1016/j.str.2014.04.012 | url = http://www.sciencedirect.com/science/article/pii/S0969212614001361 }}
8. ^{{cite web | title = Entrez Gene: LEPR leptin receptor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3953| accessdate = }}
9. ^{{cite journal | vauthors = 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 | title = Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis | journal = PLoS Biology | volume = 11 | issue = 3 | pages = e1001506 | date = March 12, 2013 | pmid = 23554574 | pmc = 3595213 | doi = 10.1371/journal.pbio.1001506 }}
10. ^{{cite journal | vauthors = Considine RV, Considine EL, Williams CJ, Nyce MR, Zhang P, Opentanova I, Ohannesian JP, Kolaczynski JW, Bauer TL, Moore JH, Caro JF | title = Mutation screening and identification of a sequence variation in the human ob gene coding region | journal = Biochemical and Biophysical Research Communications | volume = 220 | issue = 3 | pages = 735–9 | date = March 1996 | pmid = 8607834 | doi = 10.1006/bbrc.1996.0473 }}
11. ^{{cite journal | vauthors = Masuo K, Straznicky NE, Lambert GW, Katsuya T, Sugimoto K, Rakugi H, Socratous F, Hastings J, Lambert EA, Ogihara T, Esler MD | title = Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population | journal = Hypertension Research | volume = 31 | issue = 6 | pages = 1093–100 | date = June 2008 | pmid = 18716356 | doi = 10.1291/hypres.31.1093 }}
12. ^{{cite journal | vauthors = 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 | title = A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children | journal = The Journal of Clinical Investigation | volume = 121 | issue = 3 | pages = 1191–8 | date = March 2011 | pmid = 21393862 | pmc = 3049405 | doi = 10.1172/JCI45294 }}
13. ^{{cite journal | vauthors = Sharma K, McCue P, Dunn SR | title = Diabetic kidney disease in the db/db mouse | journal = American Journal of Physiology. Renal Physiology | volume = 284 | issue = 6 | pages = F1138–44 | date = June 2003 | pmid = 12736165 | doi = 10.1152/ajprenal.00315.2002 }}
14. ^{{cite journal | vauthors = Oh KS, Kim EY, Yoon M, Lee CM | title = Swim training improves leptin receptor deficiency-induced obesity and lipid disorder by activating uncoupling proteins | journal = Experimental & Molecular Medicine | volume = 39 | issue = 3 | pages = 385–94 | date = June 2007 | pmid = 17603293 | doi = 10.1038/emm.2007.43 }}