Leptin 214938 224786079 2008-07-10T12:13:40Z AndrewGNF 3172211 rvv {{Cleanup-jargon|date=March 2008}} <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB|geneid=3952}} {{protein | Name = [[leptin receptor]] | caption = | image = | width = | HGNCid = 6554 | Symbol = [[LEPR]] | AltSymbols = | EntrezGene = 3953 | OMIM = 601007 | RefSeq = NM_002303 | UniProt = P48357 | PDB = | ECnumber = | Chromosome = 1 | Arm = p | Band = 31 | LocusSupplementaryData = }} '''Leptin''' (Greek ''leptos'' meaning thin) is a 16 [[Atomic mass unit|kDa]] [[protein]] [[hormone]] that plays a key role in regulating energy intake and energy expenditure, including [[appetite]] and [[metabolism]]. Leptin is one of the most important [[adipose derived hormones]]. The effects of leptin were observed by studying [[mutant]] [[Obesity|obese]] [[mice]] that arose at random within a mouse colony at the [[Jackson Laboratory]] in 1950. These mice were massively obese and [[hyperphagic]]. Leptin itself was discovered in 1994 by [[Jeffrey M. Friedman]] and colleagues at the [[Rockefeller University]] through the study of such mice. The ''Ob(Lep)'' gene (Ob for obese, Lep for leptin) is located on [[chromosome 7]] in humans. Leptin is produced by [[adipose tissue]] and interacts with six types of receptor (LepRa&ndash;LepRf). LepRb is the only receptor isoform that contains active intracellular signaling domains. This receptor is present in a number of [[hypothalamus|hypothalamic nuclei]]. Leptin binds to the [[ventromedial nucleus]] of the [[hypothalamus]], known as the "'''appetite center'''." Leptin signals to the brain that the body has had enough to eat, or satiety. A very small group of humans possess [[homozygous mutation]]s for the leptin gene which leads to a constant desire for food, resulting in severe obesity. This condition can be successfully treated by the administration of recombinant human leptin.<ref>[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164160&rn=1 OMIM - LEPTIN; LEP]</ref> Thus, circulating leptin levels give the brain input regarding energy storage so it can regulate [[appetite]] and [[metabolism]]. Leptin works by inhibiting the activity of [[neurons]] that contain [[neuropeptide Y]] (NPY) and [[agouti-related peptide]] (AgRP), and by increasing the activity of [[neurons]] expressing [[melanocyte-stimulating hormone|α-melanocyte-stimulating hormone]] (α-MSH). The NPY neurons are a key element in the regulation of appetite; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become [[anorexia (symptom)|anorexic]]. Conversely, α-MSH is an important mediator of satiety, and differences in the [[gene]] for the receptor at which α-MSH acts in the brain are linked to [[obesity]] in humans. There is some controversy regarding the regulation of leptin by [[melatonin]] during the night. One research group suggested that increased levels of [[melatonin]] caused a downregulation of leptin.<ref>{{cite journal |author=Kus I, Sarsilmaz M, Colakoglu N, ''et al'' |title=Pinealectomy increases and exogenous melatonin decreases leptin production in rat anterior pituitary cells: an immunohistochemical study |journal=Physiological research / Academia Scientiarum Bohemoslovaca |volume=53 |issue=4 |pages=403–8 |year=2004 |pmid=15311999 |doi=}}</ref> However, in 2004, Brazilian researchers found that in the presence of [[insulin]], "melatonin interacts with insulin and upregulates insulin-stimulated leptin expression", therfore causing a decrease in appetite whilst sleeping.<ref>{{cite journal | last = Alonso-Vale | first = Maria Isabel Cardoso | coauthors = Sandra Andreotti, Sidney Barnabe Peres, Gabriel Forato Anhe, Cristina das Neves Borges-Silva, Jose Cipolla Neto, Fabio Bessa Lima | year = 2004 | month = November | title = Melatonin Enhances Leptin Expression by Rat Adipocytes in the Presence of Insulin (abstract) | journal = Am J Physiol Endocrinol Metab | url = http://ajpendo.physiology.org/cgi/content/short/00478.2004v1 | accessdate = 2007-12-15 | quote = }}</ref> ==Leptin as adiposity signal== To date, only leptin and [[insulin]] fulfill the criteria of an adiposity signal: * It circulates at levels proportional to [[adipose tissue|body fat]]. * It enters the [[central nervous system]] (CNS) in proportion to its [[blood plasma|plasma]] concentration. * Its receptors are found in brain neurons involved in regulating energy intake and expenditure. == Mechanism of action == It is unknown whether leptin can cross the [[blood-brain barrier]] to access receptor neurons, because the blood-brain barrier is somewhat absent in the area of the [[median eminence]], close to where the NPY neurons of the arcuate [[nucleus (neuroanatomy)|nucleus]] are. It is generally thought that leptin might enter the brain at the [[choroid plexus]], where there is intense expression of a form of leptin receptor molecule that could act as a transport mechanism. Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to, presumably, effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression of [[endocannabinoids]], responsible for increasing appetite. There are other intracellular pathways activated by leptin, but less is known about how they function in this system. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them. Although leptin is a circulating signal that reduces appetite, in general, obese people have an unusually high circulating concentration of leptin.<ref>{{cite journal |author=Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ & Bauer TL |title=Serum Immunoreactive-Leptin Concentrations in Normal-Weight and Obese Humans |journal= N Engl J Med |volume=334 |issue=5 |pages=292-295 |year=1996 |pmid=8532024 |doi=10.1056/NEJM199602013340503}}</ref> These people are said to be resistant to the effects of leptin, in much the same way that people with [[type 2 diabetes]] are [[insulin resistance|resistant]] to the effects of [[insulin]]. The high sustained concentrations of leptin from the enlarged [[adipose]] stores result in leptin desensitization. The pathway of leptin control in obese people might be flawed at some point so the body doesn't adequately receive the satiety feeling subsequently to eating. In mice, leptin is also required for male and female [[fertility]]. In [[mammals]] such as humans puberty in females is linked to a critical level of body fat. When fat levels fall below this threshold (as in anorexia), the ovarian cycle stops and females stop menstruating. Leptin is also strongly linked with [[angiogenesis]], increasing [[vascular endothelial growth factor|VEGF]] levels. == Leptin and reproduction == The body's fat cells, under normal conditions, are responsible for the constant production and release of leptin. This can also be produced by the [[placenta]].<ref>{{cite journal |author=Zhao J, Townsend KL, Schulz LC, Kunz TH, Li C, Widmaier EP |title=Leptin receptor expression increases in placenta, but not hypothalamus, during gestation in Mus musculus and Myotis lucifugus |journal=Placenta |volume=25 |issue=8-9 |pages=712–22 |year=2004 |pmid=15450389 |doi=10.1016/j.placenta.2004.01.017}}</ref> Leptin levels rise during pregnancy and fall after parturition (childbirth). Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin.<ref>{{cite journal |author=Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ |title=Inhibitory effect of leptin on human uterine contractility ''in vitro'' |journal=Am. J. Obstet. Gynecol. |volume=195 |issue=2 |pages=504-9 |year=2006 |pmid=16647683 |doi=10.1016/j.ajog.2006.01.106}}</ref> == Recent discoveries == Professor Cappuccio of the [[University of Warwick]] has recently discovered that short sleep duration may lead to [[obesity]] through an increase of appetite via hormonal changes. Lack of sleep produces [[ghrelin]], a hormone that stimulates appetite by lowering leptin levels. Next to a [[biomarker]] for body fat, serum leptin levels also reflect individual energy balance. Several studies have shown that [[fasting]] or following a [[very low calorie diet]] (VLCD) lowers leptin levels.<ref>Studies include: * {{cite journal |author=Dubuc G, Phinney S, Stern J, Havel P |title=Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and women |journal=Metab. Clin. Exp. |volume=47 |issue=4 |pages=429-34 |year=1998 |pmid=9550541}} * {{cite journal |author=Pratley R, Nicolson M, Bogardus C, Ravussin E |title=Plasma leptin responses to fasting in Pima Indians |journal=Am. J. Physiol. |volume=273 |issue=3 Pt 1 |pages=E644-9 |year=1997 |pmid=9316457}} * {{cite journal |author=Weigle D, Duell P, Connor W, Steiner R, Soules M, Kuijper J |title=Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels |journal=J. Clin. Endocrinol. Metab. |volume=82 |issue=2 |pages=561-5 |year=1997 |pmid=9024254 |doi=10.1210/jc.82.2.561}}</ref> It might be that on short term leptin is an indicator of energy balance. This system is more sensitive to starvation than to overfeeding,<ref>{{cite journal |author=Chin-Chance C, Polonsky K, Schoeller D |title=Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake |journal=J. Clin. Endocrinol. Metab. |volume=85 |issue=8 |pages=2685-91 |year=2000 |pmid=10946866 |doi=10.1210/jc.85.8.2685}}</ref> i.e. leptin levels do not rise extensively after overfeeding. It might be that the dynamics of leptin due to an acute change in energy balance are related to appetite and eventually in food intake. Although this is a new hypothesis, there is already some data that supports it.<ref>{{cite journal |author=Keim N, Stern J, Havel P |title=Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women |journal=Am. J. Clin. Nutr. |volume=68 |issue=4 |pages=794-801 |year=1998 |pmid=9771856}}</ref><ref>{{cite journal |author=Mars M, de Graaf C, de Groot C, van Rossum C, Kok F |title=Fasting leptin and appetite responses induced by a 4-day 65%-energy-restricted diet |journal=International journal of obesity (Lond) |volume=30 |issue=1 |pages=122-8 |year=2006 |pmid=16158086}}</ref> There is some recognition that leptin action is more decentralized than previously assumed. In addition to its endocrine action at a distance (from adipose tissue to brain), leptin also acts as a [[paracrine]] mediator.<ref name=Margetic>{{cite journal |author=Margetic S, Gazzola C, Pegg GG, Hill RA |title=Leptin: a review of its peripheral actions and interactions |journal=Int. J. Obes. Relat. Metab. Disord. |volume=26 |issue=11 |pages=1407-33 |year=2002 |doi= 10.1038/sj.ijo.0802142 |pmid=12439643}}</ref> In [[fetal]] lung leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of [[PTHrP]] secreted by formative alveolar epithelium (endoderm) under moderate stretch. The leptin from the mesenchyme in turn acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression which is one of the main functions of these type II pneumocytes.<ref>{{cite journal |author=John S. Torday, Virender K. Rehan |title=Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network |journal=Pediatr. Res. |volume=60 |issue=4 |pages=382-8 |year=2006 |pmid=16940239}} — published online before print as DOI 10.1203/01.pdr.0000238326.42590.03</ref> In addition to white adipose tissue -the major source of leptin, it can also be produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (lower part of fundic glands), mammary epithelial cells, bone marrow, pituitary and liver.<ref name=Margetic /> There is also evidence that leptin plays a role in [[hyperemesis gravidarum]] (severe [[morning sickness]]),<ref>{{cite journal |author=Aka N, Atalay S, Sayharman S, Kiliç D, Köse G, Küçüközkan T |title=Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum |journal=The Australian & New Zealand journal of obstetrics & gynaecology |volume=46 |issue=4 |pages=274-7 |year=2006 |pmid=16866785}}</ref> in [[polycystic ovary syndrome]]<ref>{{cite journal |author=Cervero A, Domínguez F, Horcajadas JA, Quiñonero A, Pellicer A, Simón C |title=The role of the leptin in reproduction |journal=Curr. Opin. Obstet. Gynecol. |volume=18 |issue=3 |pages=297-303 |year=2006 |pmid=16735830}}</ref><!-- to check: literature is controversial --> and a 2007 research suggest that hypothalamic leptin is implicated in bone growth.<ref>{{cite journal |author=Iwaniec UT, Boghossian S, Lapke PD, Turner RT, Kalra SP |title=Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice |journal=Peptides |volume= |issue= |pages= |year=2007 |pmid=17346852 |pages=1012 |doi=10.1016/j.peptides.2007.02.001}}</ref> ====Modulation of T cells activity in immune system==== The important role of Leptin/Leptin receptors were shown in experimentation with mice. It modulates the immune response to atherosclerosis, which is a predisposing factor in patients with obesity. <ref name=Taleb> {{cite journal | author=Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V, Merval R, Esposito B, Clément K, Holvoet P, Tedgui A, Mallat Z. | title=Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis. | journal=Arterioscler Thromb Vasc Biol. | year=2007 | pages=2691-2698 | volume=27 | issue=12 | pmid=17690315 | doi=10.1161/ATVBAHA.107.149567 }}</ref> == See Also == * [[Orexin]] == References == {{reflist}} == Further reading == {{refbegin|2}} * {{cite journal |author=Torday JS, Sun H, Wang L, Torres E, Sunday ME, Rubin LP |title=Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation |journal=Am. J. Physiol. Lung Cell Mol. Physiol. |volume=282 |issue=3 |pages=L405-10 |year=2002 |month=Mar |pmid=11839533}} * {{cite journal |author=Torday JS, Rehan VK |title=Stretch-stimulated surfactant synthesis is coordinated by the paracrine actions of PTHrP and leptin |journal=Am. J. Physiol. Lung Cell Mol. Physiol. |volume=283 |issue=1 |pages=L130-5 |year=2002 |month=Jul |pmid=12060569}} {{PBB_Further_reading | citations = *{{cite journal | author=Friedman JM, Halaas JL |title=Leptin and the regulation of body weight in mammals. |journal=Nature |volume=395 |issue= 6704 |pages= 763-70 |year= 1998 |pmid= 9796811 |doi= 10.1038/27376 }} *{{cite journal | author=Prolo P, Wong ML, Licinio J |title=Leptin. |journal=Int. J. Biochem. Cell Biol. |volume=30 |issue= 12 |pages= 1285-90 |year= 1999 |pmid= 9924798 |doi= }} *{{cite journal | author=Heshka JT, Jones PJ |title=A role for dietary fat in leptin receptor, OB-Rb, function. |journal=Life Sci. |volume=69 |issue= 9 |pages= 987-1003 |year= 2001 |pmid= 11508653 |doi= | doi=10.1016/S0024-3205(01)01201-2}} *{{cite journal | author=Janeckova R |title=The role of leptin in human physiology and pathophysiology. |journal=Physiological research / Academia Scientiarum Bohemoslovaca |volume=50 |issue= 5 |pages= 443-59 |year= 2002 |pmid= 11702849 |doi= }} *{{cite journal | author=Lee DW, Leinung MC, Rozhavskaya-Arena M, Grasso P |title=Leptin and the treatment of obesity: its current status. |journal=Eur. J. Pharmacol. |volume=440 |issue= 2-3 |pages= 129-39 |year= 2002 |pmid= 12007531 |doi= | doi=10.1016/S0014-2999(02)01424-3}} *{{cite journal | author=Al-Daghri N, Bartlett WA, Jones AF, Kumar S |title=Role of leptin in glucose metabolism in type 2 diabetes. |journal=Diabetes, obesity & metabolism |volume=4 |issue= 3 |pages= 147-55 |year= 2002 |pmid= 12047393 |doi= }} *{{cite journal | author=Sabath Silva EF |title=[Leptin] |journal=Rev. Invest. Clin. |volume=54 |issue= 2 |pages= 161-5 |year= 2002 |pmid= 12053815 |doi= }} *{{cite journal | author=Thomas T, Burguera B |title=Is leptin the link between fat and bone mass? |journal=J. Bone Miner. Res. |volume=17 |issue= 9 |pages= 1563-9 |year= 2003 |pmid= 12211425 |doi= }} *{{cite journal | author=Kraemer RR, Chu H, Castracane VD |title=Leptin and exercise. |journal=Exp. Biol. Med. (Maywood) |volume=227 |issue= 9 |pages= 701-8 |year= 2002 |pmid= 12324651 |doi= }} *{{cite journal | author=Waelput W, Brouckaert P, Broekaert D, Tavernier J |title=A role for leptin in the systemic inflammatory response syndrome (SIRS) and in immune response. |journal=Current drug targets. Inflammation and allergy |volume=1 |issue= 3 |pages= 277-89 |year= 2003 |pmid= 14561193 |doi= }} *{{cite journal | author=Stenvinkel P, Pecoits-Filho R, Lindholm B |title=Leptin, ghrelin, and proinflammatory cytokines: compounds with nutritional impact in chronic kidney disease? |journal=Advances in renal replacement therapy |volume=10 |issue= 4 |pages= 332-45 |year= 2004 |pmid= 14681862 |doi= }} *{{cite journal | author=Cohen P, Ntambi JM, Friedman JM |title=Stearoyl-CoA desaturase-1 and the metabolic syndrome. |journal=Curr. Drug Targets Immune Endocr. Metabol. Disord. |volume=3 |issue= 4 |pages= 271-80 |year= 2004 |pmid= 14683458 |doi= }} *{{cite journal | author=Sahu A |title=Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. |journal=Frontiers in neuroendocrinology |volume=24 |issue= 4 |pages= 225-53 |year= 2004 |pmid= 14726256 |doi= }} *{{cite journal | author=Elefteriou F, Karsenty G |title=[Bone mass regulation by leptin: a hypothalamic control of bone formation] |journal=Pathol. Biol. |volume=52 |issue= 3 |pages= 148-53 |year= 2004 |pmid= 15063934 |doi= 10.1016/j.patbio.2003.05.006 }} *{{cite journal | author=Blüher S, Mantzoros CS |title=The role of leptin in regulating neuroendocrine function in humans. |journal=J. Nutr. |volume=134 |issue= 9 |pages= 2469S-2474S |year= 2004 |pmid= 15333744 |doi= }} *{{cite journal | author=Farooqi S, O'Rahilly S |title=Genetics of obesity in humans. |journal=Endocr. Rev. |volume=27 |issue= 7 |pages= 710-18 |year= 2007 |pmid= 17122358 |doi= 10.1210/er.2006-0040 }} }} {{refend}} == External links == *[http://www.scq.ubc.ca/?p=421 Leptin biology from the Science Creative Quarterly] *[http://www.hhmi.org/bulletin/mar2003/leptin/leptin2.html Leptin in a bulletin by the Howard Hughes Medical Institute (HHMI)] *[http://www.nature.com/nature/journal/v395/n6704/full/395763a0.html Review article "Leptin and the regulation of body weight in mammals" from Nature] *[http://neuroendo.org.uk/index.php/content/view/8/11/ Leptin: Your brain, appetite and obesity by the British Society of Neuroendocrinology] *[http://www.hungerhormones.com/index.html Leptin/ghrelin and their role in obesity from hungerhormones.com], a weight control website *[http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/bodyweight/leptin.html Leptin by Colorado State University] *[http://www.3dchem.com/molecules.asp?ID=154 Leptin at 3Dchem.com], description and structure diagrams {{hormones}} [[Category:Peptide hormones]] [[ca:Leptina]] [[cs:Leptin]] [[de:Leptin]] [[es:Leptina]] [[fr:Leptine]] [[it:Leptina]] [[he:לפטין]] [[nl:Leptine]] [[ja:レプチン]] [[pl:Leptyna]] [[pt:Leptina]] [[ru:Лептин]] [[sv:Leptin]] [[zh:肥胖荷爾蒙]] {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = no | update_citations = yes }}