Leptin (obesity homolog, mouse)
|PDB rendering based on 1ax8.|
|RNA expression pattern|
|Locus||Chr. 1 p31|
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Leptin (from the Greek word leptos, meaning thin) is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including the regulation (decrease) of appetite and (increase) of metabolism.
The effects of leptin were observed by studying mutant 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 those mutant mice. The Ob(Lep) gene (Ob for obese and Lep for leptin) is located on chromosome 7 in humans. Leptin is produced by adipose tissue and interacts with six types of receptor (LepRa–LepRf). LepRb is the only receptor isoform that contains active intracellular signaling domains. This receptor is present in a number of hypothalamic nuclei, where it exerts its effects. Importantly, leptin binds to the ventral medial nucleus of the hypothalamus, known as the "appetite center." Binding of leptin to this nucleus signals to the brain that the body has had enough to eat—a sensation of satiety. A very small group of humans possess homozygous mutations for the leptin gene which lead to a constant demand for food, resulting in severe obesity. This condition can be successfully treated by the administration of recombinant human leptin.
Thus, circulating leptin levels give the brain a reading of energy storage for the purposes of regulating 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 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 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.
Leptin is also regulated (downward) by melatonin during the night. Brazilian researchers found in 2004 that, in the presence of insulin, "melatonin interacts with insulin and upregulates insulin-stimulated leptin expression."
Leptin as adiposity signal
To date, only leptin and insulin fulfill the criteria of an adiposity signal:
- It circulates at levels proportional to body fat.
- It enters the central nervous system (CNS) in proportion to its 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 are. If it does cross the blood-brain barrier, it is unknown whether this occurs via an active or passive process. 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 might act as a transport mechanism.
Once leptin has bound to the Ob-Rb receptor, it activates the molecule stat3, which is phosphorylated and travels to the nucleus, it is presumed, to effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression of endocannabinoids, responsible—among their many other functions—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. These people are said to be resistant to the effects of leptin, in much the same way that people with type 2 diabetes are resistant to the effects of insulin. Thus, obesity develops when people take in more energy than they use over a prolonged period of time, and this excess food intake is not driven by hunger signals, occurring in spite of the anti-appetite signals from circulating leptin. The high sustained concentrations of leptin from the enlarged fat stores result in the cells that respond to leptin becoming desensitized.
In mice, leptin is also required for male and female fertility. In mammals generally, and in humans in particular, 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 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. Leptin levels rise during pregnancy and fall at parturition (childbirth). Leptin is also expressed in fetal membranes and uterine tissue. Uterine muscle contractions are inhibited by leptin.
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 which, among other effects, stimulates appetite and creates less leptin which, amongst its many other effects, suppresses appetite.
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. It might be that on short term leptin is an indicator of energy balance. In line with evolution this system is more sensitive to starvation than to overfeeding, 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.
There is gradual 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. 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. 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.
There is also evidence that leptin plays a role in hyperemesis gravidarum (severe morning sickness), in polycystic ovary syndrome and a 2007 research suggest that hypothalamic leptin is implicated in bone growth.
Modulation of T cells activity in immune system
The important role of Leptin/Leptin receptors were shown in this experiment with mice. It modulates the immune response to atherosclerosis, which is a predisposing factor in patients with obesity. 
- OMIM - LEPTIN; LEP
- Kus I, Sarsilmaz M, Colakoglu N, et al (2004). "Pinealectomy increases and exogenous melatonin decreases leptin production in rat anterior pituitary cells: an immunohistochemical study". Physiological research / Academia Scientiarum Bohemoslovaca 53 (4): 403–8. PMID 15311999.
- Alonso-Vale, Maria Isabel Cardoso; Sandra Andreotti, Sidney Barnabe Peres, Gabriel Forato Anhe, Cristina das Neves Borges-Silva, Jose Cipolla Neto, Fabio Bessa Lima (November 2004). "Melatonin Enhances Leptin Expression by Rat Adipocytes in the Presence of Insulin (abstract)". Am J Physiol Endocrinol Metab.
- Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ & Bauer TL (1996). "Serum Immunoreactive-Leptin Concentrations in Normal-Weight and Obese Humans". N Engl J Med 334 (5): 292-295. PMID 8532024.
- Zhao J, Townsend KL, Schulz LC, Kunz TH, Li C, Widmaier EP (2004). "Leptin receptor expression increases in placenta, but not hypothalamus, during gestation in Mus musculus and Myotis lucifugus". Placenta 25 (8-9): 712–22. PMID 15450389.
- Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ (2006). "Inhibitory effect of leptin on human uterine contractility in vitro". Am. J. Obstet. Gynecol. 195 (2): 504-9. PMID 16647683.
- Studies include:
- Dubuc G, Phinney S, Stern J, Havel P (1998). "Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and women". Metab. Clin. Exp. 47 (4): 429-34. PMID 9550541.
- Pratley R, Nicolson M, Bogardus C, Ravussin E (1997). "Plasma leptin responses to fasting in Pima Indians". Am. J. Physiol. 273 (3 Pt 1): E644-9. PMID 9316457.
- Weigle D, Duell P, Connor W, Steiner R, Soules M, Kuijper J (1997). "Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels". J. Clin. Endocrinol. Metab. 82 (2): 561-5. PMID 9024254.
- Chin-Chance C, Polonsky K, Schoeller D (2000). "Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake". J. Clin. Endocrinol. Metab. 85 (8): 2685-91. PMID 10946866.
- Keim N, Stern J, Havel P (1998). "Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women". Am. J. Clin. Nutr. 68 (4): 794-801. PMID 9771856.
- Mars M, de Graaf C, de Groot C, van Rossum C, Kok F (2006). "Fasting leptin and appetite responses induced by a 4-day 65%-energy-restricted diet". International journal of obesity (Lond) 30 (1): 122-8. PMID 16158086.
- Margetic S, Gazzola C, Pegg GG, Hill RA (2002). "Leptin: a review of its peripheral actions and interactions". Int. J. Obes. Relat. Metab. Disord. 26 (11): 1407-33. PMID 12439643.
- John S. Torday, Virender K. Rehan (2006). "Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network". Pediatr. Res. 60 (4): 382-8. PMID 16940239. — published online before print as DOI 10.1203/01.pdr.0000238326.42590.03
- Aka N, Atalay S, Sayharman S, Kiliç D, Köse G, Küçüközkan T (2006). "Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum". The Australian & New Zealand journal of obstetrics & gynaecology 46 (4): 274-7. PMID 16866785.
- Cervero A, Domínguez F, Horcajadas JA, Quiñonero A, Pellicer A, Simón C (2006). "The role of the leptin in reproduction". Curr. Opin. Obstet. Gynecol. 18 (3): 297-303. PMID 16735830.
- Iwaniec UT, Boghossian S, Lapke PD, Turner RT, Kalra SP (2007). "Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice". Peptides. PMID 17346852.
- 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. (2007). "Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis.". Arterioscler Thromb Vasc Biol. 27 (12): 2691-2698. PMID 17690315.
- Torday JS, Sun H, Wang L, Torres E, Sunday ME, Rubin LP (Mar 2002). "Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation". Am. J. Physiol. Lung Cell Mol. Physiol. 282 (3): L405-10. PMID 11839533.
- Torday JS, Rehan VK (Jul 2002). "Stretch-stimulated surfactant synthesis is coordinated by the paracrine actions of PTHrP and leptin". Am. J. Physiol. Lung Cell Mol. Physiol. 283 (1): L130-5. PMID 12060569.
- Friedman JM, Halaas JL (1998). "Leptin and the regulation of body weight in mammals.". Nature 395 (6704): 763-70. doi:10.1038/27376. PMID 9796811.
- Prolo P, Wong ML, Licinio J (1999). "Leptin.". Int. J. Biochem. Cell Biol. 30 (12): 1285-90. PMID 9924798.
- Heshka JT, Jones PJ (2001). "A role for dietary fat in leptin receptor, OB-Rb, function.". Life Sci. 69 (9): 987-1003. PMID 11508653.
- Janeckova R (2002). "The role of leptin in human physiology and pathophysiology.". Physiological research / Academia Scientiarum Bohemoslovaca 50 (5): 443-59. PMID 11702849.
- Lee DW, Leinung MC, Rozhavskaya-Arena M, Grasso P (2002). "Leptin and the treatment of obesity: its current status.". Eur. J. Pharmacol. 440 (2-3): 129-39. PMID 12007531.
- Al-Daghri N, Bartlett WA, Jones AF, Kumar S (2002). "Role of leptin in glucose metabolism in type 2 diabetes.". Diabetes, obesity & metabolism 4 (3): 147-55. PMID 12047393.
- Sabath Silva EF (2002). "[Leptin]". Rev. Invest. Clin. 54 (2): 161-5. PMID 12053815.
- Thomas T, Burguera B (2003). "Is leptin the link between fat and bone mass?". J. Bone Miner. Res. 17 (9): 1563-9. PMID 12211425.
- Kraemer RR, Chu H, Castracane VD (2002). "Leptin and exercise.". Exp. Biol. Med. (Maywood) 227 (9): 701-8. PMID 12324651.
- Waelput W, Brouckaert P, Broekaert D, Tavernier J (2003). "A role for leptin in the systemic inflammatory response syndrome (SIRS) and in immune response.". Current drug targets. Inflammation and allergy 1 (3): 277-89. PMID 14561193.
- Stenvinkel P, Pecoits-Filho R, Lindholm B (2004). "Leptin, ghrelin, and proinflammatory cytokines: compounds with nutritional impact in chronic kidney disease?". Advances in renal replacement therapy 10 (4): 332-45. PMID 14681862.
- Cohen P, Ntambi JM, Friedman JM (2004). "Stearoyl-CoA desaturase-1 and the metabolic syndrome.". Curr. Drug Targets Immune Endocr. Metabol. Disord. 3 (4): 271-80. PMID 14683458.
- Sahu A (2004). "Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance.". Frontiers in neuroendocrinology 24 (4): 225-53. PMID 14726256.
- Elefteriou F, Karsenty G (2004). "[Bone mass regulation by leptin: a hypothalamic control of bone formation]". Pathol. Biol. 52 (3): 148-53. doi:10.1016/j.patbio.2003.05.006. PMID 15063934.
- Blüher S, Mantzoros CS (2004). "The role of leptin in regulating neuroendocrine function in humans.". J. Nutr. 134 (9): 2469S-2474S. PMID 15333744.
- Farooqi S, O'Rahilly S (2007). "Genetics of obesity in humans.". Endocr. Rev. 27 (7): 710-18. doi:10.1210/er.2006-0040. PMID 17122358.
- http://www.scq.ubc.ca/?p=421 Leptin biology from the Science Creative Quarterly], well written and illustrated
- Leptin in a bulletin by the Howard Hughes Medical Institute (HHMI)
- Review article "Leptin and the regulation of body weight in mammals" from Nature, requires subscription
- Leptin: Your brain, appetite and obesity by the British Society of Neuroendocrinology
- Leptin/ghrelin and their role in obesity from hungerhormones.com, a weight control website
- Leptin by Colorado State University
- Leptin at 3Dchem.com, description and structure diagrams
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