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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.
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.
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 is also strongly linked with [[angiogenesis]], increasing [[vascular endothelial growth factor|VEGF]] levels.

Revision as of 00:07, 6 November 2008

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leptin receptor
Identifiers
SymbolLEPR
NCBI gene3953
HGNC6554
OMIM601007
RefSeqNM_002303
UniProtP48357
Other data
LocusChr. 1 p31
Search for
StructuresSwiss-model
DomainsInterPro

Leptin (Greek leptos meaning thin) is a 16 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 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–LepRf). LepRb is the only receptor isoform that contains active intracellular signaling domains. This receptor is present in a number of 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 mutations 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.[1]

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 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.

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.[2] However, in 2004, Brazilian researchers found that in the presence of insulin, "melatonin interacts with insulin and upregulates insulin-stimulated leptin expression", therefore causing a decrease in appetite whilst sleeping.[3]

Leptin as adiposity signal

To date, only leptin and insulin are known to act as 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. 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.[4] 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. 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 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.[5] 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.[6]

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.[7] It might be that on short term leptin is an indicator of energy balance. This system is more sensitive to starvation than to overfeeding,[8] 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 to food intake. Although this is a new hypothesis, there is already some data that supports it.[9][10]

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.[11] 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.[12] 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.[11]

There is also evidence that leptin plays a role in hyperemesis gravidarum (severe morning sickness),[13] in polycystic ovary syndrome[14] and a 2007 research suggests that hypothalamic leptin is implicated in bone growth.[15]

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. [16]

See also

References

  1. ^ OMIM - LEPTIN; LEP
  2. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  3. ^ Alonso-Vale, Maria Isabel Cardoso (2004). "Melatonin Enhances Leptin Expression by Rat Adipocytes in the Presence of Insulin (abstract)". Am J Physiol Endocrinol Metab. Retrieved 2007-12-15. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  4. ^ 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. doi:10.1056/NEJM199602013340503. PMID 8532024.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ 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. doi:10.1016/j.placenta.2004.01.017. PMID 15450389.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ 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. doi:10.1016/j.ajog.2006.01.106. PMID 16647683.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    • 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. doi:10.1210/jc.82.2.561. PMID 9024254.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ 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. doi:10.1210/jc.85.8.2685. PMID 10946866.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b 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. doi:10.1038/sj.ijo.0802142. PMID 12439643.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ 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
  13. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ 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: 1012. doi:10.1016/j.peptides.2007.02.001. PMID 17346852.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ 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. doi:10.1161/ATVBAHA.107.149567. PMID 17690315.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

  • Torday JS, Sun H, Wang L, Torres E, Sunday ME, Rubin LP (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  • Torday JS, Rehan VK (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. {{cite journal}}: Unknown parameter |month= ignored (help)

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