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Leptin (obesity homolog, mouse)
PDB rendering based on 1ax8. The Protein Data Bank ( PDB) is a repository for 3-D structural data of Proteins and Nucleic acids These data typically obtained by X-ray crystallography
Available structures: 1ax8
Identifiers
Symbol(s) LEP; OB; OBS
External IDs OMIM: 164160 MGI: 104663 HomoloGene: 193
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 3952 16846
Ensembl ENSG00000174697 ENSMUSG00000059201
Uniprot P41159 Q544U0
Refseq NM_000230 (mRNA)
NP_000221 (protein)		 NM_008493 (mRNA)
NP_032519 (protein)
Location Chr 7: 127.67 - 127.68 Mb Chr 6: 29.01 - 29.02 Mb
Pubmed search [1] [2]
Identifiers
Symbol LEPR
Entrez 3953
HUGO 6554
OMIM 601007
RefSeq NM_002303
UniProt P48357
Other data
Locus Chr. 1 p31

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. The Human Genome Organisation (HUGO is an organization involved in the Human Genome Project, a project about mapping the human genome The Mouse Genome Informatics (MGI website is run by The Jackson Laboratory. HomoloGene, a tool of the National Center for Biotechnology Information (NCBI is a system for automated detection of homologs (similarity attributable to descent The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences Ensembl is a joint scientific project between the European Bioinformatics Institute and the Wellcome Trust Sanger Institute, which was launched in 1999 in response to the imminent UniProt is the uni versal prot ein resource a central repository of Protein data created by combining Swiss-Prot, TrEMBL PubMed is a free search engine for accessing the MEDLINE database of citations and abstracts of biomedical research articles Leptin receptor, also known as LEPR, is a human Gene. LEPR has also been designated as CD295 ( Cluster of differentiation 295 Leptin receptor, also known as LEPR, is a human Gene. LEPR has also been designated as CD295 ( Cluster of differentiation 295 The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences The Human Genome Organisation (HUGO is an organization involved in the Human Genome Project, a project about mapping the human genome The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The National Center for Biotechnology Information ( NCBI) is part of the United States National Library of Medicine (NLM a branch of the National Institutes Swiss-Prot is a manually curated Biological database of Protein sequences In the fields of Genetics and Evolutionary computation, a locus (plural loci) is a fixed position on a Chromosome such as the position of a Chromosome 1 is the designation for the largest Human Chromosome. The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Hormones (from Greek ὁρμή - "impetus" are chemicals released by cells that affect cells in other parts of the body Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. Leptin is one of the most important adipose derived hormones. Adipose tissue is an important Endocrine organ that secretes numerous Protein hormones into circulation

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. A mutant is an individual organism or new genetic character arising or resulting from an instance of Mutation, which is a base-pair sequence change within the DNA Obesity is a condition in which excess Body fat has accumulated to such an extent that health may be negatively affected A mouse (plural mice) is a small Animal that belongs to one The Jackson Laboratory was founded in Bar Harbor Maine in 1929 by former University of Maine and University of Michigan president C 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. Jeffrey Friedman, MD, PhD, (born July 20, 1954) is a molecular Geneticist at New York City 's Rockefeller University The Rockefeller University is a private University which focuses primarily on basic research in the biomedical fields and offers graduate and postgraduate education The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans. Chromosome 7 is one of the 23 pairs of Chromosomes in Humans People normally have two copies of this chromosome Leptin is produced by adipose tissue and interacts with six types of receptor (LepRa–LepRf). "Adipose" redirects here For the Doctor Who monster see " Partners in Crime " LepRb is the only receptor isoform that contains active intracellular signaling domains. This receptor is present in a number of hypothalamic nuclei. The hypothalamus links the Nervous system to the Endocrine system via the Pituitary gland (hypophysis Leptin binds to the ventromedial nucleus of the hypothalamus, known as the "appetite center. The ventromedial nucleus (sometimes referred to as the ventromedial hypothalamus) is a nucleus of the Hypothalamus. The hypothalamus links the Nervous system to the Endocrine system via the Pituitary gland (hypophysis " 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. Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. 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). Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information Neuropeptide Y (NPY is a 36 Amino acid peptide Neurotransmitter found in the Brain and Autonomic nervous system. Agouti-related protein also called Agouti-related peptide ( AgRP) is a Neuropeptide produced in the Brain (in the Arcuate nucleus Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information The melanocyte-stimulating hormones (collectively referred to as MSH) are a class of Peptide hormones produced by cells in the Intermediate lobe of 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. Anorexia (deriving from the Greek "α(ν-" ( a(n-, a prefix that denotes absence + "όρεξη (orexe = appetite is the decreased sensation 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. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Obesity is a condition in which excess Body fat has accumulated to such an extent that health may be negatively affected

There is some controversy regarding the regulation of leptin by melatonin during the night. Melatonin is a naturally occurring Hormone found in most animals including humans and some other living organisms including Algae. One research group suggested that increased levels of melatonin caused a downregulation of leptin. Melatonin is a naturally occurring Hormone found in most animals including humans and some other living organisms including Algae. [2] 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. Insulin is a Hormone with intensive effects on both metabolism and several other body systems (eg vascular compliance [3]

Contents

Leptin as adiposity signal

To date, only leptin and insulin fulfill the criteria of an adiposity signal:

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. The blood-brain barrier (BBB is a metabolic or cellular structure in the Central nervous system (CNS that restricts the passage of various chemical substances and microscopic The median eminence is part of the inferior boundary for the Hypothalamus part of the human Brain. In Neuroanatomy, a nucleus is a Central nervous system structure that is composed mainly of Gray matter, and that acts as a hub or transit point for 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. The choroid plexus is the area on the ventricles of the brain where Cerebrospinal fluid (CSF is produced by modified Ependymal cells.

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. Cannabinoids ( are a group of terpeno[[phenol]]ic compounds present in Cannabis ( Cannabis sativa L 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. Diabetes mellitus type 2 or Type 2 Diabetes (formerly called non - Insulin -dependent Diabetes mellitus (NIDDM or adult-onset diabetes is a metabolic Insulin resistance is the condition in which normal amounts of Insulin are inadequate to produce a normal Insulin response from Fat, Muscle Insulin is a Hormone with intensive effects on both metabolism and several other body systems (eg vascular compliance The high sustained concentrations of leptin from the enlarged adipose stores result in leptin desensitization. "Adipose" redirects here For the Doctor Who monster see " Partners in Crime " 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. Fertility is the natural capability of giving life As a measure "Fertility Rate" is the number of children born per couple person or population In mammals such as humans puberty in females is linked to a critical level of body fat. Mammals ( class Mammalia) are a class of Vertebrate Animals characterized by the presence of Sweat glands, including sweat glands 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. Angiogenesis is a physiological process involving the growth of new Blood vessels from pre-existing vessels Vascular endothelial growth factor ( VEGF) a sub-family of Growth factors, more specifically of Platelet-derived growth factor family of cystine-knot growth

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. The placenta is an Ephemeral organ present in placental Vertebrates, such as Eutherial Mammals and Sharks during Gestation [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. The University of Warwick is a British Campus university located on the outskirts of Coventry, West Midlands, England and is Obesity is a condition in which excess Body fat has accumulated to such an extent that health may be negatively affected Lack of sleep produces ghrelin, a hormone that stimulates appetite by lowering leptin levels. Ghrelin is a Hormone produced mainly by P/D1 cells lining the fundus of the human Stomach and epsilon cells of the Pancreas that stimulates

Next to a biomarker for body fat, serum leptin levels also reflect individual energy balance. A biomarker is a substance used as an indicator of a biologic state Several studies have shown that fasting or following a very low calorie diet (VLCD) lowers leptin levels. Fasting is primarily the act of willingly abstaining from some or all Food, Drink, or both for a period of time Very low calorie diet ( VLCD) is a diet with very or extremely low Calorie consumption per day [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 in 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. Paracrine signaling is a form of Cell signaling in which the target cell is near (" Para " = near the signal-releasing cell [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. A fetus (or foetus or fœtus) is a developing Mammal or other Viviparous Vertebrate, after the Embryonic stage and Parathyroid hormone-related protein (or PTHrP 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 suggest that hypothalamic leptin is implicated in bone growth. Hyperemesis gravidarum (from Greek hyper and emesis and Latin gravida; meaning "excessive vomiting of pregnant women" is Morning sickness, also called Nausea, Vomiting of Pregnancy ( emesis gravidarum or NVP) or pregnancy sickness Polycystic ovary syndrome abbreviated PCOS or PCO (also known clinically as Stein-Leventhal syndrome, Sclerocystic ovary syndrome, Hyperthecosis [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). Orexins, also called hypocretins, are the common names given to a pair of highly excitatory Neuropeptide Hormones that were simultaneously discovered by "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.  
  3. ^ 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.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 8532024.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15450389.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16647683.  
  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.  
    • 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. doi:10.1210/jc.82.2.561. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 9024254.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10946866.  
  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.  
  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.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12439643.  
  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.  
  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.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17346852.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17690315.  

Further reading

External links

Dictionary

leptin

-noun

  1. (biochemistry) A protein hormone produced in adipose tissue; it plays a role in regulating appetite and metabolism.
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