Leptin

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Leptin (obesity homolog, mouse)
PDB rendering based on 1ax8.
Available structures: 1ax8
Identifiers
Symbol(s)	LEP; OB; OBS
External IDs	OMIM: 164160 MGI: 104663 HomoloGene: 193
Gene ontology Molecular Function: • hormone activity • protein binding • growth factor activity Cellular Component: • extracellular region • extracellular space Biological Process: • glucose metabolic process • energy reserve metabolic process • lipid metabolic process • signal transduction • cell-cell signaling • bile acid metabolic process • adult feeding behavior • regulation of cholesterol absorption • negative regulation of appetite • eating behavior • positive regulation of myeloid cell differentiation
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]

leptin receptor
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. 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", therfore causing a decrease in appetite whilst sleeping.^[3]

Contents 1 Leptin as adiposity signal 2 Mechanism of action 3 Leptin and reproduction 4 Recent discoveries 4.1 Modulation of T cells activity in immune system 5 See Also 6 References 7 Further reading 8 External links

[edit] 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.

[edit] 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.

[edit] 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]

[edit] 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 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.^[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 suggest that hypothalamic leptin is implicated in bone growth.^[15]

[edit] 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]

[edit] See Also

• Orexin

[edit] References

[edit] Further reading

[edit] External links

• Leptin biology from the Science Creative Quarterly
• Leptin in a bulletin by the Howard Hughes Medical Institute (HHMI)
• Review article "Leptin and the regulation of body weight in mammals" from Nature
• 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

v • d • e Endocrine system: hormones/endocrine glands (Peptide hormones, Steroid hormones) Hypothalamic-pituitary Hypothalamus: TRH, CRH , GnRH, GHRH, somatostatin, dopamine - Posterior pituitary: vasopressin, oxytocin - Anterior pituitary: α (FSH, LH, TSH), GH, prolactin, POMC (ACTH, MSH, endorphins, lipotropin) Adrenal axis Adrenal medulla: epinephrine, norepinephrine - Adrenal cortex: aldosterone, cortisol, DHEA Thyroid axis Thyroid: thyroid hormone (T3 and T4) - calcitonin - Parathyroid: PTH Gonadal axis Testis: testosterone, AMH, inhibin - Ovary: estradiol, progesterone, inhibin/activin, relaxin (pregnancy) Other end. glands Pancreas: glucagon, insulin, somatostatin - Pineal gland: melatonin Non-end. glands Placenta: hCG, HPL, estrogen, progesterone - Kidney: renin, EPO, calcitriol, prostaglandin - Heart atrium: ANP - Stomach: gastrin, ghrelin - Duodenum: CCK, GIP, secretin, motilin, VIP - Ileum: enteroglucagon - Adipose tissue: leptin, adiponectin, resistin - Thymus: Thymosin - Thymopoietin - Thymulin - Skeleton: Osteocalcin - Liver/other: Insulin-like growth factor (IGF-1, IGF-2) Target-derived NGF, BDNF, NT-3