Everything about Leptin totally explained
| Name = Leptin (obesity homolog, mouse)
| HGNCid = 6553
| Symbol = LEP
| AltSymbols =; OB; OBS
| OMIM = 164160
| ECnumber =
| Homologene = 193
| MGIid = 104663
| GeneAtlas_image1 = PBB_GE_LEP_207092_at_tn.png
| DateOfBotUpdate = 07:32, 9 October 2007 (UTC)
| Function =
| Component =
| Process =
| Orthologs =
}}
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 those mutant 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.
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. 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.
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. It is generally thought that leptin might enter the brain at the
choroid plexus, where there's 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. 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, 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. 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.
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 which stimulates appetite and leads to less leptin to suppress 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. This system is more sensitive to starvation than to overfeeding, for example leptin levels don't 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's already some data that supports it.
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. 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. 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 experimentation with mice. It modulates the immune response to atherosclerosis, which is a predisposing factor in patients with obesity.
Further Information
Get more info on 'Leptin'.
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