Leptin

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Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including the regulation of appetite and 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 team at the Rockefeller University through the study of those mutant mice. The Ob(Lep) gene 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. A very small group of humans, mostly arising from inbred populations, are also mutant for the leptin gene. These people eat nearly constantly, and may be more than 100 pounds (45 kg) overweight by the age of 7.

Leptin is released by fat cells in amounts mirroring overall body fat stores. 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. PMID 15311999

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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.
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Mechanism of action

It is unknown whether leptin must 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 expresion 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 desensitised.

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 is also strongly linked with angiogenesis, increasing VEGF levels.

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External links

Template:Hormonesde:Leptin fr:Leptine he:לפטין nl:Leptine ja:レプチン pl:Leptyna zh:肥胖荷爾蒙

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