Leptin
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Leptin is a protein hormone produced by adipose tissue. Its concentration in the body provides the brain with a rough indication of adipose mass for the purposes of regulating appetite and metabolism. Leptin works by inhibiting the actions of neuropeptide Y (NPY) and agouti-related peptide (AgRP) and by increasing the actions of alpha-melanocortin stimulating hormone (α-MSH).
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
To interact with the CNS, leptin must first cross the blood-brain barrier. It does this via leptin receptors in endothelial cells that function as transporters.
Once leptin has bound to the Ob-Rb receptor, it produces two effects:
- Repression of anabolic circuits, causing decreased food intake and increased energy expenditure. Leptin action in the hypothalamus causes down-regulation of NPY and AgRP. These are both potent orexigenic (appetite-stimulating) molecules which stimulate increases energy intake. Whilst NPY is the more potent of the two when measured over several hours, AgRP has much longer-lasting effects. Experiments involving the measurement of hyperphagia (increased appetite for food) following intracerebroventricular (i.c.v.) administration show that the effects of AgRP are sustained for up to one week, and that AgRP is the more potent orexigen when measured by the cumulative increase in energy uptake after a single i.c.v. injection. While the reason for this is not fully understood, it is thought that AgRP may interfere with the catabolic α-MSH response and this causes its longevity.
- Activation of catabolic circuits, also causing decreased food intake and energy expenditure. Leptin is necessary for the cleavage of the pro-opiomelanocortin (POMC) precursor molecule. This allows the hormone alpha-melanocortin stimulating hormone (α-MSH) to be produced. Low α-MSH levels activate melanocortin anorexia pathways, stimulating energy intake; the increase in α-MSH therefore inhibits energy intake.
In both pathways, the response is projected from the arcuate nucleus to the paraventricular nucleus. From there central autonomic pathways carry the signal to the nucleus of the solitary tract (NTS) in the hindbrain where it is incorporated with vagal signals from the liver and stomach. Net neuronal output from the NTS causes changes in energy uptake and expenditure that influence body weight.
Leptin also plays a permissive role in female puberty, which usually will not proceed until an adequate body mass has been achieved.ja:レプチン