Hypothalamic hormones
Neuropeptide Y, NPY, peptide YY, PYY
The neuropeptide Y family consists of homolous proteins including neuropeptide Y itself, NPY, present in neurons, peptides YY, PYY like the PYY 3-36, present in pancreas, intestine and neurons and a pancreatic polypeptide, PP, present in pancreas. These peptides result from hydrolyzes of a pre-proprotéine NPY of 97 amino acids.
NPY, PYY and PP act on a family of receptors coupled with G proteins and called Y1, Y2, Y4, Y5, Y6. The existence of Y3 is probable.
- Neuropeptide Y , NPY, consists of 36 amino acids and has an orexigenic effect. It is present in the central nervous system and the autonomic nervous system (sympathetic fibers where its distribution follows that of norepinephrine). Its release at the level of the hypothalamus is increased duringfasting, is inhibited by leptin and insulin and is increased by glucocorticoids.
The most notable effect of NPY is the stimulation of appetite by a hypothalamic effect. It also decreases the thermogenesis of adipocytes and induces obesity. The NPY has anxiolytic and sedating effects and an antinociceptif effect (analgesic). It could play a part in the central regulation of arterial pressure, injected into certain domains of the brain of animals, it elicits hypotension and bradycardia. It could inhibit the release of certain transmitters, that of glutamate for example. It could induce ACTH secretion and inhibit that of GH and TSH.
- PYY is released by the digestive tract after food intake and acts on the level of the hypothalamus; it has an anorectic effect. PYY stimulates Y2 receptors in the arcuate nucleus of the hypothalamus and inhibits food intake. It decreases the release of orexigenic NPY and increases the release of the anorectic alpha-MSH. Its principal peripheral effect is vasoconstriction. It has digestive antisecretory effects.
- Pancreatic polypeptide PP has an anorectic effect by stimulation of the hypothalamic Y4 receptors.
Orexins
Orexins are also called hypocretins. Orexin A and orexin B are polypeptides of approximately 30 amino acids primarily localized in the dorsolateral part of the hypothalamus. It results from the hydrolysis of a prepro-orexin, polypeptide of 130 amino acids.
Orexins activate two types of receptors called OX-1 and OX-2. They, in particular orexin A, stimulate the appetite and modulate the release of hypothalamic hormone GnRH. They stimulate vigilance and reinforce the state of awakening. A deficiency in hypocretins or anomalies of its receptors could be one of the causes of narcolepsy. Two receptors of the hypocretins were described, they are coupled to G proteins.
Galanin
Galanin is an orexigenic neuropetide of 29 amino acid residues formed from the hydrolysis of a more important polypeptide. Galanin is present in the central nervous system and peripherally. It modulates the release of transmitters (acetylcholine, compound P), of hormones (insulin, growth hormone). Galanin has an anticonvulsivant effect and its agonists could have an antiepileptic effect. It stimulates the appetite and its antagonists could have an anorectic effect.
Melanocortins, alpha-MSH
Alpha-MSH or alpha-melanocyte-stimulating hormone, beta-MSH and gamma-MSH belong to the group of melanocortins.
Alpha-MSH is an anorectic polypeptide of 13 amino acids. It results from the proteolytic cleavage of pro-opiomelanocortine, POMC, a protein of 266 amino acids, also at the origin of ACTH and several other peptides. POMC is particularly present in the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius of the brainstem.
There are 5 types of melanocortin receptors , called MC1R to MC5R. Alpha-MSH, released in the hypothalamus under the effect of leptin, activates MC3R and MC4R and reduces appetite. A deficiency in alpha-MSH or an alteration of MC4 receptors induces an important obesity.
The antagonists of MC4 receptors could have an anxiolytic effect but also induce weight gain.
AgRP or Agouti-related protein
AgRP, Agouti-related protein, discovered in 1997, is an orexigenic neuropeptide of 132 amino acids present particularly in the arcuate nucleus of the hypothalamus. AgRP is thus called because it is related to a protein called Agouti presents normally in the skin.
It is an endogenous antagonist of melanocortin receptors MC4-R and MC3-R which are present in the brain and are normally activated by apha-MSH.
MCH, melanin-concentrating hormone
MCH, melanin-concentrating hormone, is an orexigenic cyclic neuropeptide of 19 amino acids mainly found in the hypothalamus. MCH two acts on two types of receptors called MCH-1R and MCH-2R, present in various parts of the brain.
The intracerebral administration of MCH induces an increase in the intake of food and a reduction of the expenditure of energy, and development of obesity. MCH could induce anxiety.
CART, Cocaine and Amphetamine Regulated Transcript
CART indicates the sequence of RNA messenger which is at the origin of the corresponding protein. RNA and protein CART are present in various organs, in particular the brain, particularly the hypothalamus. Their presence in the brain was discovered in animals which had received cocaine or amphetamine, because these compounds induce an increased synthesis of CART, thus easier to detect, hence their name.
Fasting decreases the synthesis of CART in the arched nucleus of the hypothalamus, leptin administration increases it and in certain obese animals one practically does not find CART.
CART reduces the requirement for food, decreases dietary intake and reduces obesity. It has the opposite effects to NPY. It induces the synthesis of mitochondrial uncoupling proteins which increases energy expenditure. It increases ACTH secretion.
Pharmacological applications
One can be astonished to not find pharmacological applications concerning each hormone and each type of receptors. There are several explanations to this: most of these hormones and their receptors are of recent discovery; it is difficult to find molecules specifically acting on a specific target and being active by oral route; each hormone has generally many effects other than the regulation of food intake and it is difficult to act on one without modifying the others; hormone regulation involves mechanisms of compensation; it should not be forgotten that “traditional” transmitters such as, serotonin, catecholamines, GABA are also involved.
One will find new drugs likely to improve appetite disorders and certain forms of obesity but probably not a panacea against obesity.
|
RSS