Appetite Control Central with Hypothalamic Peptides

This entry was posted on April 14, 2021 by Michael Jennings

The hypothalamus part of the brain is responsible for the biological function of regulating a variety of body functions and responses. It has several important nuclei responsible for the regulation of energy homeostasis and feeding.

We find the production sites of Luteinizing hormone – LH, the ventromedial hypothalamus – VHM, and the Arcuate Nucleus – ARC. As far as feeding and energy regulation in the body is concerned, the ARC is an integrated center for feeding regulation, VHM of the center of satiety, while the LH is the feeding center. Below is a brief look at some of the central hypothalamus peptides which are chains of amino acids worth knowing about when it comes to appetite control and feeding.

Neuropeptide Y

The ARC is the main site of production for the neuropeptide Y. The site is located right within the neurons in the hypothalamus of the brain. Though the production of NPY comes with diverse effects on the behavior and other functions, one of its most pronounced effects on feeding following central administration. NPY synthesis usually happens in the ARC before it is released in the PVN where it is regulated by the inhibitory effects of signaling factors such as insulin, leptin, and glucocorticoids.

The NYP neurons are always considered as potential hypothalamic targets for peptides, such as leptin. This has made it possible to explain why whenever NPY is released, leptin usually has the ability to induce weight loss and hypophagia. Insulin, on the other hand, has been shown to stop or hinder the synthesis of Leptin and therefore stops one from losing weight, as well as its secretion in PVN.

Five G-protein when coupled with NPY receptors are believed to be among the vital receptors responsible for mediating the feeding effects of NPY. The expression of Y5 receptors is known to happen at very high levels of LHA, as well as very close to the sites, known to harbor most of the NPY activities with the potential of stimulating feeding.

Melanin-Concentrating Hormone

Melanin-concentrating hormone is an orexigenic neuropeptide with 19 amino acids. The peptide is highly expressed in the LH and zona incerta within the hypothalamus, and it has been demonstrated to have very high orexygenic effects when it is infused with ICV. Most of the interests revolving around the mechanisms by which the hormone works have always been centered on the MCH1 receptors found in the nucleus accumbens shell (AcbSh). This shell is believed to play a major role when it comes to motivational aspects of eating.

Agouti-Gene Related Proteins

Agouti-gene related protein is a peptide featuring a total of 132 amino acids. The expression of the AgRP happens exclusively in the ARC within the central nervous system, where it then co-localizes with NPY cells in the nucleus. Studies conducted by Rossi et al. suggest that just like NPY, AgRP has orexigenic properties when infused with ICV or directly in DMH or PVN.

However, it is unique to observe that AgRP functions like an endogenous antagonist of melanocortin-4 and melanocortin-3 receptors. This signifies the high likelihood that AgRP plays a vital role in modulating feeding. Perhaps AgRP plays more vital roles during conditions of high energy requirements, such as during lactation or even pregnancy.

Hypocretins/orexins

The hypocretins 1 & 2, also known as orexins A & B, are produced in the cell bodies of the LH area, and they are known to be excitatory neuropeptides with extensive projections to very many regions. They usually bind to orexin receptors 1 and 2, which are usually produced from two separate genes. The two receptors have different distribution patterns within the hypothalamus, though OX1 has shown a high amount of expression in the PVN.

It should be noted that orexins fall under the category of appetite-stimulating neuropeptides. They are highly expressed in the LH and the DMH. Also, orexin-containing neuronal fibers have been spotted distributed in several nuclei, with very high projections in the ARC. Orexin-containing neurons may also project to NPY-containing neurons.

Additionally, studies suggest that orexins can increase the concentration of cytosolic Ca2+ in NPY neurons obtained from ARC. This result is a subtle indication that NPY neurons may transmit excitatory signals from neurons containing orexin. It should also be noted that the distribution of these two neurons, is very different within the hypothalamus. OX2R is mostly expressed in the PVN, while OX1R is mostly expressed in the VMH of the hypothalamus.

Cerelbellin1

Cerelbellin1 – Cbln1, shows high expression in the hypothalamus. When administered through ICV, it was perceived that the Cbln1 increases food intake, as well as increasing the release of NPY from the hypothalamus, besides reducing the levels of plasma thyroid-stimulating hormone. It has also been observed that the Cbln1 mRNA expression levels in the ventromedial nucleus in the hypothalamus went high in rats that were subjected to fasting. These results subtly indicate that Cbln1 may act as a novel orexigenic peptide.

Galanin

Galanin is a C-terminally amidated 29-amino acid peptide found in the gut and the brain. The peptide is known to co-exist with others such as NPY, 5-hydroxytryptamine, noradrenaline, and GABA in several areas of the brain. It is in the PVN, ARC, and the supraoptic nucleus of the hypothalamus, where we largely find the hypothalamic galanin neurology. Most of the galanin-positive neurons and galanin positive-fibers have been demonstrated in several studies in the dorsal vagal complex.

This suggests that galanin can produce its effects when associated with the vagal neurons. The major source of galanin terminals, is usually the nucleus of the solitary tract within the dorsal vagal complex. It is believed that the peptide galanin plays a huge role in learning, feeding, memory, pain threshold, inflammation, insulin regulation, sex behavior, and the regulation of the pituitary hormone release. It has been reported that the acute administration of galanin usually leads to an increase in fat consumption.

Galanin-Like Peptides

Galanin-like peptide, also known as GALP, is a novel peptide with 60 amino acids, with between 9 and 21 of the amino acids being identical to the biologically active N-terminal, part of galanin. In hybridization studies done in situ, it was observed that GALP mRNA, is highly expressed within the periventricular regions of the ARC, as well as in the pituitary glands of the study rats. NPY with axon terminals were also observed to be closely apposed to neurons containing GALP present in the ARC.

Additionally, studies conducted by Cunningham et al. involving double-label in situ hybridization, showed neurons containing GALP in the macaque expressed NPY receptor. This was an indication that NPY has the potential of regulating GALP neurons present in the ARC.

Melanocortins

Melanocortins are bioactive peptides obtained from the precursor molecule POMC through a very specific tissue post-translation cleavage process. The POMC gene usually demonstrated relatively significant levels in various mammalian tissues including the hypothalamic neurons, the immune system, the skin, and the pituitary glands among others. The effects of most products obtained from POMC through any tissue, is usually a factor of the various specificities that relate to the convertases found in the present tissue.

Alpha-melanocytes-stimulating hormone is produced by the intermediate lobe of the pituitary glands, and it is the peptide responsible for activating melanocortin, MC3, and MC4 receptors, which, in turn, are responsible for inhibiting food intake.

The MC3 and MC4 receptors are present in most of the areas that are known to be responsible for regulating the energy balance, as well as in regions such as the hippocampus and the cerebral cortex. Most of the bioactive peptides that are from the hypothalamic neurons may sometimes behave like endogenous ligands for melanocortin.

Glucagon-Like Peptides

The brain releases GLP-1 hormones within the nucleus of the NTS. After the release of the hormone, it is then projected to the PVN, resulting in the activation of GLP-1 receptors – these are some of the receptors which are responsible for promoting anorexia and feelings of satiety.

The activated neurons can also be projected to the ARC where it may be responsible for moderating the outflow to the pancreas of the vagal motor, leading to an increase in the secretion of insulin, while at the same time suppressing the release of glucagon.

The result of this action is a lowered blood glucose level. Some studies also suggest that it may be possible for systematic GLP-1 to get to the brain through leaks that may occur in the BBB like through the subfornical organ, as was shown in studies involving rats.

When GLP-1 is administered intravenously to normal weight, and obese human beings, it is noted that there is a decrease in food intake if the administration is done in a dose-dependent manner, and also through gastric emptying. These results are suspected to be through brainstem and vagal pathways. This is because the peripheral administration of GLP-1 usually ends up activating neurons within the brainstem in rats.

It has been observed that there exists a perfect overlap between GLP-1 and GLP-2 within the central nervous system in the distribution of the co-localized peptides. The highest concentration is normally seen in the diffuse ventral part of the dorsomedial nucleus.

Following the injection of the peptide into the lateral ventricle, it was observed that some of the effects were inhibitory in nature regarding feeding. It has also been observed that GLP-2 displays both behavioral and pharmacological effects on feeding. The GLP-2 released from the central nervous system is vital when it comes to controlling the feed behavior.

When Glp-2r is deleted from POMC neurons, it is noticed that there is an increase in food intake, which comes in the form of meal frequency amplification, as well as an increase in gastric emptying. This suggests that the GLP-2 produced within the central nervous system is an important signal for satiety for short term control of feeding, as well as gastric motility.

It also suggests that the peptide may affect the long term homeostatic control of the balance of the energy within the body system. Also, when GLP-2 is activated, it is observed that it can potentially suppress food intake and promote gastric emptying with the help of the MC4R signaling pathway.

Studies conducted by Guan et al. demonstrate that the process of gastric emptying is vital for the short-term control of feeding. The studies also suggest that suppression of food intake through mediation by POMC neurons may be possible through decelerating gastric emptying.

Corticotropin-Releasing Factor

Corticotropin-releasing Factor, CRH, is a peptide with 42 amino acids. It is a mammalian neurohormone that is associated with some major functions of the brain, such as the physiological regulation of ACTH within the pituitary glands. The hormone is highly expressed in the PVN neurons. Studies show that when the hormone is injected centrally, it can inhibit the intake of food while at the same time reducing the body weight in the model rats used in the study.

When administered peripherally, studies show that the hormone will increase the amount of energy used in the body, as well as the rates of fat oxidation in human beings. It has also been observed that infusion of leptin with the hormone stimulates its expression, and when it is used as a pretreatment as an antagonist attenuate, it also leads to reduced intake of food, as well as body weight.

Neurotensin

Neurotensin, also known as NT, is produced in the ARC of the hypothalamus. It is a 13-amino acid peptide whose injection into the PVN has been shown to drastically decrease food intake. The neurons of the peptides seem to play a huge role further along in the functions of leptin.

When ICV leptin is infused with PVN, there is increased synthesis of NT, which leads to a reduction in food intake. These results further help to suggest that the actions of leptin may be partly mediated by NT hormone.

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