The peptide hormone ghrelin is secreted by the gastrointestinal tract, and plays a pivotal role in appetite stimulation through its action on hypothalamic neurons. Ghrelin is bound by the presynaptic terminals of neurons that secrete neuropeptide Y (NPY). These cells also receive afferent signals from neurons in the area of the brain adjacent to the third ventricle, but between the ARN and PVN groups.
Ghrelin increases the activity of the arcuate neurons which secrete NPY and have NPY-like actions on the paraventricular nucleus. It is postulated that ghrelin causes the release of orexigenic molecules that increase appetite at these sites, regulating in turn energy production and its conservation in the body.
Ghrelin in the Brain
Ghrelin is a peptide hormone, and as such is unable to cross the blood-brain barrier in the absence of a transport mechanism. However, there are some structures in the brain called the sensory circumventricular organs (CVOs) which can be accessed without having to negotiate the blood-brain barrier.
CVOs have fenestrated capillaries which lack glial end-foot coverings, in addition to dense tortuous capillary beds. These features allow pooling of fluid around the vessels, and thus expose the cells to high concentrations of the substances that are carried in the blood.
Anatomically, CVOs include the subfornical organ, the organum vasculosum of the lamina terminalis, and the area postrema. They have many receptors for peptide hormones, including (but not limited to) ghrelin, and also express the growth hormone secretogogue receptors (GHS-R). In addition, they are well-connected to the control centers of the autonomic nervous system.
The subfornical organ is thus equipped to detect ghrelin in the peripheral circulation and transmit appropriate signals to autonomic centers. They are already known to act through the anorectic hormone to inhibit feeding. The CVOs are therefore thought to play a critical role in appetite regulation.
Ghrelin is involved in eating, whether to push up energy reserves or for the sake of pleasure. This action occurs when it binds to the GHS-R located in many sites in the central nervous system. These include the hypothalamic nuclei, the hippocampus, the amygdala, the caudal part of the brain stem, and the dopaminergic neurons in the midbrain.
Ghrelin in the Rest of the Body
Ghrelin also acts on insulin secretion, inhibiting it and thus reducing the level of gluconeogenesis and glycogenolysis. This effect is produced by heteromerization between the ghrelin receptor, GHS-R, and the somatostatin receptor, because different subunits are activated depending on whether ghrelin or somatostatin levels are higher. Ghrelin also acts via dopaminergic neurons in the ventral tegmental area (VTA) to produce its glycemic effect, as well as through GHS-R in the hindbrain.
Apart from its effect on increased adipogenesis and decreased lipolysis, ghrelin also acts to reduce heat production, notably by non-shivering thermogenesis in brown fat. Moreover, it reduces sympathetic nervous impulse production and transmission. A raised ghrelin concentration is therefore a favorable marker in myocardial infarction as it indicates a lower sympathetic tone.
Ghrelin promotes muscle fiber maturation and fusion. It acts in bones by regulating the osteoblast multiplication and differentiation which is responsible for new bone formation, and so increases bone mass and mineral density. It plays multiple roles, with local inhibition of osteoclast production but systemic promotion of osteoclast proliferation. The latter effect reduces with age.
It is also important in cancer metastases, as it is found in high levels in metastatic cells along with GHS-R mRNA. Its role in carcinogenesis and malignancy progression is thought to occur through paracrine/autocrine pathway.