Clarifying the Ghrelin System’s Ability to Regulate Feeding Behaviours Despite Enigmatic Spatial Separation of the GHSR and Its Endogenous Ligand

Abstract

Ghrelin is a hormone predominantly produced in and secreted from the stomach. Ghrelin is involved in many physiological processes including feeding, the stress response, and in modulating learning, memory and motivational processes. Ghrelin does this by binding to its receptor, the growth hormone secretagogue receptor (GHSR), a receptor found in relatively high concentrations in hypothalamic and mesolimbic brain regions. While the feeding and metabolic effects of ghrelin can be explained by the effects of this hormone on regions of the brain that have a more permeable blood brain barrier (BBB), ghrelin produced within the periphery demonstrates a limited ability to reach extrahypothalamic regions where GHSRs are expressed. Therefore, one of the most pressing unanswered questions plaguing ghrelin research is how GHSRs, distributed in brain regions protected by the BBB, are activated despite ghrelin’s predominant peripheral production and poor ability to transverse the BBB. This manuscript will describe how peripheral ghrelin activates central GHSRs to encourage feeding, and how central ghrelin synthesis and ghrelin independent activation of GHSRs may also contribute to the modulation of feeding behaviours.

Ghrelin as a Survival Hormone

“…Not only are GHSRs activated upon binding by acyl-ghrelin, but also they possess other fascinating biology the characterization of which is still in its early stages. Namely, as compared to most other GPCRs, GHSR has a fairly high ligand-independent, constitutive activity ([21], and reviewed in [22]). As such, even in the absence of ghrelin, the capacity for GHSR to engage downstream signaling cascades occurs at nearly 50% of its maximal capacity induced by ghrelin, when assessed in heterologous in vitro systems [21].…”

“…Supporting an important role for ghrelin-independent GHSR signaling, mutations affecting GHSR constitutive activity have been found in several unrelated Moroccan and Japanese subjects with GH deficiency and short stature [23, 24]. Furthermore, GHSRs can heterodimerize with other GPCRs, including dopamine D1 and D2 receptors, serotonin 2C receptors, and melanocortin 3 receptors, such that GHSRs can modulate signaling via these other receptors (as reviewed in [22]).…”

“…Other emerging components of the ghrelin system that are relatively less well-characterized than those mentioned above include enzymes that degrade ghrelin, such as butyrylcholinesterase, which hydrolyzes ghrelin to unacyl-ghrelin [42], ghrelin-reactive immunoglobulins (as reviewed in [43]) that may protect ghrelin from degradation, and the truncated, transmembrane domains 6 and 7-lacking GHSR1b form of GHSR, which binds and in turn reduces the constitutive activity and cell surface expression of GHSR [22]. The relative contributions of each of these facets of the ghrelin system to its overall effects on normal physiological processes and disease states deserve further attention.…”

Ghrelin level and types of eating behavior when combined with irritable bowel syndrome, arterial hypertension and obesity

“…Repeated food consumption in such patients usually includes sweet desserts, animal proteins, and does not include any fruit or vegetables, promoting both constipation and alteration of lipid metabolism 24,25 . The established domination of external and emotional types of eating behavior in patients with comorbid pathology is caused by the higher postprandial ghrelin level, which regulates and stimulates the appetite 26 .…”

The Role of Growth Hormone Secretagogue Receptor (GHSR) Signaling in the Dorsomedial Hypothalamus (DMH) and Ventral Premammilary Nucleus (PMV) In Energy Homeostasis in Mice

“…Central administration of ghrelin potently stimulates food intake, even in satiated animals (Nakazato et al, 2001), although the mechanisms through which ghrelin reaches its receptors in the CNS is an area of ghrelin research that remains highly debated (Edwards and Abizaid, 2017).…”