The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

Abstract

Ghrelin is a peptide hormone released by specialized X/A cells in the stomach and activated by acylation. Following its secretion, it binds to ghrelin receptors in the periphery to regulate energy balance, but it also acts on the central nervous system where it induces a potent orexigenic effect. Several types of stressors have been shown to stimulate ghrelin release in rodents, including nutritional stressors like food deprivation, but also physical and psychological stressors such as foot shocks, social defeat, forced immobilization or chronic unpredictable mild stress. The mechanism through which these stressors drive ghrelin release from the stomach lining remains unknown and, to date, the resulting consequences of ghrelin release for stress coping remain poorly understood. Indeed, ghrelin has been proposed to act as a stress hormone that reduces fear, anxiety-and depression-like behaviors in rodents but some studies suggest that ghrelin may-in contrast-promote such behaviors. In this review, we aim to provide a comprehensive overview of the literature on the role of the ghrelin system in stress coping. We discuss whether ghrelin release is more than a byproduct of disrupted energy homeostasis following stress exposure. Furthermore, we explore the notion that ghrelin receptor signaling in the brain may have effects independent of circulating ghrelin and in what way this might influence stress coping in rodents. Finally, we examine how the ghrelin system could be utilized as a therapeutic avenue in stressrelated psychiatric disorders (with a focus on anxiety-and trauma-related disorders), for example to develop novel biomarkers for a better diagnosis or new interventions to tackle relapse or treatment resistance in patients.

Co-Therapy of Pegylated G-CSF and Ghrelin for Enhancing Survival After Exposure to Lethal Radiation

“…In RI mice treated with either Peg-G-CSF ( Figure 1B ) or Ghrelin ( Figure 1C ) alone, % survival increases above vehicle group was 32% and 0% ( p < 0.05 vs. RI + p vs. RI + GHR), respectively ( Figure 1D ). The non-irradiated mice treated with either Peg-G-CSF, Ghrelin, or combination of the two survived by 100%, suggesting the doses used were safe, although Ghrelin has been reported to promote fear, anxiety- and depression-like behaviors in rodents ( Fritz et al, 2020 ).…”

“…Because the survival increases in Peg-G-CSF-treated RI mice is around 30% above the vehicle-treated counterpart group ( Kiang et al, 2014a ), the object of this project was to investigate remedies that could enhance Peg-G-CSF efficacy in treating RI. Ghrelin was selected for this purpose because this co-therapy has been reported to reduce the RI-induced brain hemorrhage ( Kiang et al, 2019 ; Gorbunov and Kiang, 2021 ) and Ghrelin alone was effective for other organ diseases ( Wynne et al, 2005 ; Vasileious et al, 2013 ; Pereira et al, 2017 ; Fritz et al, 2020 ). Ghrelin is a peptide containing 28 amino acids; it is produced in the stomach during hunger and released into the blood stream to go to the hypothalamus for initiating the desire of food intake ( Wynne et al, 2005 ; Vasileious et al, 2013 ; Pereira et al, 2017 ).…”

Exploratory drive, fear, and anxiety are dissociable and independent components in foraging mice

“…Starving mice on the C57BL/6 background also showed decreased anxiety in conflict-based tasks (e.g., EPM and Pavlovian food challenge test) with a prominent role of hypothalamic agouti-related peptide-expressing neurons 44 . Future studies have to explore the involvement of this class of neurons and the role of the peripheral anxiolytic “hunger hormone” ghrelin 45 in food-restricted HAB mice.…”

Gut peptides and the microbiome: focus on ghrelin

“…Moreover, ghrelin plays a role in regulation of glucose homeostasis and metabolic stress [ 51 ]. Ghrelin has recently also been explored for its therapeutic potential in stress-related psychiatric disorders [ 58 ].…”