Brain accessibility delineates the central effects of circulating ghrelin

Abstract

Ghrelin is a hormone produced in the gastrointestinal tract that acts via the growth hormone secretagogue receptor. In the central nervous system, ghrelin signalling is able to recruit different neuronal targets that regulate the behavioural, neuroendocrine, metabolic and autonomic effects of the hormone. Notably, several studies using radioactive or fluorescent variants of ghrelin have found that the accessibility of circulating ghrelin into the mouse brain is both strikingly low and restricted to some specific brain areas. A variety of studies addressing central effects of systemically injected ghrelin in mice have also provided indirect evidence that the accessibility of plasma ghrelin into the brain is limited. Here, we review these previous observations and discuss the putative pathways that would allow plasma ghrelin to gain access into the brain together with their physiological implications. Additionally, we discuss some potential features regarding the accessibility of plasma ghrelin into the human brain based on the observations reported by studies that investigate the consequences of ghrelin administration to humans.

Growth hormone secretagogue receptor signalling affects high‐fat intake independently of plasma levels of ghrelin andLEAP2, in a 4‐day binge eating model

“…43 Because we recently demonstrated that the N-terminal sequence of LEAP2 confers full receptor binding and activity, 7 a peptide containing the initial 14 residues of N-terminal LEAP2 sequence (hereafter named LEAP2 1-14 ) was employed as an analogue of full-length LEAP2. LEAP2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14] was assembled on solid support using Fmoc chemistry and starting from Amphisphere 40 RAM resin (Agilent Technologies Inc., Santa Clara, CA, USA), purified by reverse phase-high-performance liquid chromatography and characterised by liquid chromatography-mass spectrometry and matrix-assisted laser desorption/ionization-tandem mass spectrometry with a purity > 95%, as described previously. 7 LEAP2 1-14 was dissolved in PBS.…”

“…To test whether central administrations of ghrelin or LEAP2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14] affect HF intake in mice exposed to the binge-like eating protocol, ad lib. fed mice were daily i.c.v.-injected with aCSF alone or containing each of these peptides and subsequently exposed to a HF pellet for 4 consecutive days ( Figure 3A and (iii) a reduced cumulative 4-day HF intake.…”

“…Growth hormone secretagogue receptor activity potently regulates food intake. Ghrelin administration rapidly stimulates feeding in satiated humans and rodents, and LEAP2 administration abolishes ghrelin‐induced food intake in mice . The fact that plasma ghrelin in humans and rodents rises before meals and decreases post‐prandially suggests that endogenous ghrelin is linked to food intake regulation .…”

“…Central administration of ghrelin to satiated rodents enhances behaviours associated with rewarding aspects of food intake such as food seeking behaviour and the motivation to obtain palatable foods . Some studies show that peripherally injected ghrelin also modulates food reward‐related behaviours; however, no direct evidence currently exists showing that circulating ghrelin can reach reward‐related brain targets, such as the ventral tegmental area (VTA) . The effect of LEAP2 on rewarding aspects of food intake has yet not been investigated.…”

“…[25][26][27] Some studies show that peripherally injected ghrelin also modulates food reward-related behaviours 18,26,28,29 ; however, no direct evidence currently exists showing that circulating ghrelin can reach reward-related brain targets, such as the ventral tegmental area (VTA). 12 The effect of LEAP2 on rewarding aspects of food intake has yet not been investigated. Because GHSR activity enhances the rewarding value of palatable foods, 18,25,30 it has been proposed to modulate binge eating behaviours.…”