Des‐Acyl Ghrelin Directly Targets the Arcuate Nucleus in a Ghrelin‐Receptor Independent Manner and Impairs the Orexigenic Effect of Ghrelin

Abstract

Ghrelin is a stomach-derived octanoylated peptide hormone that plays a variety of well-established biological roles acting via its specific receptor known as growth hormone secretagogue receptor (GHSR). In plasma, a des-octanoylated form of ghrelin, named des-acyl ghrelin (DAG), also exists. DAG is suggested to be a signalling molecule that has specific targets, including the brain, and regulates some physiological functions. However, no specific receptor for DAG has been reported until now, and, consequently, the potential role of DAG as a hormone has remained a matter of debate. In the present study, we show that DAG specifically binds to and acts on a subset of arcuate nucleus (ARC) cells in a GHSR-independent manner. ARC cells labelled by a DAG fluorescent tracer include the neuropeptide Y (NPY) and non-NPY neurones. Given the well-established role of the ARC in appetite regulation, we tested the effect of centrally administered DAG on food intake. We found that DAG failed to affect dark phase feeding, as well as food intake, after a starvation period; however, it impaired the orexigenic actions of peripherally administered ghrelin. Thus, we conclude that DAG directly targets ARC neurones and antagonises the orexigenic effects of peripherally administered ghrelin.

Is Ghrelin Synthesized in the Central Nervous System?

“…Ghrelin is also secreted as a des-octanoylated version, named des-acyl-ghrelin, which circulates in plasma at even higher levels than ghrelin because it is also produced in plasma by ghrelin deacylation [106]. Des-acyl-ghrelin fails to bind to GHSR-1a at physiological concentrations, and it may display some GHSR-1a-independent actions [107]. However, the role of des-acyl-ghrelin as a hormone is also uncertain since no specific receptor for this peptide has been reported, yet [7].…”

Gut-Brain Neuroendocrine Signaling Under Conditions of Stress—Focus on Food Intake-Regulatory Mediators

“…Nonetheless, des-acyl ghrelin exhibits several biological actions such as decreasing anxiety after intraperitoneral injection in receptor knockout mice (30). Peripheral or intracerebroventricular pretreatment with des-acyl ghrelin blunts the orexigenic action of ghrelin in rats (31) and mice (32). Des-acyl ghrelin's action takes place in a subset of arcuate nucleus neurons distinct from those activated by ghrelin (32).…”

“…Peripheral or intracerebroventricular pretreatment with des-acyl ghrelin blunts the orexigenic action of ghrelin in rats (31) and mice (32). Des-acyl ghrelin's action takes place in a subset of arcuate nucleus neurons distinct from those activated by ghrelin (32). Studies using fluorescein des-acyl ghrelin injected intracerebroventricularly in mice demonstrate that the peptide binds selectively and mainly on arcuate neurons in a GHSR1a independent manner (32).…”

“…Des-acyl ghrelin's action takes place in a subset of arcuate nucleus neurons distinct from those activated by ghrelin (32). Studies using fluorescein des-acyl ghrelin injected intracerebroventricularly in mice demonstrate that the peptide binds selectively and mainly on arcuate neurons in a GHSR1a independent manner (32). However, to date the receptor mediating des-acyl ghrelin's effects remains to be identified.…”

Control of Food Intake by Gastrointestinal Peptides: Mechanisms of Action and Possible Modulation in the Treatment of Obesity

“…35 In line with this finding, a recent study showed that desacyl ghrelin antagonizes the orexigenic effect of peripherally administered ghrelin in mice. 36 This points towards a counteracting function of desacyl ghrelin to modulate/balance ghrelin's food intake-stimulating effect. This antagonism was also observed on colorectal motility: desacyl ghrelin reduced the motility-…”